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Abstracts

Vitamin B6: 457 Research Abstracts

Clin Chem Lab Med. 2002 Feb;40(2):137-42.

Renal function exerts only a minor influence on high plasma homocysteine concentrations in patients with acute coronary syndromes.

Jonasson T, Ohlin H, Andersson A, Arnadottir M, Hultberg B.

Department of Medicine, University of Lund, University Hospital, Sweden. torfi.jonasson@kard.lu.se

It has been suggested that hyperhomocysteinemia observed in patients with occlusive vascular disease is caused by reduced renal function secondary to renovascular disease. We have therefore used serum cystatin C, a new sensitive marker for glomerular filtration, in 59 patients with acute coronary syndromes and high plasma homocysteine (tHcy) concentration to measure renal function. Samples were also obtained from 34 patients with low-normal plasma tHcy and 50 control subjects. The patients with low-normal plasma tHcy concentration showed decreased concentrations of serum cystatin C and serum creatinine and increased concentrations of blood folate and serum cobalamin compared to the controls and to the patients with high plasma tHcy. There was a large overlap in cystatin C concentrations between patients with high and low-normal plasma tHcy. None of the parameters investigated except plasma tHcy were significantly different in the group of patients with high plasma tHcy concentration compared to the control group. In order to further demonstrate the importance of renal impairment, a subgroup of the patients with high plasma tHcy was supplemented daily with folic acid 5 mg, pyridoxine 40 mg and cyancobalamin 1 mg for 3 months. Vitamin therapy reduced plasma tHcy from 18.3+/-4.6 pmol/l to 9.6+/-2.2 pmol/l (p<0.0001). However, vitamin treatment did not strengthen the correlation between cystatin C and plasma tHcy concentrations. These findings do not support the hypothesis that subtle renal dysfunction is an important cause of high plasma tHcy concentration in patients with acute coronary syndromes.

J Nutr Sci Vitaminol (Tokyo). 2002 Feb;48(1):10-7.

Vitamin B6 status of breast-fed infants in relation to pyridoxine HCl supplementation of mothers.

Chang SJ, Kirksey A.

Department of Biology, National Cheng Kung University, Tainan, Taiwan, ROC.

The vitamin B6 nutritue of breast-fed infants was evaluated by vitamin B6 intake, plasma pyridoxal 5'-phosphate (PLP) concentration, and growth patterns during the infants' first 6 mo of age. Vitamin B6 intakes of 47 healthy, term infants were significantly correlated with four levels of maternal vitamin B6 supplements: 2.5, 4.0, 7.5, or 10.0 mg pyridoxine (PN) HCl/d and met the B6 Adequate Intake (AI, 1998) of 0.1 mg/d for infants 0 to 6 mo. Only infants whose mothers received 10.0 mg PN x HCl/d exceeded or met the Recommended Dietary Allowances (RDA, 1989) of 0.3 mg vitamin B6/d from 4 to 6 mo of age. Plasma PLP concentrations of infants, measured at 1, 4, and 6 mo of age paralleled their mother's vitamin B6 intake. Most infants showed normal growth. The findings indicated that a maternal PN x HCl supplement of 2.5 mg/d provided an adequate amount of vitamin B6 in breast milk (0.15 mg/d) for the vitamin B6 status parameters and the growth of breast-fed infants.

J Nutr Sci Vitaminol (Tokyo). 2002 Feb;48(1):65-8.

Dietary vitamin B6 suppresses colon tumorigenesis, 8-hydroxyguanosine, 4-hydroxynonenal, and inducible nitric oxide synthase protein in azoxymethane-treated mice.

Komatsu S, Watanabe H, Oka T, Tsuge H, Kat N.

Faculty of Applied Biological Science, Hiroshima University, Higashi-Hiroshima, Japan.

Recently we reported that the supplementation of vitamin B6 to low vitamin B6 diet caused suppression in colon tumorigenesis and cell proliferation of azoxymethane-treated mice in a dose-dependent manner among 1, 7, and 14 mg pyridoxine HCl/kg diet (J. Nutr. 131: 2204-2207, 2001). To examine the mechanism of the anticolon tumor effect of vitamin B6, male ICR mice were fed the diet containing 1, 7, 14, and 35 mg pyridoxine HCl/kg diet for 22 wk and simultaneously given a weekly injection of azoxymethane for an initial 10 wk. The supplementation of vitamin B6 to a low vitamin B6 diet (1 mg pyridoxine HCl/kg) suppressed the levels of colonic 8-hydroxyguanosine and 4-hydroxynonenal and inducible nitric oxide synthase protein. The results suggest that the preventive effect of vitamin B6 against colon tumorigenesis is at least in part mediated by reducing oxidative stress and nitric oxide production.

Osteoarthritis Cartilage. 2002 Feb;10(2):119-26. Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice.

Kurz B, Jost B, Schunke M.

Anatomisches Institut der CAU zu Kiel, Olshausenstr. 40, Kiel, Germany. bkurz@anat.uni-kiel.de

OBJECTIVE: To study the influence of dietary vitamins and selenium on mechanically-induced osteoarthritis (OA) and the expression of antioxidative enzymes in male STR/1N and Balb/c mice. Male STR/1N mice are prone to develop OA caused by a varus deformity-induced mechanical overload of the medial tibial plateau. METHODS: After 12 months of feeding (special diet supplemented with the vitamins E, C, A, B6, B2, and selenium) serial histological sections of the knee joints were evaluated for development of osteoarthritic changes (grade 0-4). Serum glutathione peroxidase activity (GSH-px) was measured photometrically. Expression of antioxidative enzymes was demonstrated by immunohistochemistry. RESULTS: All control STR/1N mice showed OA lesions (grade 3-4) while the special diet decreased OA incidence significantly down to approximately 65% (mostly grade 2). Even in Balb/c mice the incidence was decreased by the special diet from approximately 21% (control animals; grade 1) to approximately 14%. Serum GSH-px activity increased diet-dependently in both mouse strains but was generally higher in Balb/c mice. In both mouse strains the special diet increased the expression of GSH-px and Cu/Zn-SOD in articular cartilage while there was no expression of Mn-SOD. There was also a special diet-dependent increase in expression of GSH-px in the synovium of both mouse strains while an increase in expression of Mn-SOD and Cu/Zn-SOD could only be seen in the synovium of STR/1N mice. CONCLUSIONS: A diet supplemented with vitamins/selenium might be important in prevention or therapy of mechanically induced OA. We hypothesize that free oxygen radical species might be involved in the mechanical induction of OA. Copyright 2002 OsteoArthritis Research Society International.

Pediatr Neurol. 2002 Feb;26(2):146-7. Pyridoxal phosphate-responsive epilepsy with resistance to pyridoxine.

Kuo MF, Wang HS.

Division of Pediatric Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.

We present a female infant with seizures responsive to pyridoxal phosphate but that are resistant to pyridoxine. The mechanism by which pyridoxal phosphate controls seizures in this patient is unknown. Her seizures are perhaps not solely caused by pyridoxal phosphate deficiency. It is suggested that in addition to glutamic acid decarboxylase abnormality, the path from the absorption, transportation, phosphorylation, and oxidation of pyridoxine to pyridoxal phosphate in this patient might be defective. It should be considered whether pyridoxal phosphate can be the drug of choice instead of pyridoxine in treating patients suspected of pyridoxine-dependent epilepsy to reduce failure rate and further delay in seizure control.

Pediatrics. 2002 Feb;109(2):325-7. Ginkgo seed poisoning.

Kajiyama Y, Fujii K, Takeuchi H, Manabe Y.

Department of Pediatrics Kyoto Min-i-ren Central Hospital Kyoto, Japan. yo-f@dab.hi-ho.ne.jp

A 2-year-old girl presented with vomiting and diarrhea 7 hours after eating a large quantity of ginkgo seeds. She exhibited an afebrile convulsion 9 hours after ingestion. The serum concentration of 4-metoxypyridoxine was as high as 360 ng/mL. Although reported cases of ginkgo seed poisoning usually involve children who exhibit repetitive seizures that can be fatal, prompt administration of pyridoxal phosphate (2 mg/kg) may have prevented additional seizures. This is the first English-language case report measuring 4-metoxypyridoxine concentration during ginkgo seed poisoning. Awareness of the potential danger of overconsumption of this traditional food and its prompt treatment with pyridoxal phosphate may hasten recovery.

Percept Mot Skills. 2002 Feb;94(1):135-40.

Effects of pyridoxine on dreaming: a preliminary study.

Ebben M, Lequerica A, Spielman A.

City College of New York, USA.

The effect of pyridoxine (Vitamin B-6) on dreaming was investigated in a placebo, double-blind study to examine various claims that Vitamin B-6 increases dream vividness or the ability to recall dreams. 12 college students participated in all three treatment conditions, each of which involved ingesting either 100 mg B-6, 250 mg B-6, or a placebo prior to bedtime for a period of five consecutive days. The treatment conditions were completely counterbalanced and a two-day wash-out period occurred between the three five-day treatment blocks. Morning self-reports indicated a significant difference in dream-salience scores (this is a composite score containing measures on vividness, bizarreness, emotionality, and color) between the 250-mg condition and placebo over the first three days of each treatment. The data for dream salience suggests that Vitamin B-6 may act by increasing cortical arousal during periods of rapid eve movement (REM) sleep. An hypothesis is presented involving the role of B-6 in the conversion of tryptophan to serotonin. However, this first study needs to be replicated using the same procedures and also demonstrated in a sleep laboratory before the results can be considered certain.

Semin Neonatol. 2002 Feb;7(1):17-26. Management and emergency treatments of neonates with a suspicion of inborn errors of metabolism.

Ogier de Baulny H.

Neurology and Metabolic Diseases Unit, Hopital Robert Debre, Paris, France. helene.ogier@rdb.ap-hop-paris.fr

During the neonatal period, inborn errors of metabolism mostly present with an overwhelming illness that requires prompt diagnosis and both supportive and specific treatments. The most frequent situations are due to branched-chain organic acidurias that present with ketoacidosis and urea cycle defects that are characterized by hyperammonaemia. During both situations, toxin removal procedures and nutritional support with a free-protein and high-energy diet are pivotal treatments. In patients presenting with hypoglycaemia blood glucose levels must be corrected. Progress following glucose provision is useful in recognizing the disorders that are mainly implicated. Hyperinsulinism requires high-glucose infusion. Glycogen storage diseases and gluconeogenesis defects are easily treated with a permanent glucose provision while hypoglycaemias quickly recur. In patients with galactosaemia, hereditary fructose intolerance or tyrosinaemia type I, the presentation is dominated by a liver failure requiring galactose and fructose exclusion associated with a low-protein diet. Many patients with beta-oxidation defects may present with hypoglycaemia that is usually easily corrected. The precise diagnosis can be easily missed in those patients that do well in the following weeks but may develop cardiac failure, arrhythmia and/or liver failure. Patients presenting with intractable convulsions, vitamin responsiveness to biotin, pyridoxine and folate must be considered. Copyright 2002 Elsevier Science Ltd. All rights reserved.

Cochrane Database Syst Rev. 2002;(1):CD000145.

Comment in: • ACP J Club. 2002 Sep-Oct;137(2):67.

Update of: • Cochrane Database Syst Rev. 2000;(2):CD000145.

Interventions for nausea and vomiting in early pregnancy.

Jewell D, Young G.

Division of Primary Health Care, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK. david.jewell@bristol.ac.uk

BACKGROUND: Nausea and vomiting are the most common symptoms experienced in early pregnancy, with nausea affecting between 70 and 85% of women. About half of pregnant women experience vomiting. OBJECTIVES: The objective of this review was to assess the effects of different methods of treating nausea and vomiting in early pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register. Date of last search: October 2001. SELECTION CRITERIA: Randomised trials of any treatment for nausea and/or vomiting in early pregnancy. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: Twenty-three trials were included. These trials were of variable quality. Nausea treatments were different anti-histamine medications, vitamin B6 (pyridoxine), the combination tablet Debendox (Bendectin) and P6 acupressure. For hyperemesis gravidarum five trials were identified testing treatments with oral ginger root extract, oral corticosteroids or injected adrenocorticotropic hormone (ACTH) and intravenous diazepam. Based on 13 trials, there was an overall reduction in nausea from anti-emetic medication (odds ratio 0.17, 95% confidence interval 0.13 to 0.21). REVIEWER'S CONCLUSIONS: Anti-emetic medication appears to reduce the frequency of nausea in early pregnancy. There is some evidence of adverse effects, but there is very little information on effects on fetal outcomes from randomised controlled trials. Of newer treatments, pyridoxine (vitamin B6) appears to be more effective in reducing the severity of nausea. The results from trials of P6 acupressure are equivocal. No trials of treatments for hyperemesis gravidarum show any evidence of benefit. Evidence from observational studies suggests no evidence of teratogenicity from any of these treatments.

J Clin Psychiatry. 2002 Jan;63(1):54-8.

Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study.

Lerner V, Miodownik C, Kaptsan A, Cohen H, Loewenthal U, Kotler M.

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel. lernervld@yahoo.com

BACKGROUND: Vitamin B6, or pyridoxine, plays an intrinsic role in the synthesis of certain neurotransmitters that take part in development of psychotic states. Several reports indicate that vitamin B6 may be a factor in a number of psychiatric disorders and related conditions, such as autism, Alzheimer's disease, hyperactivity, learning disability, anxiety disorder, and depression. Moreover, there are anecdotal reports of a reduction in psychotic symptoms after vitamin B6 supplementation of psychopharmacologic treatment of patients suffering from schizophrenia or organic mental disorder. The aim of this study was to examine whether vitamin B6 therapy influences psychotic symptoms in patients suffering from schizophrenia and schizoaffective disorder. METHOD: The effects of the supplementation of vitamin B6 to antipsychotic treatment on positive and negative symptoms in 15 schizophrenic and schizoaffective patients (DSM-IV criteria) were examined in a double-blind, placebo-controlled, crossover study spanning 9 weeks. All patients had stable psychopathology for at least 1 month before entry into the study and were maintained on treatment with their prestudy psychoactive and antiparkinsonian medications throughout the study. All patients were assessed using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia on a weekly basis. Patients randomly received placebo or vitamin B6, starting at 100 mg/day in the first week and increasing to 400 mg/day in the fourth week by 100-mg increments each week. RESULTS: PANSS scores revealed no differences between vitamin B6- and placebo-treated patients in amelioration of their mental state. CONCLUSION: Further studies with larger populations and shorter duration of illness are needed to clarify the question of the possible efficacy of vitamin B6 in treatment of psychotic symptoms in schizophrenia.

J Nutr Health Aging. 2002;6(1):69-71.

Homocysteine levels in elderly Spanish people: influence of pyridoxine, vitamin B12 and folic acid intakes.

Ortega RM, Jimenez A, Andres P, Faci M, Lolo JM, Lozano MC, Bermejo LM, Lopez-Sobaler AM, Requejo AM.

Departamento de Nutricion, Facultad de Farmacia, Universidad Complutense deMadrid, Spain. rortega@farm.ucm.es

BACKGROUND: Serum homocysteine levels are a risk factor in cardiovascular disease. Knowledge on how dietary factors might affect these levels is therefore of interest. OBJECTIVE: To evaluate serum homocysteine levels in a group of elderly people and analyse the effect of pyridoxine, vitamin B12 and folic acid intakes on these levels. DESIGN: The study subjects were 130 independently-living elderly people over the age of 65. A dietetic study was performed using a 7-day food record. Serum homocysteine levels were determined by HPLC. RESULTS: Mean pyridoxine, vitamin B12 and folate intakes were 67.2+/-16.8%, 392.8+/-549.2% and 84.5+/-28.3% of recommended values respectively. With regard to sex, differences were seen only for vitamin B12 intake (9.1+/-12.7 microg/day in men, and 6.5+/-8.8 microg/day in women). Some 93.6% of subjects showed pyridoxine intakes below those recommended, as did 17.6% with respect to vitamin B12 and 72.8% with respect to folic acid. Homocysteine levels were 12.4 micromol/l (12.6+/-3.7 micromol/l in men and 12.2+/-7.9 micromol/l in women) (P<0.05). No significant differences were seen in homocysteine levels between subjects with lower than recommended intakes of pyridoxine or vitamin B12 and those with better intakes. However, subjects with folic acid intakes below 200 microg/day showed higher homocysteine levels (13.0+/-6.7 micromol/l) than did subjects with more adequate intakes (10.9+/-4.1 micromol/l) (P<0.05). CONCLUSION: The diet of the study subjects might be improved, especially with respect to pyridoxine and folic acid. Raising the intake of the latter might be especially useful in controlling homocysteine levels and the risk of cardiovascular disease.

J Nutr Health Aging. 2002;6(1):75-7.

Reduced serum concentrations of riboflavine and ascorbic acid, and blood thiamine pyrophosphate and pyridoxal-5-phosphate in geriatric patients with and without pressure sores.

Selvaag E, Bohmer T, Benkestock K.

Department of medicine, Aker University Hospital, Oslo, Norway.

