B12, Methylcobalamin, and folic acid

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    Vitamin B12 improves cognitive disturbance in rodents fed a choline-deficient diet

    Sasaki H; Matsuzaki Y; Meguro K; Ikarashi Y; Maruyama Y; Yamaguchi S; Sekizawa K Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Japan Pharmacol Biochem Behav (U.S.) Oct 1992, 43 (2) p635-9,

    The effect of vitamin B12 on learning disturbance was tested in rats. Rats were fed a choline-enriched, choline-deficient, and choline-deficient diet with vitamin B12. Concentrations of acetylcholine in the brain were significantly lower in rats fed a choline-deficient diet than rats fed a choline-enriched diet.

    Passive avoidance learning shows that rats on a choline-deficient diet showed significantly impaired learning compared to rats on a choline-enriched diet. However, there was no significant difference of acetylcholine in the brain or in the passive avoidance learning between rats fed a choline-enriched and a choline-deficient with vitamin B12 diet. We, therefore, suggest that vitamin B12 potentiates learning in an acetylcholine-deprived brain.

    Protective effects of a vitamin B12 analogue, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons Akaike A Tamura Y Sato Y Yokota T, Eur J Pharmacol (1993 Sep 7) 241(1):1-6

    The effects of methylcobalamin, a vitamin B12 analogue, on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Cell viability was markedly reduced by a brief exposure to glutamate followed by incubation with glutamate-free medium for 1 h.

    Glutamate cytotoxicity was prevented when the cultures were maintained in methylcobalamin-containing medium. Glutamate cytotoxicity was also prevented by chronic exposure to S-adenosylmethionine, which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and S- adenosylmethionine also inhibited the cytotoxicity induced by methyl-D-aspartate or sodium nitroprusside that releases nitric oxide.

    In cultures maintained in a standard medium, glutamate cytotoxicity was not affected by adding methylcobalamin to the glutamate-containing medium. In contrast, acute exposure to MK-801, a NMDA receptor antagonist, prevented glutamate cytotoxicity.

    These results indicate that chronic exposure to methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity.

    Methylcobalamin and Diabetic Neuropathy

    Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy Ide H Fujiya S Asanuma Y Tsuji M Sakai H Agishi Y, Clin Ther (1987) 9(2):183-92

    Seven men and four women with symptomatic diabetic neuropathy were treated with methylcobalamin (2,500 micrograms in 10 ml of saline) injected intrathecally. Treatment was begun when patients had good metabolic control, as determined by measurements of plasma glucose and hemoglobin, and was repeated several times with a one-month interval between injections. Three patients were re-treated one year after the last intrathecal injection. Symptoms in the legs, such as paresthesia, burning pains, and heaviness, dramatically improved.

    The effect appeared within a few hours to one week and lasted from several months to four years. The mean peroneal motor-nerve conduction velocity did not change significantly. The mean (+/- SD) concentration of methylcobalamin in spinal fluid was 114 +/- 32 pg/ml before intrathecal injection (n = 5) and 4,752 +/- 2,504 pg/ml one month after intrathecal methylcobalamin treatment (n = 11).

    Methylcobalamin caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. These findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy.

    Nerve Regeneration with Methylcobalamin

    Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. Watanabe T Kaji R Oka N Bara W Kimura J, J Neurol Sci (1994 Apr) 122(2):140-3
    Despite intensive searches for therapeutic agents, few substances have been convincingly shown to enhance nerve regeneration in patients with peripheral neuropathies. Recent biochemical evidence suggests that an ultra-high dose of methylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis.

    We examined the effects of ultra-high dose of methyl-B12 on the rate of nerve regeneration in rats with acrylamide neuropathy, using the amplitudes of compound muscle action potentials (CMAPs) after tibial nerve stimulation as an index of the number of regenerating motor fibers. After intoxication with acrylamide, all the rats showed equally decreased CMAP amplitudes. The animals were then divided into 3 groups; rats treated with ultra-high (500 micrograms/kg body weight, intraperitoneally) and low (50 micrograms/kg) doses of methyl- B12, and saline-treated control rats.

    Those treated with ultra-high dose showed significantly faster CMAP recovery than saline-treated control rats, whereas the low-dose group showed no difference from the control. Morphometric analysis revealed a similar difference in fiber density between these groups. Ultra-high doses of methyl-B12 may be of clinical use for patients with peripheral neuropathies.

    Methylcobalamin treatment of Bell's palsy

    Jalaludin MA, Methods Find Exp Clin Pharmacol (1995 Oct) 17(8):539-44

    Bell's palsy patients were assigned into three treatment groups: steroid (group 1), methylcobalamin (group 2) and methylcobalamin + steroid (group 3).

    Comparison between the three groups was based on the number of days needed to attain full recovery, facial nerve scores, and improvement of concomitant symptoms. The time required for complete recovery of facial nerve function was significantly shorter in the methylcobalamin and methylcobalamin plus steroid groups than in the steroid group. The facial nerve score after 1-3 weeks of treatment was significantly more severe (p < 0.001) in the steroid group compared to the methylcobalamin and methylcobalamin plus steroid groups.
    The improvement of concomitant symptoms was better in the methylcobalamin treated groups than the group treated with steroid alone.

    Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse.

    Yamazaki K Oda K Endo C Kikuchi T Wakabayashi T, Neurosci Lett (1994 Mar 28) 170(1):195-7

    We examined the effects of methylcobalamin (methyl-B12, mecobalamin) on degeneration of motor nerve terminals in the anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mice. GAD mice received orally methyl-B12 (1 mg/kg body wt/day) from the 40th day after birth for 25 days. In the distal endplate zone of the muscle, although most terminals were degenerated in both the untreated and methyl-B12-treated GAD mice, sprouts were more frequently observed in the latter. In the proximal endplate zone, where few degenerated terminals were seen in both groups of the mice, the perimeter of the terminals was increased and the area of the terminals was decreased significantly in the methyl-B12-treated GAD mice.

    These findings indicate that methyl-B12 promotes regeneration of degenerating nerve terminals in GAD mice.

    Protective effects of methylcobalamin, a vitamin B12 analogue, against glutamate-induced neurotoxicity in retinal cell culture.

    Kikuchi M Kashii S Honda Y Tamura Y Kaneda K Akaike, Invest Ophthalmol Vis Sci (1997 Apr) 38(5):848-54

    Purpose: To examine the effects of methylcobalamin on glutamate- induced neurotoxicity in the cultured retinal neurons.

    Methods: Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. The neurotoxicity was assessed quantitatively using the trypan blue exclusion method.

    Results: Glutamate neurotoxicity was prevented by chronic exposure to methylcobalamin and S-adenosylmethionine (SAMe), which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and SAMe also inhibited the neurotoxicity induced by sodium nitroprusside that release nitric oxide. By contrast, acute exposure to methylcobalamin did not protect retinal neurons against glutamate neurotoxicity.

    Conclusions: Chronic administration of methylcobalamin protects cultured retinal neurons against N-methyl-D- aspartate-receptor-mediated glutamate neurotoxicity, probably by altering the membrane properties through SAMe-mediated methylation.

    Effect of cobalamin derivatives on in vitro enzymatic DNA methylation: methylcobalamin can act as a methyl donor.
    Leszkowicz A Keith G Dirheimer G, Biochemistry (1991 Aug 13) 30(32):8045-51

    Methylcytosine synthesis in DNA involves the transfer of methyl groups from S-adenosylmethionine to the 5'-position of cytosine through the action of DNA (cytosine-5)-methyltransferase. The rate of this reaction has been found to be enhanced by cobalt ions. We therefore analyzed the influence of vitamin B12 and related compounds containing cobalt on DNA methylation.

    Vitamin B12, methylcobalamin, and coenzyme B12 (methylcobalamin) were found to enhance significantly the de novo DNA methylation in the presence of S-adenosylmethionine for concentrations up to 1 microM, but at higher concentrations these compounds were found to inhibit DNA methylation.

    Methylcobalamin behaves as a competitive inhibitor of the enzymatic methylation reaction (Ki = 15 microM), the Km for S-adenosylmethionine being 8 microM. In addition, the use of radioactive methylcobalamin shows that it can be used as a methyl donor in the de novo and maintenance DNA methylation reactions. Thus, two DNA methylation pathways could exist: one involving methylation from S-adenosylmethionine and a second one involving methylation from methylcobalamin.