BACKGROUND: Patients with pressure sores have as part of their treatment been reefed with energy and proteins with varying result. It has been uncertain, however, to what an extent these patients also were depleted of micronutrients which might be critical for ulcer healing. OBJECTIVE: To study the nutritional intake and nutritional status of a number of micronutrients in geriatric pressure sore patients and in matched controls. DESIGN: The nutritional intake and nutritional status as anthropometric measures, serum conc. of albumin, zinc, and of vitamins (ascorbic acid, riboflavin, calcidiol), were measured. Thiamin pyrophosphate and pyridoxal-5-phosphate were determined in whole blood from 11 geriatric in-patients with pressure sores and 11 matched controls. RESULTS: The serum conc. of ascorbic acid was significantly (p< 0.05) more reduced in pressure sore patients (mean+/-S.D.) 4.2+/-3.4 (ug/ml) than in control patients 7.4+/-5.4 (ug/ml) which still was lower than in a reference group (10.9+/-1.9) (ug/ml). In all the geriatric patients compared to the reference group, the conc. of serum-riboflavin was reduced to about 15 %, thiamine-pyrophosphate and pyridoxine-5-phosphate in whole blood and serum calcidiol to about 50 %, without any differences between the pressure sore patients and the matched controls. CONCLUSION: Refeeding of pressure sore patients who often are catabolic and have increased needs for protein and energy, should include micronutrients not only to cover recommended dietary allowances, but sufficient to reach normal nutritional status for the individual micronutrient.

Stomatologiia (Mosk). 2002;81(2):45-9.

[Complex diagnosis of congenital cranial dysostosis in children]

[Article in Russian]

Iakubov RK, Azimov MI.

Ten patients (aged 3-15 years) with congenital cranial dysostosis were examined by a pediatrician, geneticist, gastroenterologist, neuropathologist, ophthalmologist, endocrinologist, and orthopaedist. In addition to the clinical signs characteristic of hereditary multiple developmental defects, the study revealed changes in the jaws and temporomandibular joint and local factors promoting the progress of deformations of the jaws. Manifest and inapparent pathological changes and dysfunctions in gastrointestinal organs were paralleled by dysfunctions of the central and autonomic nervous systems, risk of maxillofacial and general deformations, and signs of congenital disorders in calcium, lactic acid, and pyridoxine metabolism. The results necessitate analyses of the blood and urine and development of new methods for the diagnosis of congenital cranial dysostosis and improvement of methods for the correction of this condition.

Turk J Pediatr. 2002 Jan-Mar;44(1):54-7.

Acute isoniazid neurotoxicity in childhood.

Citak A, Kaya O, Ucsel R, Karabocuoglu M, Uzel N.

Department of Pediatric Emergency, Istanbul University Institute of Child Health, , Turkey.

Acute isoniazid (INH) poisoning is uncommon in children. Although most physicians are aware of INH hepatotoxicity, acute INH poisoning and its treatment are not well recognized. INH is increasingly being used to control the spread of tuberculosis, and physicians should know its potentially fatal effects. INH overdose is known to result in rapid onset of seizures, metabolic acidosis and prolonged obtundation. We report two cases of obtundation secondary to INH overdose that was immediately reversed by pyridoxine. Parenteral pyridoxine administration is an effective method in INH intoxication. The intravenous form of pyridoxine must be available in the emergency care units, and INH toxicity should be suspected in any patient with refractory seizures and metabolic acidosis.

Arterioscler Thromb Vasc Biol. 2001 Dec;21(12):2072-9. Long-term homocysteine-lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: a 2-year, randomized, placebo-controlled trial.

van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD.

Institute for Cardiovascular Research Vrije Universiteit, Department of Internal Medicine, University Hospital Vrije Universiteit, Netherlands.

Homocysteine is associated with atherothrombotic disease, which may be mediated through associations of homocysteine levels with blood pressure, endothelial function, or arterial stiffness. In a placebo-controlled, randomized clinical trial, we measured blood pressure, brachial artery endothelium-dependent vasodilation, and common carotid artery stiffness in 158 clinically healthy siblings of patients with premature atherothrombotic disease at baseline and after 1 and 2 years of homocysteine-lowering treatment with folic acid (5 mg) plus pyridoxine (250 mg). Intention-to-treat analyses limited to participants (n=130) who underwent at least 1 measurement after the baseline visit showed that compared with placebo, treatment with folic acid plus pyridoxine was associated with a 3.7-mm Hg (95% CI -6.8 to -0.6 mm Hg) lower systolic and a 1.9-mm Hg (95% CI -3.7 to -0.02 mm Hg) lower diastolic blood pressure over the 2-year trial period. Together with the decreased occurrence of abnormal exercise electrocardiography tests reported previously, our results support the hypothesis that homocysteine-lowering treatment with folic acid plus pyridoxine has beneficial vascular effects. Because no effects could be demonstrated on brachial artery endothelium-dependent vasodilation or on common carotid artery stiffness, the present study does not support the hypothesis that the cardiovascular effects of homocysteine are mediated through these factors, at least in clinically healthy individuals.

J Inherit Metab Dis. 2001 Dec;24(8):833-42. Impact of new mutations in the methylenetetrahydrofolate reductase gene assessed on biochemical phenotypes: a familial study.

Tonetti C, Amiel J, Munnich A, Zittoun J.

Service d'Hematologie Biologique, Hopital Henri Mondor, Creteil, France.

Methylenetetrahydrofolate reductase (MTHFR) deficiency was identified in two out of four children born from nonconsanguineous parents. One of the affected children exhibited some clinical findings suggesting cystathionine beta-synthase deficiency; MTHFR activity was extremely reduced. In addition, hyperhomocysteinaemia, hypomethioninaemia, low total folate, especially methylfolate in red blood cells, and a reduced methylfolate/total folate ratio were found. Two mutations not yet reported, one on exon 1 of the gene changing an arginine to stop codon and one other on exon 9 changing an arginine to tryptophan were identified in both children in the compound heterozygous state associated with a common polymorphism, 1298A>C, also in the heterozygous state. The mother, homozygous for the mutation on exon 9 and for the polymorphism 1298A>C on exon 7, was clinically and biochemically normal, with normal folate status, mainly methylfolate levels in red blood cells, although MTHFR activity was moderately decreased. The father, heterozygous for the transition arginine to stop codon and for the common polymorphism 677C>T on exon 4, exhibited major biochemical abnormalities, hyperhomocysteinaemia and low methylfolate levels in red blood cells, but was clinically normal. The unaffected children had a biochemical pattern close to that of their mother and were heterozygous for the mutation on exon 9 and also for the two common polymorphisms, 677C>T and 1298A>C. In the affected children, some biochemical abnormalities, including folate status, especially methylfolate levels, were improved with treatment combining methyltetrahydrofolic acid, hydroxocobalamin, pyridoxine and betaine; however, homocysteine concentrations remained high and methionine concentrations were lowered. The father was treated with folic acid, which partially improved biochemical abnormalities. The impact of these mutations is discussed.

J Nutr. 2001 Dec;131(12):3208-11. Bioavailability and antioxidant activity of some food supplements in men and women using the D-Roms test as a marker of oxidative stress.

Cornelli U, Terranova R, Luca S, Cornelli M, Alberti A.

Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153, USA. corcon@katamail.com

Most antioxidants show contradictory behaviors because in the biological environment, for unpredictable reasons, they can become prooxidants. Recently, a new simple method to monitor oxidative stress in serum was developed. This test detects the derivatives of reactive oxygen metabolites (D-Roms). Hydroperoxides are converted into radicals that oxidize N,N-diethyl-para-phenylendiamine and that can be detected through spectrophotometric procedures as U.CARR. (Carratelli units). One U.CARR. corresponds to 0.8 mg/L hydrogen peroxide. In normal subjects U.CARR. values range from 250 to 300. Values outside this range indicate a modification of the prooxidant/antioxidant ratio. On the basis of this method, we tested three different formulas of antioxidants (F1, F2, F3) in 14 apparently healthy volunteers (11 men and 3 women). Formula 1 was composed of 5 mg zinc, 48 microg selenium, 400 microg vitamin A (as retinol acetate), 50 microg beta-carotene, 15 mg vitamin E (as dl-alpha-tocopheryl acetate) and 10 mg L-cysteine. Formula 2 was composed of 30 mg bioflavonoids from citrus, 30 mg vitamin C (as L-ascorbic acid), 10 mg coenzyme Q(10) and 1 mg vitamin B-6 (as pyridoxine hydrochloride). Formula 3 was composed of Formula 1 plus Formula 2. Each formula was prepared in dry capsules (formulation D1, D2, D3) or in a fluid form (formulation P1, P2, P3). Each formulation was administered for 1 wk in a crossover design. A 15% deviation of U.CARR. levels was chosen as the cut-off value for a significant change in oxidative stress. Formulas F1 and F3 reduced mean U.CARR. levels in most of the treated subjects (t test, P < 0.05), whereas F2 was not active. Fluid formulations were more active than dry formulations (chi(2) test, P < 0.05). In some cases, a slight increase in oxidative stress was detected. These minimal increases were not related to any particular antioxidant formula. In one subject only, the administration of the dry formulation (D1), increased oxidative stress to a level that reached the cut-off value. In conclusion, when antioxidants are taken in combination at low dosages they reduce oxidative stress, and little relevant prooxidant activity is detectable

J Paediatr Child Health. 2001 Dec;37(6):592-6. Pyridoxine-dependent seizures: a case report and a critical review of the literature.

Gupta VK, Mishra D, Mathur I, Singh KK.

Neonatal Division, Department of Paediatrics, Dr Ram Manohar Lohia Hospital, New Delhi, India.

Pyridoxine-dependent seizures are a recognized, although rare, cause of intractable seizures in neonates. Patients with this autosomal recessive disorder have recurrent seizures that are resistant to conventional anticonvulsants but respond dramatically to intravenous administration of pyridoxine. Life-long supplementation with pyridoxine is required to prevent seizure recurrence. In the absence of a biological marker for the disease, clinical diagnosis is often delayed and severe neurological sequelae are common. Herein, we report on the clinical course of a neonate with pyridoxine-dependent seizures. Delayed normalization of the electroencephalogram and a normal developmental outcome (at 15 months of age) on a dose of 10 mg/kg pyridoxine are distinctive features of the present case. We also review recent clinical observations and neurochemical studies that have added to our knowledge of this disorder.

N Engl J Med. 2001 Nov 29;345(22):1593-600.

Comment in: • N Engl J Med. 2002 Apr 4;346(14):1093-5. • N Engl J Med. 2002 Apr 4;346(14):1093-5. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels.

Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B, Turi ZG, Hess OM.

Division of Cardiology, Swiss Cardiovascular Center Bern, University Hospital. g.schnyder@lycos.com

BACKGROUND: We have previously demonstrated an association between elevated total plasma homocysteine levels and restenosis after percutaneous coronary angioplasty. We designed this study to evaluate the effect of lowering plasma homocysteine levels on restenosis after coronary angioplasty. METHODS: A combination of folic acid (1 mg), vitamin B12 (400 microg), and pyridoxine (10 mg)--referred to as folate treatment--or placebo was administered to 205 patients (mean [+/-SD] age, 61+/-11 years) for six months after successful coronary angioplasty in a prospective, double-blind, randomized trial. The primary end point was restenosis within six months as assessed by quantitative coronary angiography. The secondary end point was a composite of major adverse cardiac events. RESULTS: Base-tine characteristics and initial angiographic results after coronary angioplasty were similar in the two study groups. Folate treatment significantly lowered plasma homocysteine levels from 11.1+/-4.3 to 7.2+/-2.4 micromol per liter (P<0.001). At follow-up, the minimal luminal diameter was significantly larger in the group assigned to folate treatment (1.72+/-0.76 vs. 1.45+/-0.88 mm, P=0.02), and the degree of stenosis was less severe (39.9+/-20.3 vs. 48.2+/-28.3 percent, P=0.01). The rate of restenosis was significantly lower in patients assigned to folate treatment (19.6 vs. 37.6 percent, P=0.01), as was the need for revascularization of the target lesion (10.8 vs. 22.3 percent, P=0.047). CONCLUSIONS: Treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduces homocysteine levels and decreases the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. This inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty.

Orv Hetil. 2001 Nov 11;142(45):2459-67.

[The pathogenesis of diabetic and hepatic neuropathies]

[Article in Hungarian]

Winkler G, Kempler P.

Fovarosi Szent Janos Korhaz, II. Belgyogyaszati Osztaly.

The pathomechanism of neuropathies associated with diabetes and chronic liver diseases are poorly understood. Both metabolic and vascular factors are involved in the pathogenesis of diabetic neuropathy. It seems likely, that microangiopathy on the one hand and changes of various metabolic pathways due to hyperglycaemia on the other hand are much more related to each other than it was suggested previously. Nitric oxide may be the link between the metabolic and vascular hypotheses of diabetic neuropathy. Both reduced endoneurinal blood flow and increased oxidative stress leads to reduced nitric oxide synthetase activity. There are widespread inter-relationships between the most relevant metabolic changes included polyol pathway hyperactivity, reduced myoinosit concentration, advanced glycation end products formation, increased oxidative stress and lipid peroxidation. Changes of hemorheological conditions and primary hemostasis leeds to hyperviscosity just as to increased activity of the coagulation system. Among patients with chronic alcoholic liver diseases the direct toxic effect of alcohol is of particular relevance, however, malabsorption, impairment of axoplasmatic transport, changes of intermedier metabolism as well as thiamine and pyridoxine deficiency are of importance as well. The role of decreased insulin sensitivity and various degrees of glucose intolerance related to chronic liver diseases are still underestimated. Impairment of proteoglycan metabolism as well as increased oxydative stress are thought to be important factors in the pathogenesis of both diabetic and hepatic neuropathies. Glucose autooxidation and enhanced lipid peroxidation contribute to increased oxidative stress in patients with diabetes and chronic liver diseases as well. Vitamin E deficiency, autoimmun processes, circulating immune complexes, cryoglobulinemia, just as changes of vascular responsiveness associated with nitric oxide activity plays a role in the development of neural damage of hepatic origin. Most likely, similarly to diabetes mellitus, vascular changes contribute to the development of neuropathy in patients with chronic liver diseases.

Int J Mol Med. 2001 Nov;8(5):505-8.

Pyridoxal 5'-phosphate and pyridoxal inhibit angiogenesis in serum-free rat aortic ring assay.

Matsubara K, Mori M, Matsuura Y, Kato N.

Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, 111 Kuboki, Soja, Okayama 719-1197, Japan. kmatsuba@fhw.oka-pu.ac.jp

Supraphysiological doses of vitamin B6 has been reported to suppress tumor growth and metastasis in rodents. To examine if its anticancer effect is due to suppression in angiogenesis, this study was conducted to investigate the antiangiogenic effect of pyridoxal 5'-phosphate (PLP), pyridoxine, pyridoxal and pyridoxamine in an ex vivo serum-free matrix culture model using rat aortic ring. Rat aortic rings were incubated with PLP or pyridoxine (25 micromol/l to 5 mmol/l). Higher concentrations of PLP (2.5 and 5 mmol/l) and pyridoxine (5 mmol/l) caused complete inhibition of microvessel outgrowth. However, the addition of pyridoxine at 2.5 mmol/l did not show complete inhibition of angiogenesis. PLP inhibited microvessel outgrowth almost completely at a concentration of 500 micromol/l and showed antiangiogenic effect in a dose-dependent manner within the range of 25-500 micromol/l. At 250 micromol/l, pyridoxal was as effective as PLP, but pyridoxamine was inactive, implying that the aldehyde group relates to the antiangiogenic effect. These results indicated the antiangiogenic effect of PLP and pyridoxal, and suggested that the antitumor effect of high levels of vitamin B6 might be mediated through suppression of angiogenesis.

J Hum Nutr Diet. 2001 Oct;14(5):365-70. Riboflavin deficiency in cystic fibrosis: three case reports.

McCabe H.

Newcastle Nutrition, Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne NE1 4LP, UK. nutrition@trvi.nuth.northy.nhs.uk

Three cases of clinical riboflavin deficiency are reported in children aged 2-10 years attending a regional Cystic Fibrosis clinic. Riboflavin deficiency presented as angular stomatitis in all three patients. Patients were confirmed to be riboflavin deficient by assaying the activity of erythrocyte glutathione reductase. Patients were not on routine supplements of water-soluble vitamins before presentation and were treated with riboflavin supplements as part of a water-soluble vitamin complex. At presentation, one patient had poor nutritional status, but two patients were adequately nourished, receiving overnight Gastrostomy feeds. Data on these two patients indicate an adequate dietary intake of riboflavin, suggesting a mechanism for increased requirements, inadequate absorption or utilization. Additional deficiencies of thiamin, pyridoxine and iron were also observed. This paper reports the occurrence of a vitamin deficiency not previously reported in the cystic fibrosis population.

Am J Psychiatry. 2001 Sep;158(9):1511-4. Vitamin B(6) in the treatment of tardive dyskinesia: a double-blind, placebo-controlled, crossover study.

Lerner V, Miodownik C, Kaptsan A, Cohen H, Matar M, Loewenthal U, Kotler M.

Division of Psychiatry, Ministry of Health Be'er Sheva Mental Health Center, Faculty of Health Sciences Ben-Gurion University of the Negev, Israel. lernervld@yahoo.com

OBJECTIVE: The authors' goal was to conduct a double-blind trial of vitamin B(6) in the treatment of tardive dyskinesia in patients with schizophrenia. METHOD: Fifteen inpatients with schizophrenia who met research diagnostic criteria for tardive dyskinesia were randomly assigned to treatment with either vitamin B(6) or placebo for 4 weeks in a double-blind crossover paradigm. The Extrapyramidal Symptom Rating Scale was used to assess patients weekly. RESULTS: Mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B(6) than during the placebo period. CONCLUSIONS: Vitamin B(6) appears to be effective in reducing symptoms of tardive dyskinesia.