    Toxic amblyopia may be associated with Purtscher's retinopathy in alcohol-induced pancreatitis

    Spektrum der Augenheilkunde (Austria), 1996, 10/3 (129-132)

    2% of all patients with alcohol-induced pancreatitis develop visual disturbances presenting a retinal image similar to Purtscher's retinopathy.

    In a 38-year male Caucasian, suffering from chronic pancreatitis, acute retinal ischemia without vascular occlusion caused severe visual disturbances. Inspite of rapid improvement of the pancreatitis and the electroretinogram, the visual function did not recover due to severe loss of photoreceptor function and retinal nerve fibres. A lack of Vitamin B12 may have pronounced the ischemic damage of the optic nerve.

    Effects of vitamin B12 on cell proliferation and cellular alkaline phosphatase activity in human bone marrow stromal osteoprogenitor cells and UMR106 osteoblastic cells

    Clinical and Experimental (USA), 1996, 45/12 (1443-1446)

    Pernicious anemia has recently been recognized as one of the risk factors for osteoporosis and bone fractures, but the underlying pathophysiologic mechanism is still unknown. To determine whether vitamin B12 has any direct effect on osteoblasts, we studied the effects of vitamin B12 on the proliferation and alkaline phosphatase activity in human bone marrow stromal osteoprogenitor cells (hBMSC) and UMR106 osteoblastic cells.

    Vitamin B12 at concentrations as low as 10-12 mol/L significantly stimulated (3H)-thymidine incorporation in both types of cells, but concentrations higher than 10-12 mol/L did not produce a greater effect.Vitamin B12 in the concentration range from 10-12 to 10-8 mol/L concentration- dependently increased alkaline phosphatase activity in both hBMSC and UMR106 cells.

    Based on these results, we suggest that a suppressed activity of osteoblasts may contribute to osteoporosis and fractures in patients with vitamin B12 deficiency.

    Evoked potentials in subacute combined degeneration of the spinal cord

    Neurophysiologie Clinique (France), 1997, 27/1 (59-65)

    We describe visual, brain stem auditory, and somatosensory evoked potentials (VEP, BAEP, SEP) in a 49-year old male patient presenting with subacute degeneration of the spinal cord due to vitamin B12 deficiency. Neurological signs included tetraplegia with a C4-C5 spinal cord compression that was unchanged after surgical decompression.

    Before treatment, the duration of the bilateral VEP was slightly increased, though their amplitude and morphology were not modified. BAEP were normal. However, abnormalities of SEP with loss of cortical potentials were noticed. Two months after initiation of the treatment, both VEP and SEP recorded in response to median nerve stimulation had improved, but there was still no cortical response to tibial nerve stimulation.

    Eighteen months later, VEP were normal and recovery of SEP in response to tibial nerve stimulation was observed; however, alterations of peripheral sensory and motor action potentials were still present. These findings are in good agreement with previously reported pathological changes in patients presenting with subacute combined degeneration. Similar abnormalities have been described in patients with multiple sclerosis. Evoked potentials in this case proved to be useful for the diagnosis and the evaluation of the efficacy of the treatment.

    These findings also suggest that demyelination of the posterior part of the spinal cord and peripheral axonal degeneration might be the main pathological changes related to vitamin B12 deficiency. The former, but not the latter, were clearly responsive to the treatment.

    Multiple sclerosis and neurotransmission

    Biogenic Amines (Netherlands), 1996, 12/5 (353-376)

    In this study, the role of excitatory amino acids (EAA), nitrite (metabolite of nitric oxide), vitamin B12, homocysteine (HC), monoamines, and neuropeptides such as cholecystokinin (CCK) and neuropeptide Y in multiple sclerosis (MS) is defined on the basis of accumulated results obtained in cerebrospinal fluid from 47 MS patients.

    These results were compared with 25 healthy subjects. These results showed the significant increase of free radical NO, arginine, tryptophan, noradrenaline and HC, and decrease in the levels of Apartate, glutamate, dopamine, vitamin B12, CCK-4 and CCK-8 in MS patients. From these results, the role of NO, HC and deficiency of vitamin B12 are considered as some of the factors attributing to the degeneration of MS.

    Folate, vitamin B12, and neuropsychiatric disorders.

    Nutr Rev (UNITED STATES) Dec 1996, 54 (12) p382-90

    Folate and vitamin B12 are required both in the methylation of homocysteine to methionine and in the synthesis of S-adenosylmethionine. S-adenosylmethionine is involved in numerous methylation reactions involving proteins, phospholipids, DNA, and neurotransmitter metabolism. Both folate and vitamin B12 deficiency may cause similar neurologic and psychiatric disturbances including depression, dementia, and a demyelinating myelopathy.

    A current theory proposes that a defect in methylation processes is central to the biochemical basis of the neuropsychiatry of these vitamin deficiencies. Folate deficiency may specifically affect central monoamine metabolism and aggravate depressive disorders. In addition, the neurotoxic effects of homocysteine may also play a role in the neurologic and psychiatric disturbances that are associated with folate and vitamin B12 deficiency.

    Hyperhomocysteinaemia and end stage renal disease

    Journal of Nephrology (Italy), 1997, 10/2 (77-84)

    Vascular disease is a major cause of morbidity and mortality in end stage renal failure patients and cannot be explained entirely by the prevalence of traditional risk factors for atherosclerosis.

    A high plasma homocysteine concentration, which is a risk factor for vascular disease is found in patients with end stage renal disease. The exact cause for the hyperhomocysteinaemia seen in these patients is unknown, al metabolism of homocysteine. High homocysteine concentrations may also be attributable to a deficiency of folate, vitamin B6 or vitamin B12 although, because of supplementation, these vitamins may be present in high concentrations in renal patients. The occurrence of hyperhomocysteinaemia despite high plasma vitamin concentration could be due to altered metabolism or inhibition of intracellular vitamin activity.

    A number of studies have now established hyperhomocystinaemia to be an independent risk factor for atherosclerosis in patients with end-stage renal disease.

    Plasma homocysteine concentrations can be reduced by administration of folic acid either alone or combined with vitamin B12 or vitamin B6. The effects of such reduction on vascular risk in renal failure patients needs further study.

    High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients.

    Kidney Int (UNITED STATES) Jan 1996, 49 (1) p147-52

    Hyperhomocysteinemia, an arteriosclerotic risk factor, persists in 75% of dialysis patients despite routine low dose supplementation with the B-vitamin co-factors/substrates for homocysteine (Hcy) metabolism, and normal or supernormal plasma status of these vitamins (Atherosclerosis 114:93, 1995).

    We conducted a placebo-controlled eight-week trial of the effect on plasma homocysteine of adding supraphysiologic dose folic acid (15 mg/day), B-6 (100 mg/day), and B-12 (1 mg/day) to the usual daily dosing of 1 mg folic acid, 10 mg B-6, and 12 micrograms B-12, in 27 hyperhomocysteinemic dialysis patients. Total plasma homocysteine was measured at baseline, and after four and eight weeks.

    Blinded analyses revealed no evidence of toxicity in the group randomized to supraphysiologic dose B-vitamin supplementation. Plasma homocysteine was significantly reduced after both four weeks (-29.8% vs. -2.0%; P = 0.0024) and eight weeks (-25.8% vs. +0.6%; P = 0.0009) of active versus placebo treatment. Also, 5 of 15 treated versus 0 of 12 placebo group patients had their plasma Hcy reduced to within the normative range (< 15 mumol/liter).

    Supraphysiologic doses of B-vitamins may be required to correct hyperhomocysteinemia in dialysis patients.

    [Chronobiological sleep disorders and their treatment possibilities]

    Ther Umsch (SWITZERLAND) Oct 1993, 50 (10) p704-8

    A temporal discrepancy between the endogenous sleep-wake cycle and the daily structure of the surrounding social network are characteristic for chronobiological sleep disturbances. Activity rhythms that are in abnormal relation to the environment are more frequent than commonly assumed. They can arise either from external causes (such as shift-work or jet-lag) or as a result of internal changes promoting abnormal sleep behaviour. Structuring daily activities by paying attention to natural daylight (dawn and dusk) and to the social routine strengthen the synchronizing effect of external timekeepers necessary for the concordance between inner and outer rhythmic phenomena.