Atherosclerosis. 2001 Sep;158(1):161-4. Vitamin supplementation can markedly reduce the homocysteine elevation induced by fenofibrate.

Dierkes J, Westphal S, Kunstmann S, Banditt P, Lossner A, Luley C.

Institute of Clinical Chemistry and Biochemistry, Leipziger Str. 44, D-39120 Magdeburg, Germany. jutta.dierkes@medizin.uni-magdeburg.de

Elevated homocysteine concentrations are a risk factor for atherosclerotic disease. Recently it was reported that lipid lowering with fibrates increases homocysteine by up to 40%. Since elevated homocysteine concentrations can readily be lowered by vitamin supplementation, a randomized, double-blind crossover study was performed to investigate the effect of fenofibrate plus folic acid, vitamin B6 and B12 versus fenofibrate plus placebo in hyperlipidemic men. The crossover study comprised a run-in period of 6 weeks, a first treatment phase of 6 weeks, a washout phase of 8 weeks and a second treatment phase of 6 weeks. Vitamins were given at doses of 650 microg folic acid, 50 microg vitamin B12 and 5 mg vitamin B6 per day for a period of 6 weeks. After fenofibrate plus placebo the increase in homocysteine concentration was 44+/-47%. After fenofibrate plus vitamins it was 13+/-25%, being significantly lower than without vitamins. The increase in homocysteine in response to fenofibrate may counteract the cardioprotective effect of lipid lowering. The addition of vitamins involved in homocysteine metabolism can prevent most of the homocysteine increase seen after fenofibrate plus placebo. Addition of these vitamins to fenofibrate may therefore be warranted for routine use.

Expert Opin Pharmacother. 2001 Sep;2(9):1449-60. Homocysteine-lowering treatment: an overview.

van Guldener C, Stehouwer CD.

Department of Internal Medicine, University Hospital and Institute of Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands.

Elevated fasting plasma concentrations of homocysteine have a high prevalence in subjects with cardiovascular disease and have also been associated with an increased risk of atherothrombosis in most, but not all, prospective studies. The most frequent causes of hyperhomocysteinaemia are genetic defects, such as cystathionine-beta-synthase (CBS) deficiency, deficiencies of folic acid and/or vitamin B12, renal failure and interference in homocysteine metabolism by drugs or metabolic alterations. In most cases, no underlying cause can be established. Subjects with CBS deficiency are treated with pyridoxine with additional folic acid and betaine if necessary. Folic acid and vitamin B12 deficiencies should be corrected by supplementation. Increases in folate intake by dietary changes or fortification can also lower plasma homocysteine in vitamin-replete subjects with normal plasma homocysteine levels. In renal failure, folic acid treatment (1-5 mg/day) ameliorates the plasma homocysteine level in most cases but hyperhomocysteinaemia persists in the majority of patients. Primary (fasting) hyperhomocysteinaemia can be treated with folic acid (0.5-5 mg/day). An abnormal methionine-loading test identifies additional patients at risk and postmethionine-loading hyperhomocysteinaemia should be treated with a combination of pyridoxine and folic acid. In the absence of dose-effect studies, a combination of pyridoxine (50 mg) and folic acid (5 mg) is advised. Large clinical trials are currently underway to establish the role of homocysteine-lowering therapy in the secondary prevention of atherothrombotic disease. In view of the effective, cheap and safe character of therapy with folic acid and pyridoxine, a policy can be accepted to screen and treat high-risk patients until these trials have been concluded.

Heart Lung Transplant. 2001 Sep;20(9):964-9. Pyridoxine improves endothelial function in cardiac transplant recipients.

Miner SE, Cole DE, Evrovski J, Forrest Q, Hutchison S, Holmes K, Ross HJ.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

BACKGROUND: Endothelial dysfunction is common in cardiac transplant recipients and predicts the development of transplant coronary artery disease. Hyperhomocysteinemia is associated with endothelial dysfunction in the general population, is common in transplant recipients, and has been associated with transplant coronary artery disease. Thus therapy that decreases homocysteine concentrations might also improve endothelial function and decrease the risk of transplant coronary artery disease. Folate and pyridoxine are important cofactors in distinct aspects of homocysteine metabolism. The purpose of this study was to determine whether folate or pyridoxine supplementation improves endothelial function in cardiac transplant recipients. METHODS AND RESULTS: This was a double-blind, randomized, placebo-controlled trial. We assigned 31 transplant recipients to either pyridoxine (n = 11:100 mg/day), folate (n = 12:5 mg/day), or placebo (n = 8) for 10 weeks. Fasting and post-methionine-load (methionine 100 mg/kg orally) homocysteine concentrations were determined. Brachial artery flow-mediated dilatation was used as a measure of endothelial function. At follow-up, we noted no significant changes in homocysteine concentrations in any of the groups. However, pyridoxine supplementation was associated with a significant improvement in endothelial function (2.8 +/- 6.7 to 6.9 +/- 6.3, p = 0.05). No significant changes were seen in patients treated with folate or placebo. CONCLUSIONS: Pyridoxine, but not folate supplementation, significantly improves endothelial function in cardiac transplant recipients.

Vestn Oftalmol. 2001 Sep-Oct;117(5):37-40.

[Prognostic significance of local and systemic indicators of lipid peroxidation and antioxidant system in perforating wounds of the eyes and their time course during local antioxidant treatment]

[Article in Russian]

Arkhipova LT, Dolgova IG.

Lipid peroxidation parameters malonic dialdehyde (MDA) and dienic conjugates (DC) and antioxidant defense (AOD) values superoxide dismutase (SOD), catalase, alpha-tocopherol were measured in the blood neutrophils and lacrimal fluid of 66 patients on days 1-2, 7-8, 14-15, and 21-22 after perforating wound of first, second, third, and fourth degree of severity according to P, 1. Lebekhov and in repeated injury, and the time course of these parameters during local treatment with therapeutic films with emoxipin and emoxipin + piridoxine was evaluated. A stable increase of MDA and DC levels in blood neutrophils, decrease of catalase, SOD, and alpha-tocopherol levels in blood neutrophils, and decrease of catalase enzymes and SOD activities in the lacrimal fluid of injured eye starting from days 7-8 are prognostically unfavorable signs. These data prompt the use of local and systemic treatment with antioxidants (emoxipin, tocopherol, etc.) in perforating wounds starting from the first days after the injury. Good clinical and antioxidant effect was observed after treatment with ocular therapeutic films with emoxipin and piridoxine.

Ann Plast Surg. 2001 Aug;47(2):153-60. Experimental model of pyridoxine (B6) deficiency-induced neuropathy.

Dellon AL, Dellon ES, Tassler PL, Ellefson RD, Hendrickson M.

Division of Plastic Surgery and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

A pyridoxine (B6) dietary deficiency was studied in female adult Sprague-Dawley rats by hind-limb walking-track analysis. Serum levels of pyridoxine and three metabolites were quantified by high-pressure liquid chromatography with fluorescence measurement. Morphometric analysis of the sciatic and posterior tibial nerves (from within the tarsal tunnel) was performed after 1 year on a diet deficient in vitamin B6. The B6-deficient rats developed abnormal walking-track patterns by 8 months, and these track parameters were different from age- and sex-matched normal diet control rats at the p < 0.05 level. Adding B6 at 10 parts per million to the diet then partially corrected these parameters, whereas the addition of 30 parts per million B6 corrected the abnormal pattern completely. Serum pyridoxal concentration correlated with the functional parameters, dropping from a mean of 115 mg per liter to 39.5 mg per liter (p < 0.05), and correcting with the B6 additive. Morphometric analysis demonstrated that the B6-deficient nerve from the tarsal tunnel had a decreased nerve fiber density (p < 0.001), with a normal total myelinated nerve fiber number, and an increased axon-to-myelin ratio (p < 0.003). It is concluded that a diet totally deficient in vitamin B6 results in a peripheral neuropathy.

Eur J Clin Invest. 2001 Aug;31(8):667-71. Homocysteine levels in patients treated with lipid apheresis: effect of a vitamin therapy.

Julius U, Pietzsch J, Gromeier S, Schorr H, Herrmann W.

Institut und Poliklinik fur Klinische Stoffwechselforschung, Universitatsklinikum Dresden, Dresden, Germany. julius@rcs.urz.tu-dresden.de

BACKGROUND: Patients treated with lipid apheresis already suffer from familial hypercholesterolemia and severe coronary heart disease: any additional risk factor is dangerous for these patients. Hyperhomocysteinemia has been recognized as an independent risk factor for atherosclerotic disease. We checked the frequency of hyperhomocysteinemia in lipid apheresis patients and measured the effect of a vitamin therapy. MATERIALS AND METHODS: Sixteen heterozygous patients (10 males, 6 females) were studied, who were being treated by three different apheresis procedures. Homocysteine was measured using an enzyme conversion immunoassay. Cystathionine and methylmalonic acid were assessed by gas chromatography/mass spectrometry. Serum levels of folic acid, vitamin B12, and vitamin B6 were also determined. The patients received a vitamin therapy (3 mg folate, 60 microg cyanocobalamine, 10 mg pyridoxine hydrochloride daily) for 12 weeks. RESULTS: In 9 out of 16 patients, plasma homocysteine levels were found to be elevated (> 12 micromol L(-1)). Cystathionine concentrations were also increased, especially in those patients with elevated homocysteine. Methylmalonic acid levels were not elevated. Serum folic acid, vitamin B6, and vitamin B12 concentrations were initially in the normal range and not correlated to plasma homocysteine. The vitamin therapy reduced the plasma homocysteine concentrations in all patients significantly by 33%. Among those patients with elevated homocysteine levels, the optimal range < 12 micromol L(-1) for homocysteine was rarely reached. CONCLUSIONS: In patients treated with lipid apheresis, a hyperhomocysteinemia can be frequently seen. The constellation of both elevated homocysteine and cystathionine levels points to the existence of tissue vitamin deficiencies, folate and vitamin B-6, which were improved by vitamin supplements. Because methylmalonic acid was mostly normal, a vitamin B-12 deficiency was not proven.

J Nutr. 2001 Aug;131(8):2204-7. Vitamin B-6-supplemented diets compared with a low vitamin B-6 diet suppress azoxymethane-induced colon tumorigenesis in mice by reducing cell proliferation.

Komatsu SI, Watanabe H, Oka T, Tsuge H, Nii H, Kato N.

Faculty of Applied Biochemistry, Hiroshima University, Higashi-Hiroshima 739-8528, Japan.

Male ICR mice were examined for the effect of vitamin B-6 [pyridoxine (PN) HCl] on azoxymethane-induced colon tumorigenesis. Mice were fed the diets containing 1, 7, 14 or 35 mg PN HCl/kg for 22 wk, and given a weekly injection of azoxymethane (5 mg/kg body) for the initial 10 wk. Compared with the 1 mg PN HCl/kg diet, 7, 14 and 35 mg PN HCl/kg diets significantly suppressed the incidence and number of colon tumors, colon cell proliferation and expressions of c-myc and c-fos proteins. For some variables, 14 and 35 mg PN HCl/kg diets were more effective than the 7 mg/kg diet. Supplemental vitamin B-6 had no influence on the number of colon apoptotic cells. The results suggest that elevating dietary vitamin B-6 suppresses colon tumorigenesis by reducing cell proliferation.

Eur J Clin Nutr. 2001 Jul;55(7):605-9. A population study of the influence of beer consumption on folate and homocysteine concentrations.

Mayer O Jr, Simon J, Rosolova H.

Centre of Preventive Medicine, 2nd Department of Internal Medicine, Medical Faculty Charles University, Pilsen, Czech Republic. mayerjr@lfp.cuni.cz

OBJECTIVE: Mild hyperhomocysteinemia is a significant and independent risk factor for vascular diseases. Blood total homocysteine concentration (tHcy) is considered to be the product of an interaction between genetic and nutritional factors notably intake of folate, vitamin B12 and pyridoxine. The aim of the study was to determine whether regular intake of beer containing large amount of folate and other vitamins influences the tHcy blood concentrations. DESIGN: Cross-sectional population-based survey. SETTING: Adult population, residents of Pilsen (Czech Republic) and vicinity. SUBJECTS: Population series included 292 males and 251 females aged 35-65 y, mean age 53.4 y. All subjects were examined by a standard protocol for clinical, anthropometrical and laboratory estimations. MAIN OUTCOME MEASURES: tHcy was measured by high-pressure liquid chromatography with fluorescent detection, blood folate and B12 levels immunochemically using commercial kits. RESULTS: Beer intake was associated with blood folate and vitamin B12 concentrations positively and with tHcy concentration negatively. By categories of beer intake, subjects with intake of 1 l daily or more had significantly lower tHcy and higher folate concentrations than those reporting lower daily beer intake. CONCLUSION: Moderate beer consumption may help to maintain the tHcy levels in the normal range due to high folate content. Folate from beer may thus contribute to the protective effect of alcohol consumption on cardiovascular disease in population with generally low folate intake from other nutrients. SPONSORSHIP: Supported by grant 301/00/P089 Grant Agency of Czech Republic and Internal Grant Agency of the Ministry of Health.

Pediatr Gastroenterol Nutr. 2001 Jul;33(1):64-9. Thiamine, riboflavin, pyridoxine, and vitamin C status in premature infants receiving parenteral and enteral nutrition.

Friel JK, Bessie JC, Belkhode SL, Edgecombe C, Steele-Rodway M, Downton G, Kwa PG, Aziz K.

Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada. jfriel@morgan.ucs.mun.ca

BACKGROUND: There is a paucity of data about water soluble vitamin status in low birthweight infants. Therefore, the authors' objective was to assess current feeding protocols. METHODS: The authors measured serum concentrations for riboflavin, pyridoxine, and vitamin C and functional assays for thiamine and riboflavin longitudinally in 16 premature infants (birthweight, 1,336 +/- 351 g; gestational age, 30 +/- 2.5 weeks) before receiving nutrition (time 1, 2 +/- 1 days), during supplemental or parenteral nutrition (time 2, 16 +/- 10 days) and while receiving full oral feedings (time 3, 32 +/- 15 days). In plasma, vitamin C was measured colorimetrically, and riboflavin and pyridoxine were measured using high-performance liquid chromatography. The erythrocyte transketolase test as a functional evaluation of thiamine and the erythrocyte glutathione reductase test for riboflavin were measured colorimetrically. RESULTS: At time 1, nutrient intake of vitamins were negligible because infants were receiving intravenous glucose and electrolytes only. Intakes differed between time 2 and time 3 for thiamine (510 +/- 280 and 254 +/- 115 microg. kg-1. d-1, respectively), riboflavin (624 +/- 305 and 371 +/- 193 microg. kg-1. d-1, respectively), and pyridoxine (394 +/- 243 and 173 +/- 85 microg/100 kcal, respectively), but not for vitamin C (32 +/- 17 and 28 +/- 12 mg. kg-1. d-1, respectively). Blood levels at times 1, 2, and 3 were for thiamine (4.9 +/- 2.7%, 3.3 +/- 6.6%, and 4.1 +/- 9% erythrocyte transketolase test, respectively), riboflavin (0.91 +/- 0.31, 0.7 +/- 0.3, 0.91 +/- 0.18 erythrocyte glutathione reductase test, respectively), riboflavin (19.5 +/- 17, 23.3 +/- 8.6, 17.6 +/- 10 ng/mL, respectively), pyridoxine (32 +/- 25, 40 +/- 16, 37 +/- 26 ng/mL, respectively), and vitamin C (5.2 +/- 3, 5 +/- 2.2, 10 +/- 5 microg/mL, respectively) and did not differ at those times. CONCLUSIONS: Current intakes of these vitamins, except for possibly vitamin C, during parenteral and enteral nutrition seem to result in adequate plasma concentrations and normal functional indices.

Eur J Pharmacol. 2001 Jun 15;421(3):157-64. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice.

Franca DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM.

Laboratory of Pharmacology, Faculty of Pharmacy, Federal University of Minas Gerais, Avenida Olegario Maciel 2360, 30180-112 MG, Belo Horizonte, Brazil.

The effect of some B vitamins in chemical and thermal models of nociception in mice was investigated. The association thiamine/pyridoxine/cyanocobalamin (TPC, 20-200 mg/kg, i.p. or per os), thiamine, pyridoxine (50-200 mg/kg, i.p.) or riboflavin (3-100 mg/kg, i.p) induced an antinociceptive effect, not changed by naloxone (10 mg/kg, i.p.), in the acetic acid writhing model. Treatment for 7 days with thiamine/pyridoxine/cyanocobalamin (100 or 200 mg/kg, i.p.), thiamine (50 or 100 mg/kg) or pyridoxine (50 or 100 mg/kg) or acute treatment with riboflavin (6 or 12 mg/kg, i.p) inhibited the nociceptive response induced by formaldehyde. The B vitamins did not inhibit the nociceptive response in the hot-plate model. Both 7-day thiamine/pyridoxine/cyanocobalamin (100 mg/kg, i.p.) or acute riboflavin (25 or 50 mg/kg, i.p.) treatment partially reduced formaldehyde-induced hindpaw oedema. The B vitamins antinociceptive effect may involve inhibition of the synthesis and/or action of inflammatory mediators since it was not observed in the hot-plate model, was not reversed by naloxone, only the second phase of the formaldehyde-induced nociceptive response was inhibited, and formaldehyde-induced hindpaw oedema was reduced.