    Treatment of chronobiological sleep/wake-cycle disturbances require correct diagnosis and modification of their causes, particularly changes in habits consolidating such disturbances. Early recognition of a chronobiological sleep disorder can reduce the risk of misuse of sleeping pills, caffeine and nicotine. Recently developed treatment approaches such as bright light, the pineal hormone MELATONIN and vitamin B12 have provided promising results.

    Vitamin B12 affects non-photic entrainment of circadian locomotor activity rhythms in mice

    Brain Research (Netherlands), 1996, 727/1-2 (31-39)

    Administration of vitamin B12 (VB12) has been reported to normalize human sleep-wake rhythm disorders such as non-24-h sleep-wake syndrome (HNS), delayed sleep phase syndrome (DSPS) or insomnia. However, the mechanisms of the action of VB12 on the rhythm disorders ate unknown. In the present study, therefore, effects of VB12 on circadian rhythms of locomotor activity were examined in mice.

    In the first experiment, CBA/J mice were maintained under continuous light condition (LL) or blinded, and after free-running rhythms became stable, the mice were intraperitoneally injected with either VB12 or saline at a fixed time every day. In all the mice with tau > 24 h, saline injections resulted in entrainment of circadian rhythms, whereas not all the mice with tau < 24 h entrained to the injection. In contrast to saline injections, VB12 injections did not always induce entrainment and about half of the mice with tau > 24 h free-ran during the injection.

    In the second experiment, the amount of phase advances of circadian rhythms induced by a single injection of saline at circadian time (CT) 11 under LL was compared between the mice with and without VB12 silastic tubes. The results showed that the amplitude of phase advances was smaller in the mice with VB12 than those without VB12.

    In the third experiment, daily injections of saline were given to the mice with VB12 silastic tubes maintained under LL. In this chronic treatment of VB12 as well, attenuating effects of VB12 on saline-induced entrainment were observed.

    These results suggest that VB12 affects the mechanisms implicated in non-photic entrainment of circadian rhythms in mice.

    Effects of intravenously administered vitamin B12 on sleep in the rat.

    Physiol Behav (UNITED STATES) Jun 1995, 57 (6) p1019-24

    Vitamin B12 (VB12) has been reported to normalize the entrainment of circadian rhythms in the non-24-h sleep wake cycle and delayed sleep phase insomnia in humans. The purpose of this work was to clarify whether the peripheral administration of VB12 has any sleep-promoting effect on the sleep-wake rhythm in freely moving rats.

    After a baseline day of saline infusion. VB12 (500 micrograms/kg/day) was administered continuously for 4 days via the jugular vein. Polysomnographic recordings were carried out concurrently. In both the light and the 24-h periods, the amount of non-rapid eye movement (NREM) sleep increased significantly on VB12-days 2 and 3, while the amount of REM sleep increased significantly on VB12-day 2.

    In the light period, the increase in NREM sleep was due to increased duration of the episode, while the tendency to an increase in REM sleep was due to an increased number of episodes. Changes in the diurnal sleep-wake rhythm tended to appear in the earlier light period. The serum B12 concentrations in the VB12 group were 40 times higher than in controls.

    These findings suggest that peripherally infused VB12 has promoting effects on the rat's sleep, especially in the light period.

    Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12).

    Sleep (UNITED STATES) Oct 1991, 14 (5) p414-8

    Two adolescent patients suffering from persistent sleep-wake schedule disorders appear to have responded to treatment with vitamin B12 (methylcobalamin). A 15-year-old girl with delayed sleep phase syndrome (DSPS) and a 17-year-old boy with hypernychthemeral syndrome complained of not being able to attend school despite many trials of medication. The improvement of the sleep-wake rhythm disorders appeared immediately after the administration of high doses (3,000 micrograms/day) of methylcobalamin.

    Neither patient showed any laboratory or clinical evidence of vitamin B12 deficiency or hypothyroidism (which can cause B12 deficiency). Serum concentrations of vitamin B12 during treatment were in the high range of normal or above normal. The duration of the sleep period of the DSPS patient decreased gradually from 10 hours to 7 hours, and the time of sleep onset advanced from 2 a.m. to midnight.

    The period of the sleep-wake cycle of the hypernychthemeral patient was 24.6 hours before treatment and 24.0 hours after treatment. The relationship between the circadian basis of these disorders and vitamin B12 and its metabolites is discussed.

    Vitamin B12 treatment for sleep-wake rhythm disorders.

    Sleep (UNITED STATES) Feb 1990, 13 (1) p15-23

    Vitamin B12 (VB12) was administered to two patients suffering for many years from different sleep-wake rhythm disorders.

    One patient was a 15-year-old blind girl suffering from a free-running sleep-wake rhythm (hypernychthemeral syndrome) with a period of about 25 h. In spite of repeated trials to entrain her sleep-wake cycle to the environmental 24-h rhythm, her free-running rhythm persisted for about 13 years.

    When she was 14 years old, administration of VB12 per os was started at the daily dose of 1.5 mg t.i.d. Shortly thereafter, her sleep-wake rhythm was entrained to the environmental 24-h rhythm, and her 24-h sleep-wake rhythm was maintained while she was on the medication. Within 2 months of the withholding of VB12, her free-running sleep-wake rhythm reappeared.

    The VB12 level in the serum was within the normal range both before and after treatment.

    The other patient was a 55-year-old man suffering from delayed sleep phase syndrome since 18 years of age. After administration of VB12 at the daily doses of 1.5 mg, his sleep-wake rhythm disorder was improved. The good therapeutic effect lasted for more than 6 months while he was on the medication.

    [Neutropenia in HIV infection]

    An Med Interna (SPAIN) Apr 1997, 14 (4) p199-208

    The infection by human immunodeficiency virus (HIV) are commonly associated with haematologic abnormalities (anemia, leucopenia and thrombocytopenia). We review the neutropenia. In patients infected with HIV neutropenia is seen in the 8-50% of them, and also have abnormalities in the neutrophil function.

    Etiology: Direct injury of HIV on bone marrow, anti-neutrophil antibodies, drugs, opportunistic infections of bone marrow, vitamin B12 and folate deficiency, radiation therapy, and hemophagocytic syndrome.

    CONSEQUENCES: These patients have a increased risk of infections, since the neutrophils play an important role in the defense against bacterial and certain fungal infections.

    TREATMENT: It must to treat the causes. When it is not possible, Colony-Stimulating Factor can be use to stimulate the bone marrow granulopoiesis.

    Vitamin B-12 abnormalities in HIV-infected patients

    EUR. J. HAEMATOL. (Denmark), 1991, 47/1 (60-64)

    A prospective study of 60 consecutively admitted patients with HIV infection was performed to document the prevalence, etiology and manifestations of low serum vitamin B-12 in such patients. Low serum B-12 levels were found in 10 patients (16.7%). In 6, vitamin B-12 absorption was impaired and hog intrinsic factor addition did not improve it.

    Patients with low vitamin B-12 levels showed lower hemoglobin, leukocytes, lymphocytes, CD4 lymphocytes and CD4/CD8 lymphocyte ratio than HIV patients with physiological serum vitamin B-12 levels. However, bone marrow megaloblastosis was found in only 3 low vitamin B-12 patients and the deoxyuridine suppression test was pathological in only 1 case.

    In 7 patients, parenteral treatment was begun with variable response despite serum vitamin B-12 correction. In conclusion, low serum vitamin B-12 is often found in HIV-infected patients and it could be related to malabsorption, but clear megaloblastic abnormalities and treatment response could not be demonstrated. A decreased concentration of the serum binders due to disturbances in the leukocytes and related immunocompetent cell may play an additional role.

    [Patients with type-II diabetes mellitus and neuropathy have nodeficiency of vitamins A, E, beta-carotene, B1, B2, B6, B12 and folic acid]

    Med Klin (GERMANY) Aug 15 1993, 88 (8) p453-7

    The present study was aimed to determine the vitamin status of vitamins A, E, beta-carotene, B1, B2, B6, B12 and folate in plasma using HPLC and vitamins B1, B2 and B6 in erythrocytes using the apoenzyme stimulation test with the Cobas-Bio analyzer in 29 elderly type II diabetic women with (G1: n = 17, age: 68.6 +/- 3.2 years) and without (G2: n = 12, age: 71.8 +/- 2.7 years) diabetic polyneuropathy.