Dev Med Child Neurol. 2001 Jun;43(6):413-5.

Pyridoxine-dependent seizures responding to extremely low-dose pyridoxine.

Grillo E, da Silva RJ, Barbato JH Jr.

Hospital Infantil Joana de Gusmio, Servico de Neurologia, Florianopolis SC, Brasil. egrillo@matrix.com.br

We report on a male infant with pyridoxine dependency and seizures from birth, controlled with pharmacological doses of pyridoxine at 4 months of age. Seizures stopped between 30 and 80 days of age when very-low doses of pyridoxine were given in a multivitamin supplement. Daily dose was 0.5 mg that corresponded to 0.08 to 0.16 mg/kg/day when weight gain is considered. In previous reports doses have ranged from 0.2 to 30 mg/kg/day. Another distinctive feature was that this infant went into a coma and developed hypotonia and irregular breathing when pyridoxine was given by enteral tube which has usually been reported when the vitamin is given intravenously. Use of low doses of pyridoxine in multivitamin supplements could be a confounding factor for early diagnosis and appropriate treatment of pyridoxine-dependent seizures.

J Nutr. 2001 Jun;131(6):1777-86.

Erratum in: • J Nutr 2001 Aug;131(8):2224. Assessment of vitamin B-6 status in young women consuming a controlled diet containing four levels of vitamin B-6 provides an estimated average requirement and recommended dietary allowance.

Hansen CM, Shultz TD, Kwak HK, Memon HS, Leklem JE.

Department of Food Science and Human Nutrition, Washington State University, Pullman, WA 99164-6376, USA.

The Recommended Dietary Allowance (RDA) of vitamin B-6 for young women was recently reduced from 1.6 to 1.3 mg/d based on an adequate plasma pyridoxal phosphate (PLP) concentration of 20 nmol/L. To assess vitamin B-6 requirements and suggest recommendations for intake, seven healthy young women consumed a controlled diet providing 1.2 g protein/kg body weight for a 7-d adjustment period (1.0 mg vitamin B-6/d) and three successive 14-d experimental periods (1.5, 2.1 and 2.7 mg/d, respectively). Direct and indirect vitamin B-6 status indicators were measured in plasma, erythrocytes and urine. Indicators most strongly correlated with vitamin B-6 intake [i.e., plasma and erythrocyte PLP, urinary 4-pyridoxic acid (4-PA) and total vitamin B-6] were regressed on vitamin B-6 intake and the dietary vitamin B-6 to protein ratio. Inverse prediction using adequate and baseline values estimated vitamin B-6 requirement. Adequate values were determined for plasma PLP and urinary 4-PA from baseline values of 60 previous subjects, using the statistical method suggested by Sauberlich. The current study suggests a vitamin B-6 Estimated Average Requirement (EAR) for young women of 1.1 mg/d or 0.016 mg/g protein, and a RDA of 1.5 mg/d or 0.020 mg/g protein. When results from this study are combined with data from four other recent studies, the combined data predict an EAR of 1.2 mg/d or 0.015 mg/g protein, and a RDA of 1.7 mg/d or 0.018 mg/g protein. This study suggests that the current vitamin B-6 RDA may not be adequate.

J Biol Chem. 2001 May 4;276(18):15107-16. Epub 2000 Dec 29. Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II.

Farrant RD, Walker V, Mills GA, Mellor JM, Langley GJ.

Physical Sciences, GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. rdf17079@glaxowellcome.co.uk

We previously identified vitamin B6 deficiency in a child presenting with seizures whose primary diagnosis was the inherited disorder hyperprolinemia type II. This is an unrecognized association, which was not explained by diet or medication. We hypothesized that pyridoxal phosphate (vitamin B6 coenzyme) was de-activated by L-Delta(1)-pyrroline-5-carboxylic acid, the major intermediate that accumulates endogenously in hyperprolinemia type II. The proposed interaction has now been investigated in vitro with high resolution 1H nuclear magnetic resonance spectroscopy and mass spectrometry at a pH of 7.4 and temperature of 310 K. Three novel adducts were identified. These were the result of a Claisen condensation (or Knoevenagel type of reaction) of the activated C-4 carbon of the pyrroline ring with the aldehyde carbon of pyridoxal phosphate. The structures of the adducts were confirmed by a combination of high performance liquid chromatography, nuclear magnetic resonance, and mass spectrometry. This interaction has not been reported before. From preliminary observations, pyrroline-5-carboxylic acid also condenses with other aromatic and aliphatic aldehydes and ketones, and this may be a previously unsuspected generic addition reaction. Pyrroline-5-carboxylic acid is thus found to be a unique endogenous vitamin antagonist. Vitamin B6 de-activation may contribute to seizures in hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B6 supplementation.

Harefuah. 2001 May;140(5):369-73, 456.

[Antidepressive effect of pyridoxine (vitamin B6) in neuroleptic-treated schizophrenic patients with co-morbid minor depression--preliminary open-label trial]

[Article in Hebrew]

Shiloh R, Weizman A, Weizer N, Dorfman-Etrog P, Munitz H.

Geha Psychiatric Hospital, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.

BACKGROUND: Minor depression is reported in 20-60% of schizophrenic patients during various stages of their disorders; impairing patients' compliance, response to treatment and worsening their overall prognosis. Various anti-depressive treatments have been proposed for such cases but response rates are usually poor. Pyridoxine (Vitamin B6) in essential for the proper metabolism of various neurotransmitters that are considered relevant to the pathophysiology of depression and/or schizophrenia and it has been reported beneficial in ameliorating depressive symptoms as part of major depression, premenstrual syndrome or 'Chinese restaurant syndrome'. We hypothesized that addition of pyridoxine to on-going neuroleptic treatment could improve minor depression in schizophrenic patients. METHOD: Nine schizophrenic patients with co-morbid minor depression participated in this study. All participants had a stable unchanged clinical state (changes in Brief Psychiatric Rating Scale (BPRS). Scale for the Assessment of Positive Symptoms (SAPS), and Scale for the Assessment of Negative symptoms (SANS) scores < 5%) and all were maintained on unchanged doses of anti-psychotic drugs for at least 4 consecutive weeks prior to initiation of the study. Participants received, open-label, pyridoxine 150 mg/day in addition to their anti-psychotic treatment for 4 consecutive weeks. Mental status was evaluated before, during, and at the end of 4 weeks of pyridoxine administration using the BPRS, SAPS, SANS and HAM-D. RESULTS: Two of the nine patients (22%), characterized by higher initial HAM-D and SANS scores, and by older age and longer duration of illness, experienced marked improvements in depressive symptoms (23% and 28% decrease in HAM-D scores) following 4 weeks of pyridoxine administration. In one of these two, the improvement in depressive symptoms was accompanied by a parallel decrease in SANS Scores. CONCLUSION: A subgroup of schizophrenic patients with comorbid minor depression may benefit from pyridoxine addition to their on-going anti-psychotic treatment.

J Cardiovasc Pharmacol. 2001 May;37(5):630-8. Influence of endothelium in dose-dependent inhibition and potentiation by isoniazid of isosorbide dinitrate relaxation of rat aorta.

Vidrio H, Fernandez G.

Department of Pharmacology, School of Medicine, National Autonomous University of Mexico, Mexico City. vidrio@servidor.unam.mx

The influence of in vivo administration of isoniazid on the relaxant effect of isosorbide dinitrate was determined by pretreating rats with various doses of isoniazid and obtaining concentration-response curves to isosorbide dinitrate in aortic rings from these animals. In rings with endothelium, isoniazid potentiated responses to isosorbide dinitrate at doses of 10, 30, and 100 mg/kg; 3 and 300 mg/kg were without effect. In endothelium-denuded preparations, potentiation was present only at 10 mg/kg; 3 and 300 mg/kg inhibited relaxation. Other experiments indicated that isoniazid potentiation was prevented by pyridoxine, was reproduced with theophylline, and did not occur with 3-morpholinosydnonimine or papaverine. These results were deemed compatible with the hypothesis that isoniazid inhibits transsulfuration of homocysteine and causes its accumulation in vascular smooth muscle and endothelial cells, where it functions as a thiol intermediate and leads to enhanced bioactivation of isosorbide dinitrate. Potentiation appeared to occur only with moderate increases of homocysteine.

Am J Clin Nutr. 2001 Apr;73(4):759-64. Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete.

McKinley MC, McNulty H, McPartlin J, Strain JJ, Pentieva K, Ward M, Weir DG, Scott JM.

Northern Ireland Centre for Diet and Health, University of Ulster, Coleraine, United Kingdom.

BACKGROUND: Current data suggest that physiologic doses of vitamin B-6 have no significant homocysteine-lowering effect. It is possible that an effect of vitamin B-6 was missed in previous trials because of a much greater effect of folic acid, vitamin B-12, or both. OBJECTIVE: The aim of this study was to investigate the effect of low-dose vitamin B-6 supplementation on fasting total homocysteine (tHcy) concentrations in healthy elderly persons who were made replete with folate and riboflavin. DESIGN: Twenty-two healthy elderly persons aged 63-80 y were supplemented with a low dose of vitamin B-6 (1.6 mg/d) for 12 wk in a randomized, double-blind, placebo-controlled trial after repletion with folic acid (400 microg/d for 6 wk) and riboflavin (1.6 mg/d for 18 wk); none of the subjects had a vitamin B-12 deficiency. RESULTS: Folic acid supplementation lowered fasting tHcy by 19.6% (P < 0.001). After folic acid supplementation, baseline tHcy concentrations ranged from 6.22 to 23.52 micromol/L and 10 subjects had suboptimal vitamin B-6 status (plasma pyridoxal-P < 20 nmol/L). Two-way analysis of variance showed that the significant improvement in vitamin B-6 status in response to vitamin B-6 supplementation (on the basis of both pyridoxal-P: and the erythrocyte aspartate aminotransferase activation coefficient) was reflected in a significant reduction in plasma tHcy of 7.5%. CONCLUSIONS: Low-dose vitamin B-6 effectively lowers fasting plasma tHcy in healthy subjects who are both folate and riboflavin replete. This suggests that any program aimed at the treatment or prevention of hyperhomocysteinemia should include vitamin B-6 supplementation.

Am J Epidemiol. 2001 Apr 1;153(7):688-94. Association of the B-vitamins pyridoxal 5'-phosphate (B(6)), B(12), and folate with lung cancer risk in older men.

Hartman TJ, Woodson K, Stolzenberg-Solomon R, Virtamo J, Selhub J, Barrett MJ, Albanes D.

Department of Nutrition, The Pennsylvania State University, University Park, PA, USA.

A nested case-control study was conducted within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort to test for associations between selected B-vitamins (folate, vitamin B(6), vitamin B(12)) and incident lung cancer. This trial was conducted in Finland between 1985 and 1993. Serum was analyzed for these nutrients and homocysteine among 300 lung cancer cases and matched controls (1:1). Odds ratios and 95% confidence intervals were determined in conditional and unconditional (controlling for the matching factors) logistic regression models, after adjusting for body mass index, years of smoking, and number of cigarettes smoked per day. No significant associations were seen between serum folate, vitamin B(12), or homocysteine and lung cancer risk. The authors found significantly lower risk of lung cancer among men who had higher serum vitamin B(6) levels. Compared with men with the lowest vitamin B(6) concentration, men in the fifth quintile had about one half of the risk of lung cancer (odds ratio = 0.51; 95% confidence interval: 0.23, 0.93; p-trend = 0.02). Adjusting for any of the other serum factors (folate, B(12), and homocysteine) either alone or jointly did not significantly alter these estimates. This is the first report from a prospectively conducted study to suggest a role for vitamin B(6) in lung cancer.

Eur J Obstet Gynecol Reprod Biol. 2001 Apr;95(2):218-21. Non-pregnant circulatory volume status predicts subsequent pregnancy outcome in normotensive thrombophilic formerly preeclamptic women.

Spaanderman ME, Aardenburg R, Ekhart TH, van Eyndhoven HW, van der Heijden OW, van Eyck J, de Leeuw PW, Peeters LL.

Academic Hospital Maastricht and Sophia Hospital Zwolle, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. marc.spaanderman@og.unimaas.nl

BACKGROUND: Preeclampsia seems to be superimposed upon a preexisting hemodynamic, hemostatic, autoimmune or metabolic disorder. We tested the hypothesis that in normotensive thrombophilic formerly preeclamptic subjects, the non-pregnant circulatory volume status predicts the development of subsequent hypertensive pregnancy and/or fetal growth restriction. METHODS: In 250 non-diabetic formerly preeclamptic women and 15 normal parous controls, we measured and calculated the following variables at least 5 months postpartum at day 5 (+/-2) of the menstrual cycle: mean arterial pressure, body mass index, plasma volume and the clotting function. In the subsequent pregnancy we determined, birth weight, birth-weight centile and the incidence of preterm birth, fetal growth restriction, pregnancy-induced hypertension, preeclampsia and HELLP-syndrome. We only included in the final analysis normotensive subjects with a thrombophilic phenotype at the time of the pre-pregnant screening, who had a subsequent singleton pregnancy, ongoing beyond 16 weeks gestation within 1 year after pre-pregnant evaluation. As a consequence, 23 formerly preeclamptic women and 12 controls were eligible for final analysis. The thrombophilic formerly preeclamptic participants received aspirin in combination with low-molecular-weight heparin throughout pregnancy. If thrombophilia was diagnosed on the basis of hyperhomocysteinemia, the treatment consisted of aspirin, pyridoxine and folic acid, instead. RESULTS: Among 250 formerly preeclamptic 131/250 (52%) had a normotensive thrombophilic phenotype. Only 23 (18%) of these 131 participants had an ongoing pregnancy within 1 year. They were allocated to subgroup THROMB. None of the controls had hypertension or thrombophilia. In contrast, 12/15 (80%) controls had an ongoing pregnancy within a year. The observations in the THROMB subgroup were compared with those in the control group. None of the baseline demographic and blood pressure variables differed between THROMB and controls. With respect to pregnancy outcome, the incidence of the following pregnancy complications were observed in THROMB subjects: preterm birth: 9%, pregnancy-induced hypertension: 44%, preeclampsia: 13%, HELLP-syndrome: 13%, and fetal growth restriction: 30%. A low non-pregnant plasma volume was found to predispose for hypertensive complications in a subsequent pregnancy. CONCLUSION: Pre-pregnant plasma volume in normotensive thrombophilic formerly preeclamptic women have predictive value with respect to hypertensive complications in the subsequent pregnancy.

J Adolesc Health. 2001 Apr;28(4):328-37. Dietary intake as a cardiovascular risk factor in Costa Rican adolescents.

Monge-Rojas R.

Costa Rican Institute for Research and Education on Nutrition and Health (INCIENSA), Ministry of Health, Tres Rios, Costa Rica.

PURPOSE: To evaluate Costa Rican adolescents' dietary intake as a cardiovascular disease (CVD) risk factor. METHODS: Dietary intake was determined using 3-day food records; nutrient content of fast foods prepared in school cafeteria was calculated by the weighted records. RESULTS: Around 30% of adolescents exceed the American Heart Association dietary recommendation for total fat and saturated fat. About 50% reported a cholesterol intake higher than 100 mg/1000 kcal. On average, 45% of adolescents do not meet the dietary fiber recommendation of 10 g/1000 kcal, the 66% of the recommended daily allowance for vitamins E and B(6), or around 25% for folic acid. A higher proportion of urban adolescents do not satisfy the established dietary recommendation to prevent CVD. CONCLUSIONS: To avoid further increases in the Costa Rican CVD mortality rate, it is necessary to develop primary prevention programs, oriented to modify adolescent's nutrition habits. Schools have the potential to carry out such programs, as at least 60% of all adolescents in Costa Rica are enrolled in high schools.

J Ren Nutr. 2001 Apr;11(2):67-72. Homocysteine lowering effect of different multivitamin preparations in patients with end-stage renal disease.

Dierkes J, Domrose U, Bosselmann KP, Neumann KH, Luley C.

Institute of Clinical Chemistry and Biochemistry, Magdeburg, Germany.

OBJECTIVE: Hyperhomocysteinemia occurs in nearly 100% of patients with end-stage renal disease (ESRD) and is associated with increased morbidity and mortality. Means to reduce elevated homocysteine concentrations is supplementation with folic acid, vitamin B6, and vitamin B12. However, doses of vitamins required for optimized treatment are subject of debate. Therefore, the effect of 2 different multivitamin preparations on the homocysteine concentrations in patients with ESRD were compared. DESIGN: Patients received 3 times per week either 2 tablets of preparation A (800 microg folic acid, 6 microg vitamin B12, 10 mg vitamin B6), 2 tablets of preparation B (160 microg folic acid, no vitamin B12, 10 mg vitamin B6), or placebo for a period of 12 weeks with control of total homocysteine (tHcy) levels at baseline, and at 4, 8, and 12 weeks. SETTING: The study was performed at the University Hospital of Magdeburg, Germany in patients with ESRD treated with chronic intermittent maintenance hemodialysis. RESULTS: Preparation A reduced the tHcy concentration significantly by nearly 50%, whereas preparation B did not change the tHcy concentration in comparison with placebo. However, tHcy was not normalized in the majority of patients receiving preparation A. CONCLUSION: The reduction of tHcy achieved by a multivitamin containing 800 microg folic acid was substantial and even higher than the reduction reported in supplementation studies using higher doses of folic acid alone. Nevertheless, hyperhomocysteinemia in ESRD patients appears relatively refractory to vitamin supplementation, in contrast with results obtained in healthy volunteers.

Jpn J Clin Oncol. 2001 Apr;31(4):172-4. Case report: hand-foot syndrome induced by the oral fluoropyrimidine S-1.

Elasmar SA, Saad ED, Hoff PM.

Department of Gastrointestinal Medical Oncology and Digestive Diseases, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

Hand-foot syndrome (HFS) is a relatively common side effect of fluorouracil (5-FU) chemotherapy that has also been associated with the oral fluoropyrimidine capecitabine. Interestingly, HFS is virtually unknown to result from treatment with UFT, a combination of tegafur and uracil. Tegafur is a prodrug of 5-FU and is a component of S-1, another oral fluoropyrimidine active in a variety of solid tumors. We know of only one previously described case of S-1-induced HFS and the case reported here is the first to provide full documentation of this occurrence. The pathophysiology of chemotherapy-induced HFS remains unknown and very little pathological information is available. Treatment consists of topical emollient therapy, although pyridoxine has occasionally been beneficial. The study of HFS may provide an important insight into the pharmacology of fluoropyrimidines and allow for effective preventive strategies for this side effect of chemotherapy.

Med Sci Sports Exerc. 2001 Apr;33(4):512-8. Effect of energy restriction and exercise on vitamin B-6 status of women during lactation.

Lovelady CA, Williams JP, Garner KE, Moreno KL, Taylor ML, Leklem JE.

Department of Nutrition and Foodservice Systems, The University of North Carolina at Greensboro, 27402-6170, USA. Cheryl_Lovelady@uncg.edu

PURPOSE: Lactation increases vitamin B-6 requirements because its concentration in breast milk is related to maternal intake and it is essential for infants. Exercise may also increase the requirement because it increases utilization and excretion of vitamin B-6. Therefore, the purpose of this study was to determine whether energy restriction and exercise affected vitamin B-6 status of lactating women. METHODS: Breastfeeding women with a body mass index > or = 25 and < or = 30 kg x m(-2) were randomly assigned at 4 wk postpartum to either restrict energy intake by 500 kcal x d(-1) and exercise for 45 min x d(-1), 4 d x wk(-1) (weight loss group, WG) or maintain usual diet and not exercise (control group, CG) for 10 wk. Women were given a supplement containing 2.0 mg of vitamin B-6. Measurements included vitamin B-6 concentrations in breast milk and plasma, plasma pyridoxal 5'-phosphate, and erythrocyte alanine aminotransferase activity. RESULTS: The WG lost more weight (-4.4 +/- 0.4 vs -0.9 +/- 0.5 kg, P < 0.01) than the CG. Cardiovascular fitness increased by 12% in the WG, compared to 3% in the CG (P = 0.09). Milk vitamin B-6 concentrations increased in both groups (161 +/- 107 and 191 +/- 85 nmol x L(-1), WG and CG, respectively, P = 0.05). There were no significant differences in other vitamin B-6 parameters. Weight and length gain (2.06 +/- 0.21 and 1.83 +/- 0.17 kg; 8.6 +/- 0.6 and 7.2 +/- 0.5 cm; WG and CG, respectively) of infants was not significantly different between groups. CONCLUSIONS: Energy restriction and exercise from 4 to 14 wk postpartum in overweight, breastfeeding women consuming adequate dietary intakes and 2.0 mg of supplemental vitamin B-6 does not adversely affect vitamin B-6 status or infant growth.

Prostaglandins Leukot Essent Fatty Acids. 2001 Apr-May;64(4-5):265-71. Effects of short-term dietary administration of marginal levels of vitamin B(6)and fish oil on lipid composition and antioxidant defences in rat tissues.

Cabrini L, Bergami R, Maranesi M, Carloni A, Marchetti M, Tolomelli B.

Dipartimento di Biochimica "G. Moruzzi", via Irnerio 48, Bologna, 40126, Italy.

Previous reports have shown that vitamin B(6)deficiency leads to peroxidative stress in rat organs. In this paper, we evaluated the effects on lipid peroxidation of short-term (six weeks) dietary administration of marginal contents of vitamin B(6). A further risk factor of susceptibility to peroxidation was the presence of fish oil with higher contents of n-3 polyunsaturated fatty acid (LCPUFA). The contemporaneous vitamin B(6)deficiency and presence of fish oil caused a C18:2 increase, a C20:4 decrease, and replacement of some n-6 LCPUFA with n-3 LCPUFA, without changes in the unsaturation index. In liver, TBARS production did not show any differences between dietary conditions, whereas the activities of glutathione-dependent enzymes were stimulated. In heart, fish oil increased lipid peroxidation, especially in the vitamin B(6)-deficient group. Copyright 2001 Harcourt Publishers Ltd.

Am J Clin Nutr. 2001 Mar;73(3):613-21.

Comment in: • Am J Clin Nutr. 2001 Mar;73(3):499-500. • Am J Clin Nutr. 2001 Oct;74(4):558-9. • Am J Clin Nutr. 2002 May;75(5):948. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort.

Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J.

Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. paul@hnrc.tufts.edu

BACKGROUND: Established determinants of fasting total homocysteine (tHcy) concentration include folate and vitamin B-12 status, serum creatinine concentration, and renal function. OBJECTIVE: Our objective was to examine the relation between known and suspected determinants of fasting plasma tHcy in a population-based cohort. DESIGN: We examined the relations between fasting plasma tHcy concentrations and nutritional and other health factors in 1960 men and women, aged 28-82 y, from the fifth examination cycle of the Framingham Offspring Study between 1991 and 1994, before the implementation of folic acid fortification. RESULTS: Geometric mean tHcy was 11% higher in men than in women and 23% higher in persons aged > or = 65 y than in persons aged < 45 y (P < 0.001). tHcy was associated with plasma folate, vitamin B-12, and pyridoxal phosphate (P for trend < 0.001). Dietary folate, vitamin B-6, and riboflavin were associated with tHcy among non-supplement users (P for trend < 0.01). The tHcy concentrations of persons who used vitamin B supplements were 18% lower than those of persons who did not (P < 0.001). tHcy was positively associated with alcohol intake (P for trend = 0.004), caffeine intake (P for trend < 0.001), serum creatinine (P for trend < 0.001), number of cigarettes smoked (P for trend < 0.001), and antihypertensive medication use (P < 0.001). CONCLUSIONS: Our study confirmed, in a population-based setting, the importance of the known determinants of fasting tHcy and suggested that other dietary and lifestyle factors, including vitamin B-6, riboflavin, alcohol, and caffeine intakes as well as smoking and hypertension, influence circulating tHcy concentrations.

J Clin Invest. 2001 Mar;107(6):675-83.

Comment in: • J Clin Invest. 2001 Mar;107(6):663-4. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.

Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, Ferran LJ Jr, Kohl B, Rao V, Kisiel W, Stern DM, Schmidt AM.

College of Physicians and Surgeons, Columbia University, 630 W. 168th Street, P&S 17-501, New York, NY 10032, USA. mah81@columbia.edu

Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

J Heart Lung Transplant. 2001 Mar;20(3):310-5. Effective treatment of hyperhomocysteinemia in heart transplant recipients with and without renal failure.

Cook RC, Parker S, Kingsbury K, Frohlich JJ, Abel JG, Gao M, Ignaszewski AP.

University of British Columbia Heart Transplant Program, St. Paul's Hospital, Vancouver, British Columbia, Canada.

BACKGROUND: Elevated total plasma homocysteine (tHcy) levels have been associated with vascular disease and higher mortality in patients with coronary artery disease. Graft coronary disease is a major cause of mortality in long-term survivors of heart transplantation, and hyperhomocysteinemia may be one of its causes. The objectives of our study were to establish the effectiveness of a 3 stage homocysteine-lowering algorithm in a group of 84 heart transplant (HTx) patients and to evaluate the effect of renal function on the response to homocysteine-lowering therapy. METHODS: Prospective treatment of 84 Htx patients (64 male; mean age, 48 +/- 13 years) with tHcy > 75th percentile consisted of a 3-stage treatment algorithm: Stage 1, folic acid (FA) 2 mg + vitamin (vit) B(12) 500 mcg daily; Stage 2, addition of vit B(6) 100 mg daily; Stage 3, increase FA to 15 mg daily. Serum creatinine (Cr) and tHcy levels were measured before treatment and 21 +/- 19 weeks after each stage of treatment. RESULTS: All 3 stages of treatment significantly lowered mean tHcy from 22.4 +/- 16.3 (mean +/- SD) micromol/liter to 16.3 +/- 6.7 micromol/liter (p < 0.00001), from 17.6 +/- 6.1 micromol/liter to 15.2 +/- 5.3 micromol/liter (p < 0.0001), and from 16.8 +/- 5.2 micromol/liter to 15.6 +/- 5.3 micromol/liter (p < 0.05), respectively. The average reduction from baseline was 38%. Creatinine levels did not change significantly during the study period. Total plasma homocysteine levels decreased below the 75th percentile in 55% of patients, with Cr levels significantly lower in this group of patients (126 +/- 36 micromol/liter vs 182 +/- 65 micromol/liter, p < 0.00001). However, we found no significant relationship between % change in tHcy and baseline Cr. CONCLUSIONS: In a group of 84 heart transplant patients with tHcy levels >75th percentile, treatment with FA and vit B(6) and B(12) according to a 3-stage algorithm resulted in statistically significant declines in mean tHcy levels. Overall, tHcy levels decreased 38%, with target tHcy levels <75th percentile achieved in 55% of the patients. The % change in tHcy was not related to Cr. Further studies are needed to correlate treatment of hyperhomocysteinemia with clinical endpoints, such as the time to development of transplant vasculopathy and long-term survival, and to define the most appropriate targets for therapy.

Nefrologia. 2001 Mar-Apr;21(2):167-73.

[Effect of folic acid supplementation on total homocysteine levels in hemodialysis patients]

[Article in Spanish]

Armada E, Perez Melon C, Otero A, Gayoso P, Rodriguez M, Esteban Morcillo J.

Servicio de Nefrologia C. Hospitalario Cristal Pinor Ramon Puga 32004 Ourense, Espana.

Hyperhomocysteinemia is an independent risk factor for cardiovascular mortality in ESRD, but about 80% of total homocysteine (tHcy) is bound to albumin (alb). We have tried, prospectively, to reduce tHcy levels by using folic acid (f.a.) and vitamin B6 (P.P.) supplementation. All patients on HD, not receiving f.a. or P.P. and all new patients, after their third month on HD, were supplemented with f.a. 5 mg/48 hours p.o and P.P. 40 mg/week. We determined folate, P.P. (RIA), vit. B12, KTV, residual renal function (KRU), PCRn, alb and tHcy levels (HPLC). 80 patients, age 62.6 +/- 13.6 years, time on HD 16.2 +/- 25.1 months, all dialysed with AN69 or PPMA, and bicarbonate, were included. The prevalence of hyperhomocysteinemia was 84.4%, and P.P. deficit was present in 32%, with folate in the low normal range. At the beginning of the study, before supplementation, tHcy was negatively correlating only with folate (r = -0.336) (p = 0.01), and not with P.P., vitamin B12, age, albumin, KTV, KRU or PCRn. 58 patients received six months of supplementation, with normalization of P.P. levels, a significant increase of folate (7.25; I.C = 95% confidence intervals: 6.45, 8.05 vs 61.29; I.C.: 44.47, 78.11) (p < 0.001), and decrease of tHcy (24.1; IC: 21.5, 26.3 vs 19.9; I.C: 17.5, 22.4) (p < 0.05). 33 patients have received 12 months of supplementation, but in spite of a continued increase of folate (100.78; I.C: 74.81, 126.74) (p < 0.001), only 3 have normal levels of tHcy; correlating directly tHcy with albumin (r = 0.56) (p = 0.001), that had increased compared to the beginning of the study (3.39; I.C. 3.29, 3.49 vs 3.50; I.C: 3.37, 3.63) (p < 0.05). CONCLUSION: After f.a. and P.P. supplementation, though initially tHcy is reduced, this response is short lived, and tHcy directly correlates with albumin levels. Good nutrition associated with HD adequacy, in absence of B vitamin deficits, seems to be the best determinant of tHcy levels rather than its removal by dialysis tHcy levels should be interpreted taking into account the serum albumin

Res Exp Med (Berl). 2001 Mar;200(3):155-68. Homocyst(e)ine metabolism in hemodialysis patients treated with vitamins B6, B12 and folate.

Henning BF, Zidek W, Riezler R, Graefe U, Tepel M.

Severi Med GmbH, Munster, Germany.

Hyperhomocyst(e)inemia is commonly accepted as an independent atherosclerotic risk factor. In most hemodialysis patients, serum homocyst(e)ine is markedly elevated and may contribute to premature atherosclerosis in these patients. Whereas the beneficial effect of folate supplementation on serum homocyst(e)ine has been extensively studied, there are less detailed studies on the effects of cobalamin and pyridoxal phosphate alone, or in combination with folate. We examined the effect of a four-week course of intravenous treatment with folate (1.1 mg), cobalamin (1.0 mg), and pyridoxal phosphate (5.0 mg), administered once (group 1), twice (group 2) or thrice (group 3) weekly in 33 hemodialysis patients divided in three groups of 11 patients. All patients were followed for a further four weeks after treatment was stopped. Serum homocyst(e)ine, cobalamin, folate and pyridoxal phosphate, as well as the metabolites of homocyst(e)ine, methylmalonate, 2-methylcitrate and cystathionine, were determined before, during and after treatment. Baseline serum homocyst(e)ine correlated significantly with serum folate (P=0.0149), cobalamin (P=0.0047) and pyridoxal phosphate (P=0.0408). Correlations independent from the other metabolites or vitamins were found for methylmalonate (P=0.003) and folate (P=0.029). All regimens increased serum cobalamin significantly (in group 1 from 444 +/- 215 to 17,303 +/- 11,989 pg/ml, P<0.01; in group 2 from 542 +/- 633 to 44,896 +/- 15,772 pg/ml, P<0.001; in group 3 from 548 +/- 394 to 77,961 +/- 31,546 pg/ml, P<0.001), but did not increase any of the other vitamin levels. Serum homocyst(e)ine was lowered significantly by 39.8% +/- 31.9% (P<0.05) with two and by 30.1% +/- 26.9% (P<0.05) with three vitamin dosages weekly, but not with one dosage weekly. Since methylmalonate is known to be a sensitive marker of cobalamin deficiency, the data support an important influence of cobalamin levels on baseline homocyst(e)ine levels. Increasing cobalamin levels and additional treatment with folate and pyridoxal phosphate 156 may decrease serum homocyst(e)ine in the same way as high doses of folate alone.

Rev Invest Clin. 2001 Mar-Apr;53(2):141-51.

Erratum in: • Rev Invest Clin 2001 Jul-Aug;53(4):378.

[Homocysteine metabolism and risk of cardiovascular diseases: importance of the nutritional status on folic acid, vitamins B6 and B12]

[Article in Spanish]

Aleman G, Tovar AR, Torres N.

Depto. Fisiologia de la Nutricion, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico, D.F.

Homocysteine is a thiol-containing amino acid derived from methionine metabolism that can be degraded through two enzymatic pathways: remethylation and trans-sulfuration. In remethylation, homocysteine regenerates methionine. In the trans-sulfuration pathway, homocysteine forms cysteine. Due to the rapid metabolic utilization, the plasma concentration of this amino acid is low. Homocysteine circulates as free thiol, homocystine, or bound to free cysteine or to cysteine residues of proteins. Genetic defects of some enzymes in the homocysteine metabolism, or nutritional deficiencies of folic acid, vitamin B6 and B12 lead to an increase in homocysteine plasma concentration and is associated to an increment in cardiovascular diseases. On the basis of clinical and epidemiological studies, homocysteine plasma concentration is considered to be an independent risk factor for the development of atherothrombotic and cardiovascular diseases. The present review describes the homocysteine metabolism, the epidemiological evidence showing the association between homocysteine and the incidence of cardiovascular diseases. The mechanisms by which homocysteine produces vascular damage are indicated. Finally, some recommendations are given for the nutritional therapy of patients with hyperhomocysteinemia.

Circulation. 2001 Feb 20;103(7):1006-11. Supplementation of atherogenic diet with B vitamins does not prevent atherosclerosis or vascular dysfunction in monkeys.

Lentz SR, Piegors DJ, Malinow MR, Heistad DD.