    The basic parameters as age, hemoglobin A1c, fructosamine and duration of the disease did not differ in both groups. Furthermore, retinopathy was assessed with fundoscopy and nephropathy with creatinine clearance. The creatinine clearance (G1: 50.6 +/- 3.4 vs. G2: 63.6 +/- 3.7 ml/min, 2p < 0.025) and the percentage of retinopathy (G1: 76.5% vs. G2: 16.7%, 2p = 0.002) were different indicating that G1 had significantly more severe late complications than G2.

    Current plasma levels of all measured vitamins (A, E, beta-carotene, B1, B2, B6, B12 and folate) and the status of B1, B2 and B6 in erythrocytes did not vary between the two groups (2p > 0.1). In summary, we found a lack of association between the actual vitamin condition in plasma and erythrocytes and diabetic neuropathy.

    Tissue concentrations of water-soluble vitamins in normal and diabetic rats.

    Int J Vitam Nutr Res (SWITZERLAND) 1993, 63 (2) p140-4

    Changes in circulating and tissue concentrations of several vitamins have been reported in diabetic animals and human subjects. In this study, the effect of short-term (2 weeks) streptozotocin diabetes on folate, B6, B12, thiamin, nicotinate, pantothenate, riboflavin and biotin in liver, kidney, pancreas, heart, brain and skeletal muscle of rats was investigated.

    The tissue distribution of vitamins varied widely in normal rats. Diabetes significantly lowered folate in kidney, heart, brain, and muscle; B6 in brain; B12 in heart; thiamin in liver and heart; nicotinate in liver, kidney, heart and brain; pantothenate in all tissues; riboflavin in liver, kidney, heart, and muscle.

    These results indicate that experimental diabetes causes a depression of several water-soluble vitamins in various tissues of rats.

    The role of serum protein in congestive heart failure
    Nutritional support in organ failure: proceedings of the

    International Symposium, 1990, -/- (45-52)

    We searched to elucidate the influence of hypoalbuminemia upon congestive heart failure (CHF) by experimental aortic regurgitation (AR) in dogs and by a follow-up study of patients with CHF (NYHA classes III, IV).

    We found that

    (1) In the dog with AR the incorporation of 14C-labeled glycine into myocardial actomyosin was decreased in the condition of hypoproteinemia produced by the combination of plasmapheresis with a low protein diet. But this phenomenon was improved by daily injection of vitamin B12 for 10 days.

    (2) In the study on protein metabolism using 15N-labeled glycine in humans, over 70 g day of protein intake (28% of total calorie intake) was necessary to prevent a decrease in the active protein pool produced by low calorie intake.

    (3) In the follow-up study on patients with CHF, we found that the mortality rate from CHF was worse in the patients with both low body mass index and hypoalbuminemia.

    In conclusion, maintaining both serum albumin and body weight on normal levels may be an important factor in the management of CHF and the prevention of cachexia.

    Clinical rise of a combination containing phosphocreatinine as adjuvant to physiokinesiotherapy

    RIABILITAZIONE (ITALY), 1976, 9/2 (51-62)

    The authors make a clinical contribution to the therapeutic use of phosphocreatinine, both alone and in combination with vitamin B12, folic acid, vitamin B6 and fructose 1-6 diphosphate.

    The study was carried out on 24 adult patients of both sexes, suffering from neuromyolesions (paraplegia, hemiparesis, tetraparesis, neuraxitis, myopathy, radiculoneuritis) and presenting, as therapeutic indications, conditions of organic wasting, marked asthenia, cachexia, or the requirement of physical performance and intense muscular effort in connection with the use of kinesitherapy techniques.

    An analysis of the collected data showed that both phosphocreatinine preparations (the simple form and combined with vitaminic coenzymes) induced significant improvements in the initial symptomatology; no statistically significant difference was observed between the 2 treatments.

    Particular interest is placed on the finding with regard to the effect on motor re education; in fact, the 2 preparations considered phosphocreatinine influenced this parameter favourably in over half the cases investigated.

    The drug was excellently tolerated in all the cases studied, from both the clinical point of view and the blood chemistry standpoint. In conclusion, the results obtained make the therapeutic use of phosphocreatinine undoubtedly useful as a valid factor in association with physiokinesitherapy.

    Partial amelioration of AZT-induced macrocytic anemia in the mouse by folic acid.

    Stem Cells (Dayt) (UNITED STATES) Sep 1993, 11 (5) p393-7
    CBA/Ca mice being maintained on azidothymidine (AZT) in drinking water were given vitamin B12 and folate in an effort to ameliorate the macrocytic anemia associated with AZT administration. The B12/folate regimen was ineffectual, but higher doses of folate given daily resulted in an increase in RBC and a decrease in mean corpuscular hemoglobin (MCH) and polychromatophilic erythrocytes (PCE) while mean corpuscular volume (MCV) remained relatively constant. The implications of these findings on RBC production and hemoglobin synthesis are discussed.

    Megaloblastic anemia in patients receiving total parenteral nutrition without folic acid or vitamin B12 supplementation.

    Can Med Assoc J (CANADA) Jul 23 1977, 117 (2) p144-6

    Pancytopenia developed in four patients receiving postoperatively total parenteral nutrition (TPN). Symptoms and signs were related mainly to underlying bowel disease. Hematologic abnormalities, first noted from 4 to 7 weeks following institution of TPN, consisted of normocytic anemia (mean decrease in hemoglobin value, 2.2 g/dL), occasional macrocytes being noted, leukopenia (range of leukocyte counts, 1.2 to 3.6 X 10(9) L), some hypersegmented neutrophils being detected, and clinically significant thrombocytopenia (range of platelet counts, 25 to 52 X 10(9)/L). In all patients the bone marrow showed megaloblastic changes, with ring sideroblasts, although pyridoxine was included in the TPN regimens. Serum vitamin B12 values were normal in one patient and at the lower limit of normal in the other two patients in whom it was measured, while serum or erythrocyte folate values, or both, were reduced in three patients.

    Full hematologic response was observed in the four patients after folic acid replacement therapy; leukocytosis and thrombocytosis were noted in three. Thus, folic acid and possibly vitamin B12 should be added routinely to TPN regimens to prevent deficiency of either substance.

    [Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism]

    Rev Prat (FRANCE) Jun 1 1993, 43 (11) p1358-63

    Macrocytic megaloblastic anemia is the most typical but the latest sign of a cobalamin (vitamin B12) and/or folic acid deficiency or of a congenital abnormality of cobalamin and folate metabolism. Macrocytosis in blood and megaloblastosis in bone marrow are the morphological features of a disturbance in cell division related to a defect in DNA biosynthesis.

    Macrocytosis without anemia, normocytic normochronic anemia with a low reticulocyte cell count or microcytic hypochromic anemia in case of associated iron deficiency do not exclude a vitamin deficiency. Neurological or psychiatric disorders and immune abnormalities have been reported in patients with vitamin B12 or folate deficiencies or in children with congenital abnormalities of these 2 vitamins; such manifestations may even occur without anemia.

    Intakes of vitamins and minerals by pregnant women with selected clinical symptoms.

    J Am Diet Assoc (UNITED STATES) May 1981, 78 (5) p477-82

    Toxemia in pregnancy is characterized by a combination of at least two of the following clinical symptoms: hypertension, edema, and proteinuria.

    In this study the dietary intakes of young pregnant women attending a Maternal and Infant Care Program at Tuskegee Institute were evaluated for selected vitamins and minerals. Women with toxemia were identified, and women without toxemia served as controls. The toxemia group generally consumed lesser amounts of vitamins and minerals than the controls. However, both groups were deficient (less than two-thirds RDA) in calcium, magnesium, vitamin B6, vitamin B12, and thiamin. Milk, meat, and grains supplied an appreciable proportion of each vitamin except vitamin A, which was found primarily in the two vegetable groups. Meat and grains contained the greatest quantities of minerals, but milk provided a relatively good proportion of potassium, calcium, magnesium, and phosphorus.

    Anemia was not related to the incidence of toxemia. Women exhibiting anemia consumed smaller amounts of vitamins studied than did women without anemia.

    Premature infants require additional folate and vitamin B-12 to reduce the severity of the anemia of prematurity.

    Am J Clin Nutr (UNITED STATES) Dec 1994, 60 (6) p930-5
    One hundred eighty-four premature infants, < 1800 g at birth and < 36 wk gestation, were entered into a study investigating the role of additional folate and vitamin B-12 supplementation of the anemia of prematurity.

    All patients initially received vitamin E and iron in accordance with accepted standards. Patients were randomly assigned to four groups to receive orally 0.1 mg folate/d for 4 mo, 100 micrograms vitamin B-12 intramuscularly monthly for 4 mo, both supplements, or neither. All other activities including parenteral nutrition were carried out according to established practices, irrespective of study group. By 10-12 wk, infants treated with vitamin B-12 alone or combined with folate had higher hemoglobin values than the untreated (P < 0.0005) or solely folate-treated (P < 0.01) groups.

    These findings held true irrespective of wide variations in treatment and feeding practices. The only uncontrolled hematologic nutritional factor, selenium, showed a similar pattern of decline for 10-12 wk in all study patients, whether or not they received additional vitamin supplements.

    [Vitamin B12 deficiency due to abnormal eating habits]

    Ned Tijdschr Geneeskd (NETHERLANDS) Feb 26 1994

    Vitamin B12 deficiency is an uncommon disorder in a prosperous western country. In two children a nutritional vitamin B12 deficiency was observed.

    The first was a 2-year-old girl with neurodevelopmental regression and macrocytic anaemia, a result of a combination of a maternal vitamin B12 deficiency and inadequate feeding after birth.

    The second patient was a 14-year-old adipose girl with severe polyneuropathy and mild macrocytic anaemia as a result of a nutritional vitamin B12 deficiency. In her case the deficiency resulted from a bizarre feeding pattern. She turned out to be the victim of child abuse. It is concluded that even in a prosperous western country like the Netherlands vitamin B12 deficiency in children can develop as a result of an inadequate feeding pattern. It can lead not only to macrocytic anaemia but also to severe neurological abnormalities.

    Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment.

    Am J Clin Nutr (UNITED STATES) Jan 1997, 65 (1) p20-9

    Associations between nutritional status and cognitive performance were examined in 137 elderly (aged 66-90 y) community residents.

    Participants were well-educated, adequately nourished, and free of significant cognitive impairment. Performance on cognitive tests in 1986 was related to both past (1980) and concurrent (1986) nutritional status. Several significant associations (P < 0.05) were observed between cognition and concurrent vitamin status, including better abstraction performance with higher biochemical status and dietary intake of thiamine, riboflavin, niacin, and folate (rs = 0.19-0.29) and better visuospatial performance with higher plasma ascorbate (r = 0.22). Concurrent dietary protein in 1986 correlated significantly (rs = 0.25-0.26) with memory scores, and serum albumin or transferrin with memory, visuospatial, or abstraction scores (rs = 0.18-0.22). Higher past intake of vitamins E, A, B-6, and B-12 was related to better performance on visuospatial recall and/or abstraction tests (rs = 0.19-0.28).

    Use of self-selected vitamin supplements was associated with better performance on a difficult visuospatial test and an abstraction test. Although associations were relatively weak in this well-nourished and cognitively intact sample, the pattern of outcomes suggests some direction for further research on cognition-nutrition associations in aging.

    Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study.

    Am J Clin Nutr (UNITED STATES) Mar 1996, 63 (3) p306-14

    We investigated the relations between plasma concentrations of homocysteine and vitamins B-12 and B-6 and folate, and scores from a battery of cognitive tests for 70 male subjects, aged 54-81 y, in the Normative Aging Study.

    Lower concentrations of vitamin B-12 (P=0.04) and folate (P=0.003) and higher concentrations of homocysteine (P=0.0009 ) were associated with poorer spatial copying skills. Plasma homocysteine was a stronger predictor of spatial copying performance than either vitamin B-12 or folate. The association of homocysteine with spatial copying performance was not explained by clinical diagnoses of vascular disease.

    Higher concentrations of vitamin B-6 were related to better performance on two measures of memory (P=0.03 and P=0.05).

    The results suggest that vitamins (and homocysteine) may have differential effects on cognitive abilities. Individual vitamins and homocysteine should be explored further as determinants of patterns of cognitive impairment.

    Vitamin intake: A possible determinant of plasma homocyst(e)ine among middle-aged adults

    Annals of Epidemiology (USA), 1997, 7/4 (285-293)

    PURPOSE: Many epidemiologic studies have identified elevated plasma homocyst(e)ine as a risk factor for atherosclerosis and thromboembolic diseases. To examine the relationship between vitamin intakes and plasma homocyst(e)ine, we analyzed dietary intake data from a case-control study of 322 middle-aged individuals with atherosclerosis in the carotid artery and 318 control subjects without evidence of this disease.

    METHODS: All of these individuals were selected from a probability sample of 15,800 men and women who participated in the Atherosclerosis Risk in Communities (ARIC) study.

    RESULTS: Plasma homocyst(e)ine was inversely associated with intakes of folate, vitamin B6, and vitamin B12 (controls only for this vitamin)-the three key vitamins in homocyst(e)ine metabolism. Among nonusers of vitamin supplement products, on average each fertile increase in intake of these vitamins was associated with 0.4 to 0.7 micromol/L decrease in plasma homocyst(e)ine. An inverse association of plaine was also found with thiamin, riboflavin, calcium, phosphorus, and iron. Methionine and protein intake did not show any significant association with plasma homocyst(e)ine.

    CONCLUSIONS: In almost all analyses, cases and controls showed similar associations between dietary variables and plasma homocyst(e)ine. Plasma homocyst(e)ine among users of vitamin supplement products was 1.5 micromol/L lower than that among nonusers. Further studies to examine possible caused relationships among vitamin intake, plasma homocyst(e)ine, and cardiovascular disease are needed.

    Atherogenesis and the homocysteine-folate-cobalamin triad: Do we need standardized analyses?

    Journal of the American College of Nutrition (USA), 1997, 16/3 (258-267)

    Background: Bioscientists, physicians and nutritionists are newly interested in the homocysteine folate cobalamin triad, in part because homocysteine may be important both in atherogenesis and thrombogenesis Homocysteine imbalance may be an early marker for cobalamin disorders because cobalamin is a cofactor in remethylation of homocysteine to methionine.

    Methods: In 139 men and 32 women of similar mean age of 65 years, we measured markers which have been cited as risk for atherosclerosis: serum homocysteine, folate, total cobalamin, holotranscobalamin I and II, (TCI and TCII), total serum cholesterol (SCHOL), high density lipoprotein cholesterol (HDLC), triglycerides (STG) as well as red blood cell (RBC) folate, food records and body composition by whole body counting of potassium-forty (40K). Results: Statistical relationships among the data showed healthy women had lower mean serum homocysteine and their mean RBC folate and TCI and TCII were higher than men. Eighty-three subjects had TCII much lower than 60 pg/ml (subnormal), yet only 11 of these men and two women had total cobalamin <200 pg/ml (abnormal). Fifty-two subjects with serum homocysteine greater than 17.5 nmol/ml had TCII less than 60 pg/ml, suggesting serum homocysteine may be a marker for early cobalamin negative balance. None of the subjects in the study had serum folate below abnormal values, i.e., less than 1.6 mg/ml. All subjects had RBC folate within normal range. Serum homocysteine showed inverse relationship with RBC folate and serum total cobalamin, TCI and TCII.

    Conclusions: 1) importance of using serum holotranscobalamin TCI and TCII as markers of cobalamin deficiency, 2) necessity to uke if strong comparisons are to be made among quantitative values of serum or plasma homocysteine, folate, cobalamin, and nutrients in food intake.

    Dietary methionine imbalance, endothelial cell dysfunction and atherosclerosis

    Nutrition Research (USA), 1996, 16/7 (1251-1266)

    Dietary factors can play a crucial role in the development of atherosclerosis. High fat, high calorie diets are well known risk factors for this disease. In addition, there is strong evidence that dietary animal proteins also can contribute to the development of atherosclerosis. Atherogenic effects of animal proteins are related, at least in part, to high levels of methionine in these proteins. An excess of dietary methionine may induce atherosclerosis by increasing plasma lipid levels and/or by contributing to endothelial cell injury or dysfunction. In addition, methionine imbalance elevates plasma/tissue homocysteine which may induce oxidative stress and injury to endothelial cells.