Veterans Affairs Medical Center, Departments of Internal Medicine, University of Iowa College of Medicine, Iowa City, USA. steven-lentz@uiowa.edu

BACKGROUND: Hyperhomocysteinemia is associated with increased risk of atherosclerotic and thrombotic vascular disease. In many patients, hyperhomocysteinemia can be treated or prevented by dietary supplementation with B vitamins, but the clinical benefit of B vitamins for the prevention of vascular disease has not been proven. METHODS AND RESULTS: Using an atherogenic diet that produces both hyperhomocysteinemia and hypercholesterolemia, we tested the hypothesis that dietary supplementation with B vitamins (folic acid, vitamin B(12), and vitamin B(6)) would prevent hyperhomocysteinemia, vascular dysfunction, and atherosclerotic lesions in monkeys. After 17 months, plasma total homocysteine increased from 3.6+/-0.3 to 11.8+/-1.7 micromol/L in monkeys fed an unsupplemented atherogenic diet (P<0.01) but did not increase in monkeys fed an atherogenic diet supplemented with B vitamins (3.8+/-0.3 micromol/L). Serum cholesterol increased from 122+/-7 to 550+/-59 mg/dL in the unsupplemented group (P<0.001) and from 118+/-5 to 492+/-55 mg/dL in the supplemented group (P<0.001). Responses to endothelium-dependent vasodilators, both in resistance vessels in vivo and in the carotid artery ex vivo, were impaired to a similar extent in groups that did and did not receive vitamin supplements. Anticoagulant responses to the infusion of thrombin were also impaired to a similar extent in both groups. Vitamin supplementation failed to prevent intimal thickening in the carotid or iliac arteries. CONCLUSIONS: These findings demonstrate that supplementation with B vitamins prevents hyperhomocysteinemia but is not sufficient to prevent the development of vascular dysfunction or atherosclerotic lesions in monkeys with marked hypercholesterolemia, even in the absence of preexisting atherosclerosis.

Am J Clin Nutr. 2001 Feb;73(2):232-9.

Comment in: • Am J Clin Nutr. 2001 Oct;74(4):558-9. Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore.

Saw SM, Yuan JM, Ong CN, Arakawa K, Lee HP, Coetzee GA, Yu MC.

Department of Community, Occupational, and Family Medicine, National University of Singapore.

BACKGROUND: Epidemiologic studies have identified the plasma homocysteine concentration as a risk factor for atherothrombotic vascular disease. There is little information on the distributions and determinants of homocysteine concentrations in Asian populations. OBJECTIVE: The present study was designed to examine the relations between genetic and lifestyle factors and plasma homocysteine concentrations among Chinese in Singapore. DESIGN: Plasma total homocysteine, folate, vitamin B-12, and vitamin B-6 concentrations and genetic variation at the methylenetetrahydrofolate reductase (MTHFR) locus were measured in 486 Chinese men and women aged 45-74 y in Singapore. Data on dietary and other lifestyle factors were collected in face-to-face interviews. RESULTS: Men had higher plasma concentrations of total homocysteine than women (P = 0.0001). Age was positively associated with plasma homocysteine in both sexes (P for trend = 0.0001). Plasma concentrations of folate, vitamin B-12, and vitamin B-6 were inversely associated with homocysteine concentrations. Among individuals with low plasma folate, those possessing 2 copies of MTHFR mutant alleles had significantly higher homocysteine concentrations than did those with > or = 1 copy of the wild-type allele. Cigarette smoking, daily coffee consumption, and physical inactivity were positively related to plasma homocysteine concentrations in both sexes (P < 0.05). However, these associations disappeared after adjustment for plasma folate concentrations. CONCLUSIONS: Age, sex, plasma folate, vitamin B-12 and B-6 concentrations, and MTHFR genotype are independent determinants of plasma homocysteine in middle-aged and older Chinese in Singapore. These factors combined could account for up to 40% of the total variation in homocysteine concentrations in this Asian population.

Free Radic Biol Med. 2001 Feb 1;30(3):232-7. Pyridoxine and pyridoxamine inhibits superoxide radicals and prevents lipid peroxidation, protein glycosylation, and (Na+ + K+)-ATPase activity reduction in high glucose-treated human erythrocytes.

Jain SK, Lim G.

Department of Pediatrics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. sjain@lsuhsc.edu

Vitamin B(6) (pyridoxine) supplementation has been found beneficial in preventing diabetic neuropathy and retinopathy, and the glycosylation of proteins. Oxygen radicals and oxidative damage have been implicated in the cellular dysfunction and complications of diabetes. This study was undertaken to test the hypothesis that pyridoxine (P) and pyridoxamine (PM) inhibit superoxide radical production, reduce lipid peroxidation and glycosylation, and increase the (Na+ + K+)-ATPase activity in high glucose-exposed red blood cells (RBC). Superoxide radical production was assessed by the reduction of cytochrome C by glucose in the presence and absence of P or PM in a cell-free buffered solution. To examine cellular effects, washed normal human RBC were treated with control and high glucose concentrations with and without P or PM. Both P and PM significantly lowered lipid peroxidation and glycated hemoglobin (HbA(1)) formation in high glucose-exposed RBC. P and PM significantly prevented the reduction in (Na+ + K+)-ATPase activity in high glucose-treated RBC. Thus, P or PM can inhibit oxygen radical production, which in turn prevents the lipid peroxidation, protein glycosylation, and (Na+ + K+)-ATPase activity reduction induced by the hyperglycemia. This study describes a new biochemical mechanism by which P or PM supplementation may delay or inhibit the development of complications in diabetes.

J Biopharm Stat. 2001 Feb-May;11(1-2):65-74.

Analyzing counts, durations, and recurrences in clinical trials.

McIntosh J.

Department of Economics, Concordia University, Montreal, PQ, Canada. jamesm@vax2.concordia.ca

In 1985 the (Byar and Blackard, Urology, Vol. X, 556-561, 1978) data set on bladder cancer became available to researchers. Since then, a number of studies have made use of it. However, none of these has fully utilized all of the data nor have they developed a methodology in which it is possible to estimate models of the number of recurrences and durations that are consistent with each other. The purpose of this research is to determine which, if any, of the two drugs used in the trial, pyridoxine and theotepa, were effective and, by example, illustrate procedures that could be useful in the analysis of other clinical trial data sets. First, the number of recurrences is modeled as a count using the Poisson and negative binomial distributions with covariates. Then Poisson models are tested on the durations. Finally, durations and tumor counts per recurrence are fitted to more general autoregressive Wiebull and negative binomial distributions, respectively. Poisson models for durations are rejected in favor of the more general autoregressive models. The data on durations and tumor counts are shown to be more reliable from an inference point of view than the data on the number of recurrences. The data on durations and tumor counts show quite conclusively that both drugs are effective in treating bladder cancer, a result that differs from what others have found.

Metabolism. 2001 Feb;50(2):131-4. Homocysteine, fibrinogen, and lipoprotein(a) levels are simultaneously reduced in patients with chronic renal failure treated with folic acid, pyridoxine, and cyanocobalamin.

Naruszewicz M, Klinke M, Dziewanowski K, Staniewicz A, Bukowska H.

Regional Center for Atherosclerosis Research, Pomeranian Academy of Medicine, and the Dialysis Unit of the Provincial Hospital, Szczecin, Poland.

Ischemic heart disease and other complications of atherosclerosis are the usual cause of death in patients with chronic renal failure. Important factors associated with early onset of atherosclerosis in these patients are hyperhomocysteinemia, hyperfibrinogenemia, and elevated levels of lipoprotein(a) (Lp(a)). Folic acid (15 mg/d), pyridoxine (150 mg/d), and cyanocobalamin (1 mg/wk) were administered for 4 weeks in 21 patients receiving dialysis, and a simultaneous, statistically significant reduction in the concentration of homocysteine, fibrinogen, and Lp(a) was found. A positive correlation between decreasing homocysteine and fibrinogen levels was also noted. The parameters studied approached presupplementation values 6 months after vitamins were discontinued. The results suggest that vitamin supplementation has a favorable effect on risk factors of atherosclerosis in patients with renal failure and that interactions may exist between homocysteine, fibrinogen, and Lp(a).

Ann Nutr Metab. 2001;45(6):255-8. Plasma folate but not vitamin B(12) or homocysteine concentrations are reduced after short-term vitamin B(6) supplementation.

Bosy-Westphal A, Holzapfel A, Czech N, Muller MJ.

Institut fur Humanernahrung und Lebensmittelkunde, Christian-Albrechts-Universitat zu Kiel, Dusternbrooker Weg 17, D-24105 Kiel, Germany. abosyw@nutrfoodsc.uni-kiel.de

Adverse effects of high vitamin B(6) intake include peripheral neuropathy. Recent studies focussing on the reduction of plasma homocysteine as a risk factor for vascular disease showed that vitamin B(6) reduces plasma folate levels. The significance of this finding is unclear. We therefore analyzed plasma folate and basal homocysteine levels as well as the response to an oral methionine loading test in 8 healthy individuals before and after a controlled supplementation with oral doses of 25 mg pyridoxine for 10 days. Plasma pyridoxal phosphate increased from 40.6 +/- 13.6 to 426.8 +/- 200.3 nmol/l (p < 0.001), whereas plasma folate decreased from 6.3 +/- 1.6 to 4.6 +/-1.5 ng/ml (p < 0.01), respectively. Plasma vitamin B(12) and basal homocysteine levels remained unchanged (234.0 +/- 27.8 vs. 217.1 +/- 50.4 pg/ml and 10.9 +/- 4.8 vs. 10.1 +/- 3.6 micromol/l). There was no significant effect of vitamin B(6) supplementation on the area under methionine and homocysteine concentration versus time curve. Significant correlations were found between pre- and post-supplement levels of folate as well as PLP levels (r = 0.73, p < 0.05; r = 0.75, p < 0.05). These data suggest that a dose of 25 mg vitamin B(6) supplemented for 10 days reduces plasma folate but did not affect basal and postprandial homocysteine levels suggesting (1) a normal cellular availability of folate or (2) a compensation of impaired homocysteine remethylation by increased transsulfuration. Copyright 2001 S. Karger AG, Basel

Drug Saf. 2001;24(7):553-65.

Drug treatment for tuberculosis during pregnancy: safety considerations.

Bothamley G.

East London Tuberculosis Service, Homerton Hospital, England. graham.bothamley@homerton-hospital.uk

Untreated tuberculosis in pregnancy poses a significant threat to the mother, fetus and family. Adherence to treatment is especially difficult in pregnancy because of the general fear of any medication and pregnancy-related nausea. Supervised treatment is especially helpful in encouraging adherence. All 4 first line drugs [isoniazid, rifampicin (rifampin), ethambutol and pyrazinamide] have an excellent safety record in pregnancy and are not associated with human fetal malformations. Drug-induced hepatitis, especially with isoniazid, is a significant problem in treating tuberculosis, not peculiar to pregnancy; close monitoring of liver function is recommended. Liver enzyme induction by rifampicin alters the metabolism of other drugs, e.g. methadone doses will need to be increased. Streptomycin should not be used in pregnancy, as perhaps 1 in 6 babies will have problems with hearing and/or balance. Ciprofloxacin has the best safety profile of second line drugs in the treatment of drug-resistant tuberculosis. Preventive treatment with isoniazid can be undertaken safely during pregnancy. Pyridoxine (vitamin B6) should be added to the drug treatment of tuberculosis in all pregnant women taking isoniazid. Neither tuberculin nor the bacille Calmette Guerin (BCG) vaccine are treatments for tuberculosis, but they play an important role in the management of the disease. Tuberculin testing is safe, but BCG vaccination should be avoided in pregnancy and instead given earlier in life.

Gerontology. 2001 Jan-Feb;47(1):30-5. Long-term effects of vitamin B(12), folate, and vitamin B(6) supplements in elderly people with normal serum vitamin B(12) concentrations.

Henning BF, Tepel M, Riezler R, Naurath HJ.

Department of Internal Medicine I, Marienhospital, University of Bochum, Germany.

BACKGROUND: In the elderly, deficiencies of folate, cobalamin (vitamin B(12)) and pyridoxal phosphate (vitamin B(6)) are common. The metabolites homocysteine, methylmalonic acid, 2-methylcitric acid and cystathionine have been reported to be sensitive markers of these vitamin deficiencies. OBJECTIVE: The long-term (269 days) effect of an intramuscular vitamin supplement containing 1 mg vitamin B(12), 1.1 mg folate, and 5 mg vitamin B(6) on serum concentrations of homocysteine (tHcy), methylmalonic acid (MMA), 2-methylcitric acid (2-MCA), and cystathionine (Cysta) was studied in 49 elderly subjects with normal levels of vitamin B(12). METHODS: Vitamin supplement was administered 8 times over a 21-day period, metabolite concentrations were measured until day 269 (e.g. 248 days after the end of vitamin supplementation). RESULTS: From day 0 to 21, the serum levels of the 3 vitamins increased significantly, after cessation of supplementation the levels returned to baseline within the follow-up period. The MMA, 2-MCA and tHcy levels decreased during the treatment period significantly and did not reach baseline values within the 248-day period. Cysta levels did not differ significantly from baseline, either during or after treatment. CONCLUSION: MMA and 2-MCA levels rather reflect the availability of vitamins, especially cobalamin, than the actual serum levels. Since deficiencies of folate, cobalamin and pyridoxal phosphate in the elderly may cause hyerhomocysteinemia and hence may have unfavorable effects on mental performance, determination of MMA and 2-MCA levels in elderly patients with mental disturbances may be a cost-effective measure to improve or maintain mental performance. Copyright 2001 S. Karger AG, Basel.

J Nephrol. 2001 Jan-Feb;14(1):36-42. Hyperhomocysteinemia in renal transplant patients: an independent factor of cardiovascular disease.

Bertoni E, Marcucci R, Zanazzi M, Rosati A, Brunelli T, Fedi S, Pepe G, Di Maria L, Colonna FM, Lombardi A, Abbate R, Salvadori M.

Renal Unit, Careggi University Hospital, Florence, Italy. salvadorim@ao-careggi.toscana.it

Hyperhomocysteinemia (Hcy) is an independent factor of cardiovascular disease, which is the main cause of morbidity and mortality both in uremic and kidney transplant patients. The aim of the study was to determine Hcy, plasminogen activator inhibitor (PAI-1) and lipoprotein (a) (Lp(a)) serum levels in 70 patients with a well functioning renal transplant. We also verified whether these levels were modified by a multivitamin therapy. The genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR) enzyme which plays a main role in Hcy metabolism, was studied as well. We found Hcy, PAI-1 and Lp(a) levels significantly elevated with respect to healthy control subjects. The thermolabile form of the MTHFR enzyme was linked to higher Hcy levels. After a short time on therapy with B6, B12 and folic acid vitamins, Hcy and PAI-1 decreased to normal levels. The authors conclude that high Hcy levels could be a relevant covariate for cardiovascular disease in transplant patients and they suggest that vitamin supplementation be recommended as a part of therapy.

J Pathol. 2001 Jan;193(1):125-33. Abnormal vitamin B6 metabolism in alkaline phosphatase knock-out mice causes multiple abnormalities, but not the impaired bone mineralization.

Narisawa S, Wennberg C, Millan JL.

The Burnham Institute, La Jolla Cancer Research Center, La Jolla, CA 92037, USA.

The tissue non-specific alkaline phosphatase (TNAP) knock-out mouse is a model of infantile hypophosphatasia displaying impaired bone mineralization, epileptic seizures, apnoea, abnormal apoptosis in the thymus, abnormal lumbar nerve roots, and postnatal death. Administration of vitamin B6 suppresses the epileptic seizures in TNAP-/- mice. This paper examines to what extent the diverse abnormalities seen in these mice are due to impaired utilization of vitamin B6, using two complementary approaches: administration of vitamin B6 to TNAP null mice and deprivation of vitamin B6 in wild-type and TNAP heterozygous mice. Administration of exogenous pyridoxal HCl delayed the onset of epileptic attacks and increased the life span of TNAP-/- mice. The episodes of apnoea ceased and the appearance of lumbar nerve roots improved, but hypomineralization and accumulation of osteoid continued to worsen with age. Control mice fed a vitamin B6-depleted diet developed epileptic seizures indistinguishable from those observed in TNAP-/- mice, abnormal apoptosis in the thymus, and thinning of the nerve roots, but showed no evidence of bone mineralization abnormalities. Depletion of vitamin B6 did not affect the ability of primary cultures of osteoblasts to deposit bone mineral in vitro. While abnormal metabolism of vitamin B6 explains many of the abnormalities in this mouse model of infantile hypophosphatasia, it is not the basis of the abnormal mineralization that characterizes this disease.

Przegl Lek. 2001;58(4):290-2.

Clinical and institutional aspects of antidote therapy in Russia.

Ostapenko YN, Luzhnikov EA, Nechiporenko SP, Petrov AN.

Toxicology Information and Advisory Center, Ministry of Health of the Russian Federation, 3 block 7, Sukharevskaya ploshad, 129090 Moscow, Russia. rtiac@mednet.ru

The problem of antidote application for treatment of acute poisoning is related to epidemiology and characterization of poisoning cases, and possibilities for supplying antidotes to health care institutions. To investigate the situation in Russia we have analyzed reports by poisoning treatment centers for 1997-1999, comparison of medical aid standards for poisoning treatment in Russia with WHO recommendations. Acute poisoning pattern varies in different regions. Particularly, poisoning pattern in large cities in European Russia and the Urals is dominated by pharmaceuticals (up to 63.1%). Pesticide and insecticide poisoning cases do not exceed 1 to 2%, metal compounds and methemoglobin forming poisons (below 1% in each group). Antidotes are used in Russia in line with the recommendations adopted in international toxicological practice. The most actual are antagonists of opiates and benzodiazepines, physostigmine, atropine, pyridoxine, antagonists of beta-adrenergic blockers, activated charcoal. Such antidotes as DMPS (Unithiol), N-acetylcysteine, methylene blue, amyl nitrite (or sodium nitrite), complex formers of EDTA group are also included in the list of specific agents. The main problem is that some important antidotes are currently not produced in Russia. The Ministry of Health of the Russian Federation is taking efforts to launch production of some previously known and also newly developed important antidotes.

Vopr Pitan. 2001;70(1):12-4.

[Effects of biologically active supplements on the antioxidant and vitamin status of patients with hypertension and ischemic heart disease]

[Article in Russian]

Tutel'ian VA, Pogozheva AV, Rumiantseva OI, Akol'zina SE, Lysikova SL, Kodentsova VM, Mal'tsev GIu.

Biologically active additives in integrated therapy of patients with cardiovascular diseases against a background body overweight. The influence of antiaterosclerotic diet with including some biologically active additives, which contain vitamins C, E, B2, B6, beta-carotene, Zn, Mg, Na, K, Ca, I was studied in 91 patients with ischemic heart disease, hypertension disease. The usage of biologically active additives during 4 weeks has promoted positive changes of clinical symptoms of diseases against a background of lowering of serum cholesterol, triglycerides and increasing of vitamins A, E, C, B2, B6.

Wiad Lek. 2001;54(1-2):11-8.

[Evaluation of vitamin B6 and calcium pantothenate effectiveness on hair growth from clinical and trichographic aspects for treatment of diffuse alopecia in women]

[Article in Polish]

Brzezinska-Wcislo L.

Katedry i Kliniki Dermatologii Slaskiej Akademii Medycznej w Katowicach.

The aim of the study was the clinical and trichological examination (trichogram and hair loss evaluation) conducted comparatively before and after the treatment in 46 women between pubescence and 30 years of age who had symptoms of diffuse alopecia. Calcium pantothenate was administered twice a day orally in doses 100 mg for 4-5 months. Vitamin B6 was injected every day (i ampoule intramusculary) for the period of 20 to 30 days and repeated again after 6 month. On the basis of clinical and trichological studies it was revealed that vitamin B6 administered parenterally for a period of several weeks induces improvement in the hair condition in a number of women and it reduces the hair loss especially in alopecia of telogenic patomechanism. Whereas calcium pantothenate in feminine diffuse alopecia did not show clearly the positive effect.

Mech Ageing Dev. 2000 Dec 20;121(1-3):251-61.

Elevated plasma homocysteine levels in centenarians are not associated with cognitive impairment.

Ravaglia G, Forti P, Maioli F, Vettori C, Grossi G, Bargossi AM, Caldarera M, Franceschi C, Facchini A, Mariani E, Cavalli G.

Department of Internal Medicine, Cardioangiology, and Hepatology, University Hospital S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy. ravaglia@almadns.unibo.it

BACKGROUND: Previous reports have shown elevated plasma total homocysteine (tHcy) levels in elderly person with impaired cognition. OBJECTIVE: To study the association between cognitive status and plasma tHcy levels in centenarians. DESIGN: Cross-sectional survey. SETTING: Centenarians living in two northern Italian provinces. PARTICIPANTS: Thirteen cognitively normal centenarians, ten cognitively impaired not-demented centenarians, and 34 demented centenarians with a clinical diagnosis of Alzheimer's disease (AD). MEASUREMENTS: Blood levels of homocysteine's biological determinants vitamin B12, folate, and vitamin B6. RESULTS: Elevated plasma tHcy levels (>17 micromol/l) were common in the general population (77% of normal centenarians, 100% of cognitively impaired not-demented centenarians, 82% of AD centenarians). Demented centenarians had the lowest folate serum levels. Low or borderline vitamin B12 serum levels (<221 pmol/l) and low vitamin B6 plasma levels (<11.7 nmol/l) were found in 33 and 66% of all centenarians independently of cognitive status. Among demented centenarians only plasma tHcy correlated inversely with both serum vitamin B12 and folate. No significant difference was found for plasma tHcy levels among the three diagnostic groups, even after adjusting for B vitamin levels. CONCLUSIONS: Hyperhomocysteinemia is very common among centenarians, probably due to vitamin deficiencies, but does not seem to be associated with cognitive impairment.

Blood. 2000 Dec 15;96(13):4363-5.

Comment in: • Blood. 2001 Jun 15;97(12):4000-2. Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females.

Cazzola M, May A, Bergamaschi G, Cerani P, Rosti V, Bishop DF.

Department of Hematology, University of Pavia Medical School, Italy. m.cazzola@iol.it

X-linked sideroblastic anemia (XLSA) is caused by mutations in the erythroid-specific 5-aminolevulinic acid synthase (ALAS2) gene. An elderly woman who presented with an acquired sideroblastic anemia is studied. Molecular analysis revealed that she was heterozygous for a missense mutation in the ALAS2 gene, but she expressed only the mutated gene in reticulocytes. Her 2 daughters and a granddaughter were heterozygous for this mutation, had normal hemoglobin levels, and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia both in the proband and her grandson. All women who were analyzed in this family showed skewed X-chromosome inactivation in leukocytes, which indicated a hereditary condition associated with unbalanced lyonization. Because the preferentially active X chromosome carried the mutant ALAS2 allele, acquired skewing in the elderly likely worsened the genetic condition and abolished the normal ALAS2 allele expression in the proband. (Blood. 2000;96:4363-4365)

Eur J Clin Invest. 2000 Dec;30(12):1083-9. Role of homocysteine, cystathionine and methylmalonic acid measurement for diagnosis of vitamin deficiency in high-aged subjects.

Herrmann W, Schorr H, Bodis M, Knapp JP, Muller A, Stein G, Geisel J.

University Hospital of the Saarland, Homburg/Saar, Germany. kchwher@med-rz.uni-sb.de

BACKGROUND: Intracellular B-vitamin and folate deficiency indicated by hyperhomocysteinemia is very frequent in the elderly population. Hyperhomocysteinemia increases the risk of atherothrombotic diseases and neuropsychiatric complications. Our aim was to evaluate the prevalence of increased serum metabolite concentrations in subjects of a higher age, and whether the measurement of metabolite concentrations is more effective in diagnosing B-vitamin deficiency than mere homocysteine. MATERIALS AND METHODS: Homocysteine (HCY), cystathionine (CYS) and methylmalonic acid (MMA) were investigated in serum together with vitamin B-12, B-6 and folate in 90 high-aged subjects (85-102 years), 92 seniors (65-75 years), and in 50 younger subjects (19-50 years). RESULTS: Elderly subjects (high-aged and senior) had elevated serum concentrations of metabolites. High-aged subjects had a higher frequency of pathological increases than seniors: HCY 62% vs. 24%; MMA 62% vs. 23%; CYS 81% vs. 36%. Folate and vitamin B-6 concentrations were significantly decreased in both elderly groups; vitamin B-12 was only decreased in high-aged subjects. Utilising vitamin B-6, B-12 and folate for diagnosis of intracellular vitamin deficiency, the rate was 30% in seniors and 55% in high aged subjects. However, utilising the metabolites (HCY, MMA and CYS) for the diagnosis of intracellular vitamin deficiency, there was a distinctly increased rate of 55% in seniors respective to 90% in high-aged subjects. Backward multiple regression analysis revealed that only folate, MMA, creatinine and age were independent variables influencing the HCY concentration. Furthermore, the MMA concentration was significantly and independently influenced by folate, vitamin B-12, HCY and creatinine, and the serum concentration of CYS by vitamin B-12, creatinine and age. CONCLUSION: The metabolites HCY, MMA and CYS are sensitive indicators diagnosing impaired remethylation of homocysteine to methionine with parallel activation of catabolic pathway. Compared to mere HCY or B-vitamins in serum, the efficiency of diagnosing a disturbed HCY metabolism increases very much in utilising the metabolites HCY, MMA and CYS. For differential diagnosis, parallel measurement of folate and creatinine is recommended. The early and correct diagnosis of B-vitamin deficiency in elderly subjects is of high clinical relevance.

Int Angiol. 2000 Dec;19(4):369-72.

Extensive deep vein thrombosis in a young woman. Case report.

De Backer T, Voet J, De Buyzere M, Vertongen P, Tsjoen G, Duprez D, Clement D.

Department of Cardiology, Dijkzigt Ziekenhuis, Erasmus University, Rotterdam, The Netherlands.

We report a case of a young lady with an extensive deep vein thrombosis (DVT) diagnosed by CT scan and duplex ultrasound examination. Contributory factors were relative immobilisation, oral contraception and hyperhomocysteinemia after methionine loading. No other thrombophilic factors could be found. The three main causes of hyperhomocysteinemia are genetic defects, nutritional deficiencies and insufficient elimination. In our case a genetic defect for one of the key enzymes of homocysteine metabolism, may be the underlying cause. Besides stopping oral contraceptive drugs, anticoagulation and supplementation with pyridoxine and folate was started. Family screening was carried out and revealed other members with hyperhomocysteinemia. Whether therapy with pyridoxine and folate can substantially reduce the recurrence of venous thromboembolic disease remains to be established.

Postgrad Med J. 2000 Dec;76(902):791-3. Reiter's syndrome following intravesical BCG immunotherapy.

Hogarth MB, Thomas S, Seifert MH, Tariq SM.

Department of Rheumatology, St Mary's Hospital, Praed Street, London W2 1NY, UK.

A 71 year old woman developed conjunctivitis, asymmetrical oligoarthritis, and cystitis (Reiter's syndrome) secondary to intravesical BCG treatment for transitional cell carcinoma of the bladder. She received oral prednisolone, izoniazid, and pyridoxine and made a full recovery. Increasing use of BCG as immunotherapy will lead to an increase in the incidence of BCG associated reactive arthritis. Prompt recognition and early diagnosis will facilitate treatment and recovery.

Br J Nutr. 2000 Nov;84 Suppl 1:S155-9. Bioactive substances in milk with properties decreasing risk of cardiovascular diseases.

Pfeuffer M, Schrezenmeir J.

Federal Dairy Research Center, Department of Physiology and Biochemistry of Nutrition, Kiel, Germany. pfeuffer@bafm.de

Milk is often seen as a potential promotor of atherosclerosis and coronary heart disease because it is a source of cholesterol and saturated fatty acids. But there are several studies indicating that milk and milk products may not affect adversely blood lipids as would be predicted from its fat content and fat composition. There are even factors in milk and milk products which may actively protect from this condition by improving several risk factors. Calcium, bioactive peptides and as yet unidentified components in whole milk may protect from hypertension, and folic acid, vitamin B6 (pyridoxine) and B12 (cyanocobalamin) or other unidentified components of skim milk may contribute to low homocysteine levels. Conjugated linoleic acid may have hypolipidaemic and antioxidative and thus antiatherosclerotic properties. Epidemiological studies suggest that milk and milk products fit well into a healthy eating pattern emphasizing cereals and vegetables.

Endocr Pract. 2000 Nov-Dec;6(6):435-41.

Hyperhomocysteinemia in type 2 diabetes mellitus: cardiovascular risk factors and effect of treatment with folic acid and pyridoxine.

Baliga BS, Reynolds T, Fink LM, Fonseca VA.

Department of Pathology, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, Arkansas, USA.

OBJECTIVE: To determine whether hyperhomocysteinemia (HH) exacerbates other cardiovascular risk factors and markers of coagulation and hemostasis in patients with type 2 diabetes mellitus (DM) and whether treatment of HH with vitamins will alter these risk factors. METHODS: We measured several cardiovascular risk factors and markers of coagulation and hemostasis in patients with type 2 DM with and without HH. We also treated patients with type 2 DM and coexistent HH with high doses of folic acid and pyridoxine to determine whether this treatment would lower plasma total homocysteine concentrations as well as correct other associated cardiovascular risk factors in this population. RESULTS: Plasma levels of plasminogen activator inhibitor type 1 and fibrinogen were significantly higher in all patients with DM in comparison with control subjects (P<0.01), whether they had HH or not. No significant difference was noted between the two groups of patients with DM. The presence of hypertension and microalbuminuria did not lead to a higher plasma total homocysteine. After treatment with folic acid, 15 mg daily, and pyridoxine, 600 mg daily, fasting (basal) plasma total homocysteine declined significantly in patients with DM from 12.3 +/- 2.9 micromol/L to 9.1 +/- 1.1 micromol/L (P<0.01). The peak post-methionine load plasma total homocysteine in the patients with DM decreased from 39.9 +/- 11.4 micromol/L to 30.4 +/- 6.5 micromol/L (P<0.05). Neither fasting nor peak plasma total homocysteine changed in normal subjects. None of the cardiovascular risk factors measured changed significantly with the vitamin treatment. CONCLUSION: The coexistence of type 2 DM and HH does not lead to an exacerbation of abnormalities in the measured variables of coagulation and hemostasis. Treatment with high doses of folic acid and pyridoxine lowers the plasma total homocysteine significantly but does not improve any of the associated cardiovascular risk factors that we measured. Long-term clinical trials should be conducted to determine whether high-dose vitamin treatment will diminish the increased morbidity and mortality associated with cardiovascular disease in patients with type 2 DM.

Arch Neurol. 2000 Oct;57(10):1422-7. Homocysteine and neurologic disease.

Diaz-Arrastia R.

Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9036. RdiazA@mednet.swmed.edu.

Over the last 10 years, there has been an explosion of interest in homocysteine, a sulfur-containing amino acid that occupies a central location in the metabolic pathways of thiol compounds. This interest is primarily because of the realization that hyperhomocysteinemia is an important risk factor for vascular disease, including stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Since elevated homocysteine levels can often be normalized by supplementing the diet with folic acid (folate), pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)), these observations raise the exciting possibility that this inexpensive and well-tolerated therapy may be effective in decreasing the incidence of vascular disease. In addition to its association with cerebrovascular disease, homocysteine may play a role in neurodegenerative disorders, even if only as a marker of functional vitamin B(12) deficiency. Homocysteine is also important to neurologists since most anticonvulsants raise homocysteine levels, an effect that may explain the teratogenic effects of these drugs. Practical knowledge concerning some details of homocysteine metabolism, the diagnosis of hyperhomocysteinemia, and the use of polyvitamin therapy to lower homocysteine levels will be increasingly important in the treatment of patients with neurologic disease. Arch Neurol. 2000;57:1422-1428

Indian J Pediatr. 2000 Oct;67(10):725-8.

Homocystinuria with congenital/developmental cataract.

Sulochana KN, Amirthalakshmi S, Vasanthi SB, Tamilselvi R, Ramakrishnan S.

Biochemistry Research Department, Medical Research Foundation, Sankara Nethralaya, Chennai, India.

The aim of the study is to screen patients for homocystinuria with and without cataract and analyse for homocystine and methionine. Fifty-eight samples from 29 patients, i.e., plasma and urine collected after overnight fasting were analysed by the screening test for homocystine, and paper chromatography for homocystine and methionine. Out of 29 homocystinuric patients, 24 had cataract. Only one had appreciable amounts of methionine in his serum. He also had mental retardation as expected and belongs to Type I. The other types did not have methionine but had only homocystine. There was no mental retardation or ectopia lentis. So they belonged to Types II, III or IV. As there is excess methionine in Type I, with low cystine, cataract may be due to deficiency of cysteine and reduced glutathione and might be averted by suitable therapy, i.e., high cystine-low methionine diet with B6. In other types with low methionine, cataract may be due to decreased availability of amino acids for the synthesis of lens proteins; the treatment of choice should be B12, and folate with methionine.

J Ren Nutr. 2000 Oct;10(4):196-201. Folic acid and pyridoxal-5'-phosphate losses during high-efficiency hemodialysis in patients without hydrosoluble vitamin supplementation.

Leblanc M, Pichette V, Geadah D, Ouimet D.

Nephrology and Biochemistry Department, Maisonneuve-Rosemont Hospital and Guy-Bernier Research Center, University of Montreal, Montreal, Canada.

OBJECTIVES: To determine the serum status in folate, pyridoxal-5'-phosphate (the active moiety of pyridoxine), cobalamin, and total homocysteine of chronic dialysis patients not routinely supplemented with B-complex vitamins and to evaluate induced intradialytic losses during high-efficiency hemodialysis. DESIGN: A cross-sectional study. SETTING: A university medical center providing tertiary care. PATIENTS: Thirty-six chronic dialysis patients (23 men and 13 women, mean age 57+/-13 years) treated since 3.8+/-2.2 years by hemodialysis and not supplemented with hydrosoluble vitamins. METHODS: Thrice-weekly hemodialysis was performed using CT-190G (Baxter, IL) or F-20 (Hospal, St-Leonard, Canada) reused dialyzers with a mean blood flow rate of 371+/-40 mL/min, a dialysate flow rate of 500 mL/min, and a mean session time of 3.7+/-0.4 hours. Prehemodialysis serum vitamin B(12) and homocysteine, and predialysis and postdialysis serum folate, pyridoxal-5'-phosphate, and urea were measured. Blood-side folate and pyridoxal-5'-phosphate clearances were calculated. RESULTS: Predialysis serum total homocysteine was above normal in all patients, with values ranging from 14.4 to 158.0 micromol/L (mean 40.2+/-29.6 micromol/L, median 33.5 micromol/L). Whereas the majority, 21 patients, had evidence of coronary, cerebrovascular, and/or peripheral vascular diseases, there was no difference in total homocysteine in patients with or without vascular disease (respectively, 40.8+/-37.0 micromol/L v 39.4+/-15.1 micromol/L, P = NS). Predialysis serum concentrations of pyridoxal-5'-phosphate were reduced in 20 patients (56%) and were in the lower normal range for 14 patients. Predialysis and postdialysis serum folate concentrations were 12.4+/-6.1 nmol/L and 8.6 +/- 3.6 nmol/L, whereas predialysis and postdialysis serum pyridoxal-5'-phosphate concentrations were 11.1+/-7.5 nmol/L and 8.0 +/-5.9 nmol/L. Percent reduction ratios were 68.4% +/- 6.6% for urea, 26.3%+/-16.0% for folates, and 27.9%+/-14.2% for pyridoxal-5'-phosphate. Blood-side clearances reached 134.7+/-22.2 mL/min for folates and 54.4+/-38.2 mL/min for pyridoxal-5'-phosphate. There was no significant difference in predialysis serum folate and pyridoxal-5'-phosphate in patients with or without evidence of vascular disease. CONCLUSION: This study confirms that: (1) total serum homocysteine levels are very high in chronic hemodialysis patients not supplemented with B-complex vitamins; (2) folate is significantly cleared or lost during high-efficiency hemodialysis; and (3) pyridoxal-5'-phosphate, the active moiety of pyridoxine, is depleted in most chronic hemodialysis patients without supplementation and that high-efficiency hemodialysis contributes to its depletion. Copyright 2000 by the National Kidney Foundation, Inc.