    Methionine and homocysteine metabolism is regulated by the cellular content of vitamins B6, B12, riboflavin and folic acid. Therefore, deficiencies of these vitamins may significantly influence methionine and homocysteine levels and their effects on the development of atherosclerosis.

    Homocysteine, folate, and vascular disease

    Journal of Myocardial Ischemia (USA), 1996, 8/2 (60-63)

    Current evidence indicates that the genesis of atherosclerotic disease is multifactorial. One of the newly recognized factors that contributes to this process is raised homocysteine blood levels. A variety of atherosclerotic procd by elevated homocysteine levels, including stimulation of smooth muscle cell growth, impairment of endothelial regeneration, oxidation of LDL particles, and thrombogenesis.

    A generic defect may account for some instances of hyperhomocysteinemia, but the majority of persons with high levels do not have known genetic defects to account for their elevations.

    Low levels of folic acid, vitamin B12, and pyridoxine appear to underlie most cases of elevated homocysteine levels.

    Adding folic acid to the diet may reduce homocysteine levels, but a link between increasing folic acid and lower risk of atherosclerotic disease has yet to be demonstrated in clinical trials. However, increasing daily folic acid intake is not unjustified in some patients. Since this may mask B12 deficiency, a supplement of cobalamin, 1 mg/d, has been proposed.

    In the final analysis, a clinical trial is needed to determine the true significance of hyperhomocysteinemia. Meanwhile, physicians and patients can consider increasing the daily folate intake by eating more oranges, leafy vegetables, wheat products, and cereals.

    Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease.

    Curr Opin Lipidol (UNITED STATES) Feb 1997, 8 (1) p28-34

    Homocysteine is an intermediate compound formed during metabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis.

    The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation.

    Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.

    [Homocysteine, a risk factor of atherosclerosis]

    Arch Mal Coeur Vaiss (FRANCE) Dec 1996, 89 (12) p1667-71

    Homocysteine is a sulphurated amino acid which, at high plasma concentrations, predisposes to thrombosis and induces focal arteriosclerosis. These characteristics have been established both in patients with homocystinuria, a genetic disease in which homocysteine accumulates in the blood, and in animals submitted to intravenous infusions of this amino acid.

    Many recent publications have addressed the problem of whether mild increases in plasma homocysteine predisposed to the development of the usual forms of atherosclerosis. Transverse epidemiological studies have established a correlation between homocysteine levels and atherosclerosis at all its vascular localisations, coronary, carotid and lower limb. Multivariate analysis in several prospective studies have shown plasma homocysteine to be an independent risk factor for cerebrovascular accidents and myocardial infarction.

    Causes of mild increases in plasma homocysteine are usually dietetic deficiencies in folic acid, vitamin B6 or B12, or genetic by mutation of the methylene-tetrahydrofolate reductase. Renal failure is also associated with a high risk in plasma homocysteine levels. However, the toxicity of homocysteine to the arterial wall at slightly elevated concentration remains speculative.

    Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.

    Circulation (UNITED STATES) Dec 1 1996, 94 (11) p2743-8

    BACKGROUND: A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease.

    METHODS AND RESULTS: Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3 +/- 14.8 years). Folate, vitamin B12, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6 +/- 1.5 versus 10.1 +/- 1.7 mumol/L; P < .01). Abnormally high concentrations (> 95th percentile for control subjects, 16.3 mumol/L) were seen in 149 patients (85%) with end-stage renal disease (P < .001). Patients with a homocysteine concentration in the upper two quintiles (> 27.8 mumol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P = .007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B6 deficiency was more frequent in patients than in the normal reference population (18% versus 2%; P < .01). CONCLUSIONS: A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.

    [Homocysteine, a less well-known risk factor in cardiac and vascular diseases]

    Cas Lek Cesk (CZECH REPUBLIC) May 2 1996, 135 (9) p263-5

    Hyperhomocyst(e)mia (Hcy) negatively influences vascular endothelium and coagulation factors. Association of Hcy with premature arteriosclerosis (rather than atherosclerosis), stroke, myocardial infarction and peripheral arterial and venous disease was proved in clinical and epidemiological studies, even as the association with conventional risk factors like age, male sex, smoking, hypertension and hypercholesterolemia. Vitamin substitution of folates, vitamin B6 and B12 decreases Hcy blood levels, however definite evidence is still lacking, whether it results in lower incidence and mortality from cardiovascular diseases. Therefore clinical and epidemiological studies are necessary. Before the grant-application we proved in a pilot study significantly higher Hcy levels in 97 patients with manifest ischaemic heart disease than in 37 controls.

    Homocysteine and coronary atherosclerosis.

    J Am Coll Cardiol (UNITED STATES) Mar 1 1996, 27 (3) p517-27

    Homocysteine is increasingly recognized as a risk factor for coronary artery disease. An understanding of its metabolism and of the importance of vitamins B6 and B12 and folate as well as enzyme levels in its regulation will aid the development of therapeutic strategies that, by lowering circulating concentrations, may also lower risk.

    Possible mechanisms by which elevated homocysteine levels lead to the development and progression of vascular disease include effects on platelets, clotting factors and endothelium. This review presents the clinical and basic scientific evidence supporting the risk and mechanisms of vascular disease associated with elevated homocysteine concentrations as well as the results of preliminary therapeutic trials.

    Influence of vitamin B12 on brain methionine adenosyltransferase activity in senile dementia of the Alzheimer's type.

    J Neural Transm Gen Sect (AUSTRIA) 1996, 103 (7) p861-72

    The influence of vitamin B12 on the activity of methionine adenosyltransferase (MAT) in postmortem brains of patients with senile dementia of the Alzheimer's type (SDAT) was investigated.

    In samples of cortex gyrus frontalis from SDAT patients with normal and low levels of serum B12, MAT Vmax was significantly increased by 25% and 19%, respectively. MAT Vmax from a SDAT group chronically treated with B12 was similar to controls. In contrast to cortex gyrus frontalis, no significant alterations were seen in MAT activity in nucleus caudatus.

    This study provides evidence that SDAT is associated with significant alterations in transmethylation mechanisms in specific regions of the brain. The relationship between blood levels of B12 and the actual status of this vitamin in the brain influencing the rates of synthesis of both methionine and SAM may, however, be far more complex and cannot be directly clarified on the basis of the present human brain results.

    Dementia and subnormal levels of vitamin B12: effects of replacement therapy on dementia.

    J Neurol (GERMANY) Jul 1996, 243 (7) p522-9

    Routine determination of serum vitamin B12 levels is generally recommended as part of the screening of demented patients, based on the notion that vitamin B12 deficiency is one of the causes of reversible dementia. We studied the effects of vitamin B12 replacement therapy in a prospective longitudinal study at a memory clinic, with special emphasis on assessment of severity of dementia: not only cognitive deterioration, but also disability in the activities of daily life, behavioural problems, and the burden experienced by the caregiver were examined using instruments of proven validity.

    In a series of 170 consecutive patients with dementia, subnormal serum vitamin B12 levels were found in 26 cases (15%); all but one fulfilled diagnostic criteria for possible Alzheimer's disease. Cobalamin supplementation was given to all patients and the effect was evaluated after 6 months. When the size and pattern of individual change scores, and the mean change scores on all instruments were taken into account, functioning after replacement therapy was not improved. When change scores of treated patients were compared with those of patients with Alzheimer's disease (n = 69), vitamin B12 replacement did not result in slowing of the progression of dementia. Contrary to widely accepted beliefs, subnormal serum vitamin B12 levels are not a (quantitatively) important cause of reversible dementia.

    Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer's disease?

    J Gerontol A Biol Sci Med Sci (UNITED STATES) Mar 1997, 52 (2) pM76-9

    BACKGROUND: It is still unclear whether there is an association between Alzheimer's disease and vitamin B-12 or folate deficiency. This study was designed to investigate whether patients with Alzheimer's disease are particularly prone to metabolically significant cobalamin or folate deficiency as compared to nondemented hospitalized controls and healthy elderly controls living at home.

    METHODS: Evaluation for the diagnosis of Alzheimer's disease, routine laboratory tests, serum folate and vitamin B-12, serum methylmalonic acid (MMA), total homocysteine (tHcy), and radiological tests was performed in 52 patients with Alzheimer's disease (AD), 50 nondemented hospitalized controls, and 49 healthy elderly subjects living at home.

    RESULTS: Serum vitamin B-12 and folate levels are comparable between patients with AD, hospitalized control patients, and subjects living at home. Patients with AD have the highest serum MMA and tHcy levels. The MMA levels of patients with AD and hospitalized controls are not different, but the mean tHcy level is significantly higher in patients with AD as compared to nondemented patients or subjects living at home.

    CONCLUSION: The interpretation of the vitamin B-12 and folate status in patients with AD depends largely on the methodology (i.e., serum vitamin vs metabolite levels) and the selection of the control group. Although patients with AD have the highest tHcy and MMA levels, metabolically significant vitamin B-12 and folate deficiency is also a substantial problem in nondemented elderly patients.

    [A clinic for the study of dementia--110 consecutive patients]

    Ugeskr Laeger (DENMARK) Feb 24 1997, 159 (9) p1246-51

    Case reports of 110 patients referred to a neurological dementia clinic were reviewed to evaluate a standardized diagnostic program. The patients were evaluated by a neurologist, a gerontopsychiatrist, and a neuropsychologist. ICD-10 criteria were used. Fifty-two patients had dementia while 58 had not; of these, 27 suffered from other non-dementia diseases and 31 were without dementia or other psychiatric or neurological disease.

    Thirteen patients with Alzheimer's disease were treated with tacrine. Four patients underwent cobalamin substitution treatment and seven started antidepressant medication. Ten patients received acetylsalicylic acid (150 mg Q.D.) and two a levo-dopa-type drug. Twenty-six patients were followed by gerontopsychiatric district care. Because only 47% of the patients suspected of dementia actually fulfilled dementia criteria, the evaluation suggests that patients suspected of dementia benefit from a standardized diagnostic program in a specialist setting.

    Decreased methionine adenosyltransferase activity in erythrocytes of patients with dementia disorders

    Sweden European Neuropsychopharmacology (Netherlands), 1995, 5/2 (107-114)

    ATP:1-methionine S-adenosyltransferase (EC, MAT) activity was analyzed in erythrocytes from nine patients with a clinical diagosis of probable Alzheimer's disease (Pro.AD), four with possible Alzheimer's disease (Pos.AD), three with mild cognitive dysfunction (MCD) and two with dementia of vascular origin (VD), and 10 age-matched control subjects. Significantly lower kinetic parameters (V(max) and K(m) towards methionine) for MAT were observed in all the dementia cases.

    In the subgroup of Pro.AD patients who also had low plasma levels of vitamin B12 (B12), the reduction in MAT K(m) was significantly correlated with an increase in the serum levels of homocysteine, while no such correlation was observed in all the other dementia groups.

    Treatment for 6 months of this subgroup of Pro.AD patients with B12 (1 mg x 7 days + 1 mg/week, i.m.), S-adenosylmethionine (SAM, 200 mg twice daily, p.o.) and folate (2.5 mg every 2 days, p.o.) caused a significant decrease in homocysteine in parallel with a significant increase in K(m) for MAT.

    These findings support the hypothesis Familial Alzheimer's disease and vitamin B12 deficiency that aberrations in the B12 dependent transmethylation reactions might be involved in the pathogenesis of dementia, and suggest that the evaluation of erythrocyte MAT activity may be a useful marker for the detection of such an aberration.

    Folate, vitamin B12 and cognitive impairment in patients with Alzheimer's disease

    ACTA PSYCHIATR. SCAND. (Denmark), 1992, 86/4 (301-305)

    This study examines the relationship between folate, vitamin B12 and severity of cognitive impairment in patients with Alzheimer's disease (AD) as compared with other disorders associated with cognitive impairment. The patients were 97 consecutive referrals to an AD clinic.

    Forty patients had either possible or probable AD, 31 had other dementias (OD) and 26 had mild cognitive impairment (cognitively impaired, not demented; CIND). Patients had blood drawn for serum, red cell folate and B12, as well as other biochemical indicators of nutrition, within 24 h of the Mini-Mental State Examination (MMSE). In the AD group, only B12 was significantly correlated with MMSE. Using regression analysis, B12 contributed significantly to variance in MMSE. There was no correlation between MMSE and serum, red cell folate or B12 in the OD or CIND group and no significant correlation between MMSE and other nutritional indices in any group.

    These findings suggest the possibility of a specific relationship between B12 levels and severity of cognitive impairment in patients with AD.

    Alzheimer's Disease: A 'cobalaminergic' hypothesis

    MED. HYPOTHESES (United Kingdom), 1992, 37/3 (161-165)

    An association between Alzheimer's Disease (AD) and low CSF and serum vitamin B12 (B12) has recently been described (1, 2, 3). This is apparently independent of nutritional intake (4). It has been suggested that such patients may exhibit an atypical form of cobalamin deficiency (3, 4).

    it is therefore proposed that these deficiencies may be aetiologically important, at least in sub-groups of AD, and a mechanism is described whereby B12 deficiency may result in the characteristic neurotransmitter changes of the disease. The hypothesis generates predictions regarding biochemical evaluation of such patients and suggests associations between the neurochemical disturbances and structural abnormalities of AD.<br>[<i>This Message was Edited on 09/26/2005</i>]
  2. tansy

    tansy New Member

    Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia

    J. NEUROL. NEUROSURG. PSYCHIATRY (United Kingdom), 1990, 53/11 (951-954)

    Vitamin B12 and folate concentrations were measured in serum and cerebrospinal fluid (CSF) in 293 neurological patients. Serum and CSF vitamin B12 concentrations showed a positive correlation. In individual patients CSF B12 concentrations varied considerably for a given serum concentration.

    The median serum vitamin B12 concentration of the Alzheimer's type dementia group was significantly lower compared with that of a control group.

    Lower median CSF vitamin B12 concentrations were found in groups of patients with multiple sclerosis and Alzheimer's type dementia. Five patients with heterogeneous clinical pictures had unexplained low serum and CSF B12 concentrations without macrocytosis.

    Two patients had very high serum B12 and low-normal CSF concentrations which could be explained by a blood-brain barrier transport defect. Serum and CSF folate concentrations did not show significant differences between the various groups.

    Vitamin B12 levels in serum and cerebrospinal fluid of people with Alzheimer's disease

    ACTA PSYCHIATR. SCAND. (Denmark), 1990, 82/4 (327-329)

    Vitamin B12 levels in the serum and the cerebrospinal fluid (CSF) were compared between patients with Alzheimer's disease (AD) and senile dementia of Alzheimer's type (SDAT) (AD group) and patients with multi-infarct dementia (MID group). The B12 levels in the serum and the CSF were 742 plus or minus 359 pg/ml and 28 plus or minus 7 pg/ml (mean plus or minus SD), respectively, in the AD group, and 962 plus or minus 254 pg/ml and 50 plus or minus 26 pg/ml, respectively, in the MID group. CSF B12 levels were significantly lower in the AD group than in the MID group, whereas the serum levels were not different. At the same time, the serum levels of almost all patients were within the normal range, whereas the CSF levels were 25 pg/ml or lower in 10 of 12 AD patients.

    Therefore, this low level in the CSF is considered to be a characteristic finding in the AD group.

    Alzheimers disease/alcohol dementia: Association with zinc deficiency and cerebral vitamin B12 deficiency

    J. ORTHOMOL. PSYCHIATRY (CANADA), 1984, 13/2 (97-104)
    It is demonstrated that patients with senile dementia Alzheimer's type (SDAT) and alcohol related brain damage (AD) show a significant increase in ratio se-Cu/se-Zn when compared with patients with multi-infarct dementia (MID) and when compared with a matched control group.

    This is regarded as an indicator of zinc deficiency and relative copper toxicity in SDAT and AD, not in MID.

    In the same groups with SDAT and AD a high incidence of pathologically low levels of vitamin B12 in cerebrospinal fluid (CSF) was found, despite normal serum B12 levels. In MID the normal serum B12 corresponded with a normal CSF B12. This indicates abnormal function of the choroid plexus and possibly of the bloodbrain barrier in SDAT and AD, not in MID.

    Discussed is the possibility that in a large sub-group of SDAT and AD the clinical, neurochemical and neuropathological data can be explained by the hypothesis that the combination of zinc deficiency and copper toxicity results in limbic disinhibition and defective central noradrenergic neurotransmission.

    The neuroendocrine effects of the limbic disinhibition and the impaired regulation of the cerebral micro-circulation by the defective noradrenergic system will result in dysfunction of the blood-brain barrier and the choroid plexus, resulting as has been demonstrated in a CSF B12 deficiency. Such an effect is strongly potentiated by a co-existent depression. Due to the reduced plasticity of the aging brain the presentation of this organic affective syndrome and/or depression is under a 'dementia' disguise, facilitated by organic cerebral changes caused primarily by zinc deficiency and copper toxicity, secondarily by the cerebral B12 deficiency.

    Early recognition and adequate treatment with nutritional supplementation can possibly prevent irreversible damage in subgroups of SDAT and AD. Primary prevention by nutritional strategies can be a realistic perspective. The need for further research into this challenging hypothesis is stressed.

    Vitamin status in patients with inflammatory bowel disease

    Fernandez-Banares F.; Abad-Lacruz A.; Xiol X.; Gine J.J.; Dolz C.; Cabre E.; Esteve M.; Gonzalez-Huix F.; Gassull M.A.

    Department of Gastroenterology, Hospital de Bellvitge 'Princeps d'Espanya', Barcelona Spain
    AM. J. GASTROENTEROL. (USA), 1989, 84/7 (744-748)

    The status of water- and fat-soluble vitamins was prospectively evaluated in 23 patients (13 men, 10 women, mean age 33 plus or minus 3 yr) admitted to the hospital with acute or subacute attacks of inflammatory bowel disease.

    Protein-energy status was also assessed by means of simultaneous measurement of triceps skin-fold thickness, mid-arm muscle circumference, and serum albumin.

    Fifteen patients (group A) had extensive acute colitis (ulcerative or Crohn's colitis), and eight cases (group B) had small bowel or ileocecal Crohn's disease. Eighty-nine healthy subjects (36 men, 53 women, mean age 34 plus or minus 2 yr) acted as controls.

    In both groups of patients, the levels of biotin, folate, beta-carotene, and vitamins A, C, and B1 were significantly lower than in controls (p < 0.05). Plasma levels of vitamin B12 were decreased only in group B (p < 0.01), whereas riboflavin was lower in group A (p < 0.01).

    The percentage of patients at risk of developing hypovitaminosis was 40% or higher for vitamin A, beta-carotene, folate, biotin, vitamin C, and thiamin in both groups of patients. Although some subjects had extremely low vitamin values, in no case were clinical symptoms of vitamin deficiency observed. Only a weak correlation was found between protein-energy nutritional parameters and vitamin values, probably due to the small size of the sample studied.

    The pathophysiological and clinical implications of the suboptimal vitamin status observed in acute inflammatory bowel disease are unknown. Further studies on long-term vitamin status and clinical outcome in these patients are necessary.

    Vitamins for seeing

    COMPR. THER. (USA), 1990, 16/4 (62)

    It has long been known that an inadequate diet lacking in certain essential vitamins can cause ocular disorders. On an Egyptian papyrus dated about 1500 BC, it is recorded that liver was used as a food to cure night blindness.

    Healthy eyes depend on a well-balanced diet. Vitamin A maintains the normal function of the epithelial cells of the eye and is essential for the synthesis of visual photosensitive pigments. Deficiencies of vitamin A lead to clinical manifestations including night blindness, conjunctival pigmentation, and dry eyes.

    The B vitamins are important for maintaining good vision.

    Vitamin B1 (thiamine) deficiency produces optic nerve dysfunction.
    Vitamin B12 deficiency can produce vascular changes in the retina.
    Deficiency of riboflavin (part of the B complex) has been implicated in the formation of cataracts and may also be a factor in producting xerophthalmia (dry eyes).
    Vitamin C is necessary to prevent scurvy. The scorbutic manifestations in the eyes are bleeding from the lids, conjunctiva, anterior chamber, and retina. Vitamin C deficiency may also be a factor in cataract formation. Finally, vitamin K deficiency causes retinal hemorrhages in neonates.
    Deficiencies of vitamin D and E have not been shown to have a negative effect on the visual process, but vitamin E therapy improves retrolental fibroplasia (retinopathy of prematurity).

  3. deliarose

    deliarose New Member

    do you ever sleep?

    Seriously.. some food for thought here .. I understand that Vit B12 helps the body with the production of red blood cells.. which is presumably why it is part of the conventional CFS treatment regime.

    I was reading somewhere though that there are different forms of cobalamin and some are more beneficial than others...and that doctors in the UK favour a different kind than the one commonly used in the US in the treatment of PWCS.

    Ring any bells?


  4. tansy

    tansy New Member

    Hi Delia

    I think they use Hydroxocobalamin in the UK. Since my GP will not Rx B12, despite recommendations from 2 specialists, I opted for the sublingual methyl B12. Oddly my GP was happy to Rx the folic acid that was recommended as well but only on a self funded RX that was cheaper than the the standard NHS charge.

    love, Tansy
    [This Message was Edited on 09/29/2005]
  5. JimB

    JimB New Member

    Tell me when the movie version comes out!
    I read parts of it. Very interesting.
    I'll have to print it out.

    ANYWAY, I'll just add this info...
    Excerpts from Dr. Cheney's Report: (from the Library).

    Dr. Paul Cheney’s
    Treatment pyramid for Chronic Fatigue Syndrome (CFIDS)
    by Dr. Paul Cheney

    - Magnesium is an important element. They are magnesium depleted.

    - Extra vitamin E because they’re vitamin E depleted.

    In chronic fatigue syndrome patients,
    two thirds of them have no detectable B-12 in their brains, even though their blood levels are normal. We use high doses. We prefer hydroxycobalamin, and perhaps methylcobalamin.
    Cyanocobalamin is the usual B12.
    Methylcobalamin** (neuro-B12) is a form of B12 that gets PAST the blood brain-barrier to the brain.

    **You can buy this in sublingual(absorbed under the tongue)

  6. elsa

    elsa New Member


    This is such an excellent research article. Thank you for taking the time to find it and post it for us.

    I continue to learn so much through your efforts. I attribute my improvement quite a bit to your articles.

    If I may, what amount of the sublingual methyl B12 do you take daily? I would like to compare it with my intake.

    I'm going to print out this article. It deserves a 3rd and 4th reading ... LOL

    Take care,

  7. Rosiebud

    Rosiebud New Member

    I'm going to re-read this article as I didnt quite make it first time

    I'm seeing GP on Monday about B12 and will copy this out for him.


  8. tansy

    tansy New Member


    I started with Pro Health’s sublingual methyl B12, I use another make now but only because the localised reaction to the flavouring got worse over time, even so it still worked well.


    I started on 1,000mcg and raised it to 10,000 mcgs but with hindsight realised I went up too quickly and my final dose was too high, so I reduced the dose to 5,000mcg and stayed on that for some time. I also took grape seed extract and astaxanthin (it's what turns salmon, shrimp and flamingos such a deep shade of pink); first the GSE and then the astaxanthin. These antioxidants cross the blood brain barrier too.

    To begin with my head pains got a lot worse, this problem eased down somewhat when I reduced my dose of methyl B12 to 5,000 mcgs. Then miraculously after suffering many years that horrible pain went away, it only starts to come back if I don’t keep up the methyl B12, but I no longer need the anti oxidants.

    Now I take a maintenance dose of 1,000 mcgs, and sometimes 2,000 mcgs if I feel the need for more. When herxing significantly I raise the dose back up to 5,000 mcgs for a short time then go back to my maintenance dose.


    Some GPs are willing to use it as a treatment, not just for a deficiency, since anecdotal evidence suggests it helps in a variety of neurological conditions. Better the NHS fund your B12; it's about time they provided more suitable Tx rather than just offer us GET or CBT.

    Love, Tansy[This Message was Edited on 09/30/2005]
  9. elsa

    elsa New Member

    Thanks so much for your help. I have been taking 2000mcg for a while now ... the label just doesn't tell which kind of B12 it is. I'll have to do something about that.

    It is interesting to me that you mentioned headaches after raising the dose . I had a IV treatment Monday that consisted of quite a few B vits. ( as well as others ).

    I had a horrible headache starting about 1 1/2 to 2 hours after receiving the IV and continued for about 36 hours afterwards. I obviously didn't need that large of an amount.

    I hope you are doing well and enjoying the fall season. (Well, if the fall season is a nice time of year for all you UK'ers! I don't know since I have never been. LOL)

    Take care,


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