Med Hypotheses. 2000 Oct;55(4):289-93. Increased homocyst(e)ine associated with smoking, chronic inflammation, and aging may reflect acute-phase induction of pyridoxal phosphatase activity.

McCarty MF.

Pantox Laboratories, San Diego, CA 92109, USA.

Smokers, patients with chronic inflammatory disorders, and the elderly, are characterized by increased production of IL-6 as well as increased plasma levels of homocyst(e)ine. Analysis of cirrhotic livers suggests that IL-6 may stimulate the activity of pyridoxal phosphatase in hepatocytes, thereby diminishing pyridoxal phosphate levels, compromising cystathionine beta-synthase activity, and raising plasma homocyst(e)ine. Adequate supplemental intakes of pyridoxine may be corrective in this regard. Copyright 2000 Harcourt Publishers Ltd.

Wei Sheng Wu Xue Bao. 2000 Oct;40(5):528-34.

[The important role of vitamins in the over-production of pyruvic acid]

[Article in Chinese]

Li Y, Chen J, Lun S, Rui X.

Lab of Environmental Biotechnology, School of Biotechnology, Wuxi University of Light Industry, Wuxi 214036.

The effect of nicotinic acid, thiamine, pyridoxine, biotin and riboflavin on the production of pyruvic acid by Torulopsis glabrata WSH-IP303 with glucose as carbon source and NH4Cl as sole nitrogen source was investigated. By using orthogonal experiment method, thiamine was confirmed to be the most important factor affecting the production of pyruvic acid. Based on a certain concentration range of thiamine (0.01-0.015 mg/L), glucose consumption rate can be enhanced by increasing the concentration of nicotinic acid. When the concentration of nicotinic acid, thiamine, pyridoxine, biotin and riboflavin were 8, 0.015, 0.4, 0.04 and 0.1 mg/L, respectively, the concentration and yield to glucose of pyruvic acid reached 52.4 g/L and 0.525 g/g at 48 h in flask culture, respectively. Batch culture was conducted in a 2.5 L fermentor with initial glucose concentration of 120 g/L. By adopting the optimal concentration combination of vitamins, the concentration and yield to glucose of pyruvic acid reached 69.4 g/L and 0.593 g/g at 57.5 h, which were increased by 32.4% and 13% than the best results in flask culture, respectively.

Tidsskr Nor Laegeforen. 2000 Sep 20;120(22):2648-53.

[Nutrition, dietary supplementation and coronary heart disease]

[Article in Norwegian]

Landmark K, Reikvam A.

Institutt for farmakoterapi, Oslo. k.h.landmark@ioks.uio.no

BACKGROUND: During the last decade, lipid lowering agents, in particular statins, have become increasingly important in the treatment of cardiovascular diseases and dyslipidaemias. This might imply that emphasis on diet and supplementary nutrients do not receive sufficient attention. MATERIAL AND METHODS: On the basis of studies of the literature, the scientific documentation for a possible beneficial effect of the following elements are reviewed: intake of fat, fish and fish oil, alpha-linolenic acid, folic acid, vitamin B6 and vitamin B12, nuts, plant sterols and psyllium. RESULTS: Reduced intake of saturated fat causes improvement in serum lipid values and prevents cardiovascular events. Intake of fish, fish oils and alpha-linolenic acid has positive effects on several clinical end points, often without marked decrease in serum cholesterol. Homocysteine appears to be an independent risk factor for cardiovascular diseases, but a causal relationship remains to be proven. The cofactors folic acid, vitamin B6 and B12 reduce the homocysteine level, but effects of this intervention on hard clinical end points are lacking. There are indications that intake of nuts can prevent coronary events. Plant sterols and psyllium in the diet reduce cholesterol levels. INTERPRETATION: Thus, dietary intervention is important in the prevention and treatment of coronary heart disease. Also when drug treatment is indicated, a focus on diet and nutrient supplementation is highly warranted. Some nutrients may have preventive effect in relation to coronary events, despite their small effect on cholesterol levels.

J Intern Med. 2000 Sep;248(3):223-9. The effect of different treatment regimens in reducing fasting and postmethionine-load homocysteine concentrations.

van der Griend R, Biesma DH, Haas FJ, Faber JA, Duran M, Meuwissen OJ, Banga JD.

Departments of Internal Medicine and Clinical Chemistry, Sint Antonius Hospital, Nieuwegei, The Netherlands.

OBJECTIVES: To determine the homocysteine-lowering effect of different treatment regimens on both fasting and postmethionine-load plasma total homocysteine (tHcy) concentrations. DESIGN: Descriptive study of consecutive hyperhomocysteinaemic subjects per treatment regimen. Homocysteine was measured in the fasting state and 6 h after methionine loading, both before and after 8 weeks of vitamin therapy. Hyperhomocysteinaemia was defined as a fasting tHcy and/or increase in tHcy (postmethionine-load minus fasting tHcy concentration) exceeding the 95th percentile of local controls. SETTING: Outpatient clinic of internal medicine of a large non-academic teaching hospital. SUBJECTS: One hundred and seventeen hyperhomocysteinaemic subjects (vascular patients and first-degree relatives). INTERVENTIONS: There were four regimens: pyridoxine, 200 mg; folic acid, 5 mg; combination of folic acid 0.5 mg and pyridoxine 100 mg; and folic acid, 0.5 mg daily. RESULTS: All regimens, except pyridoxine 200 mg, significantly reduced fasting tHcy without differences in the percentage reduction (32-38%). All regimens produced a significant reduction in the increase in tHcy and postmethionine-load tHcy. The reduction in postmethionine-load tHcy was smaller for pyridoxine 200 mg than for combination therapy. No differences were found in the percentage reduction (for both increase in tHcy and postmethionine-load tHcy) between folic acid 5 mg and folic acid 0.5 mg. CONCLUSIONS: Monotherapy folic acid (0.5 mg daily) is the lowest effective therapy for reducing both fasting and postmethionine-load tHcy concentrations, with the same results as high-dose folic acid (5 mg daily). Pyridoxine has no additional value.

Mol Cell Biochem. 1999 Jul;197(1-2):79-85.

Vitamin B6-deficient diet plus 4-deoxypyridoxine (4-DPD) reduces the inflammatory response induced by T. spiralis in diaphragm, masseter and heart muscle tissue of mice.

Frydas S, Papaioanou N, Vlemmas I, Theodoridis I, Anogiannakis G, Vacalis D, Trakatellis A, Barbacane RC, Reale M, Conti P.

Immunology Division, University of Chieti School of Medicine, Italy.

Animals fed diets deficient in vitamin B6 develop microcytic anemia, alterations of growth, and other pathologies. 4-deoxypirydoxine is a potent antagonist of vitamin B6 coenzyme which depresses IL-1, TNF and IL-6 and has anti-inflammatory properties. The aim of this study was to show the anti-inflammatory effects of 4-DPD on chronic inflammation caused by the nematode parasite T. spiralis, specifically on the recruitment and the activation of inflammatory cells. Two groups of mice, 6 weeks of age, were used: one was maintained on a vitamin B6-deficient synthetic pellet diet for 15 days before injection of the nematode, and administered an intraperitoneal injection (i.p.) of 4-DPD (250 microg/mouse) for 15 days (the first, 5 days before infection), and the second group was maintained on a normal diet for the total duration of the experiment. These two groups were then injected with 150 larvae (L1-T7 spiralis) per os. Chronic inflammation was caused by infection of treated or untreated mice with T7 spiralis parasite. After 14 days post-infection all mice developed a chronic inflammatory response. Mice fed with a B6-deficient diet showed a significant decrease in the number of cysts found in the diaphragm when compared to mice treated with normal diet. In addition, in all mice treated with vitamin B6-deficient diet plus 4-DPD the average body weight was significantly lower, compared to the mice on normal diet in all weeks examined. Moreover, in sections of the diaphragm, masseter and myocardium muscles, the infiltration of inflammatory cells, such as macrophages, lymphocytes, and eosinophils were more intense in untreated mice compared to those fed a vitamin B6-deficient diet. These results show that BALB/c mice infected with T. spiralis and fed a vitamin B6-deficient diet plus the vitamin B6 antagonist, 4-DPD, prolong the time of invasion of the larvae in the muscle cells, influence the recruitment of inflammatory cells and the intensity of the inflammatory reaction compared to infected untreated mice (control).

Nutr Hosp. 1999 Jul-Aug;14(4):164-9.

[Adjustment of the average diet offered by the Valencian Charity Association to the nutritional recommendation for the adult population]

[Article in Spanish]

Farre Rovira R, Frasquet Pons I, Martinez Martinez MI.

Facultat de Farmacia, Universitat de Valencia, Estudi General, Espana.

For several reasons, in industrialized countries like ours, there is a growing number of people who require institutional or private help to survive. The Valencian Charity Association has been running a free dining hall for more than 300 people since 1906, which serves lunch (2 courses, bread, fruit, and a dairy product) and a sandwich dinner. The objective of this study is to evaluate the degree of adjustment of the diet offered to the nutritional needs of those who eat there. For this, we calculated the amounts of each of the foods included in a monthly menu, expressed in g or ml per person per day, and these are transformed into energy supply and nutritional supply, and these are then compared to the recommended ingestion of the Spanish population. The menus provided, considered to be the sole dietary intake of those eating there, provide proteins, thiamin, cyanocobalamine, retinol, and vitamin C in amounts that are similar or greater than those recommended for both sexes and all age groups, while the zinc, magnesium, pyridoxine, folates, and tocopherol quantities are less than 54% of the recommended ingestion for the groups with the greatest needs (adolescents or pregnant or lactating women). Supplementing the basic diet with a breakfast (glass of whole milk with sugar and Maria cookies), a yogurt, a portion of dried fruits, and a portion of fruit for dinner, would increase the supply of magnesium, folates, and vitamin E to levels that meet the requirements of the most needy, those of pregnant and lactating women, but the levels of pyridoxine would continue to be low, just like in other studies, and the recommended intake levels hereof appear unattainable even if this diet is supplemented with nutrients that can easily be accessed by this population group.

An Esp Pediatr. 1999 Jun;50(6):576-80.

[The benefits and risks of following dietary guidelines aimed at decreasing cardiovascular risk from childhood]

[Article in Spanish]

Ortega Anta RM.

Departamento de Nutricion, Facultad de Farmacia, Universidad Complutense, Madrid.

OBJECTIVE: In recent years much attention has been given to the possibility of establishing precocious dietary recommendations which might help reduce the risk of cardiovascular disease later in life. The aim of the present review is to analyze the possible risks associated with such practices. RESULTS: Some authors suggest that restriction of total fat, saturated fat and cholesterol intake might lead to nutritional imbalances and deficiencies in minerals and vitamins, especially fat-soluble vitamins, pyridoxine, riboflavin, calcium, zinc, iron, iodine and magnesium. It might also be associated with changes in the growth and development of children, increased risk of cardiovascular disease and mortality due to other causes. All authors and organizations agree that in children, the principle objective should be that the diet provides the correct quantities of energy and nutrients in order for them to achieve optimum growth and development. With respect to the prevention of cardiovascular disease, it would seem best that a slow transition occur from the high fat intake of early infancy to those recommended in adult life (less than 30% of energy from fats, less than 10% from saturated fat and less than 300 mg/day cholesterol). CONCLUSIONS: In general, a transition stage should be respected with a gradual decrease in the amount of fat consumed between the age of two years and the end of the growth period. When restriction diets are absolutely necessary, their criteria should be carefully considered. The nutritional status of children following such diets should be monitored so that the fight against cardiovascular disease does not condition nutritional deficiencies with repercussions similar to, or even more serious than, the condition they intend to avoid.

Atherosclerosis. 1999 Jun;144(2):419-27. Antioxidants, but not B-group vitamins increase the resistance of low-density lipoprotein to oxidation: a randomized, factorial design, placebo-controlled trial.

Woodside JV, Young IS, Yarnell JW, Roxborough HE, McMaster D, McCrum EE, Gey KF, Evans A.

School of Clinical Medicine, Queen's University of Belfast, Northern Ireland, UK.

We have conducted an intervention trial to assess the effects of antioxidants and B-group vitamins on the susceptibility of low-density lipoprotein (LDL) to oxidation. A total of 509 men aged 30-49 from a local workforce were screened for total plasma homocysteine. The 132 selected (homocysteine concentration > or = 8.34 mumol/l) men were randomly assigned, using a factorial design, to one of four groups receiving supplementation with B group vitamins alone (1 mg folic acid, 7.2 mg pyridoxine, 0.02 mg cyanocobalamin), antioxidant vitamins (150 mg ascorbic acid, 67 mg alpha-tocopherol, 9 mg beta-carotene), B vitamins with antioxidant vitamins, or placebo. Intervention was double-blind. A total of 101 men completed the 8-week study. The lag time of LDL isolated ex vivo to oxidation (induced by 2 mumol/l cupric chloride) was increased in the two groups receiving antioxidants whether with (6.88 +/- 1.65 min) or without (8.51 +/- 1.77 min) B-vitamins, compared with placebo (-2.03 +/- 1.50) or B-vitamins alone (-3.34 +/- 1.08) (Mean +/- S.E., P < 0.001). Antibodies to malondialdehyde (MDA) modified LDL were also measured, but there were no significant changes in titers of these antibodies in any group of subjects whether receiving antioxidants or not. Contrast analysis showed that there was no interaction between antioxidants and B-group vitamins. This study indicates that while B-group vitamins lower plasma homocysteine they do not have an antioxidant effect. Thus B-group vitamins and antioxidants appear to have separate, independent effects in reducing cardiovascular risk.

Cancer Epidemiol Biomarkers Prev. 1999 Jun;8(6):513-8. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.

Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M.

University of Utah Medical School, Salt Lake City 84108, USA.

Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12.

Clin Invest Med. 1999 Jun;22(3):106-10.

Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation.

Emelianova S, Mazzotta P, Einarson A, Koren G.

Department of Pediatrics, Hospital for Sick Children, Toronto, Ont.

OBJECTIVE: Although nausea and vomiting of pregnancy is the most common medical condition during pregnancy, there are many unanswered questions regarding its cause, epidemiologic features and optimal management. The objectives of this study were to ascertain the prevalence of nausea and vomiting in a sample of Canadian women, to characterize the distribution of their severity and to investigate the role of vitamin B6 deficiency in their etiology. DESIGN: Prospective study. SETTING: Antenatal counselling service for pregnant women. PATIENTS: Three cohorts of women: a prospective, population-based cohort of 193 women, to estimate the rate and severity of nausea and vomiting (cohort A); a cohort of 555 women who sought advice for nausea with or without vomiting, to study the correlation between the maximal daily number of episodes of vomiting and maximal weight loss (cohort B); and a prospective cohort of 301 women who reported vomiting, to correlate vitamin supplementation with vomiting (cohort C). INTERVENTIONS: All 3 cohorts were interviewed during the counselling session, and cohort B was followed up prospectively. OUTCOME MEASURES: Frequency of nausea and vomiting, weight loss, maximal number of daily episodes of vomiting, rate of multivitamin supplementation. RESULTS: Overall, 67% of the women in cohort A reported experiencing nausea or vomiting, or both; 22% reported vomiting, and 9% experienced weight loss. In cohort B there was a significant correlation between the maximal number of daily episodes of vomiting and maximal weight loss, although there was wide variation (r2 = 0.25, p < 0.001). There was a highly significant correlation between the number of daily vomiting episodes and mean weight loss (r2 = 0.99). In cohort C, vomiting was significantly associated with lack of supplementation with multivitamins before 6 weeks' gestation (p = 0.002). CONCLUSIONS: The relation between number of daily vomiting episodes and mean weight loss may serve as a clinical tool to assess the severity of nausea and vomiting in pregnancy and the success of anti-emetics and rehydration regimens. Further study is needed to elucidate the biologic basis of the observed association between vomiting and lack of multivitamin supplementation in early pregnancy.

J Am Soc Nephrol. 1999 Jun;10(6):1287-96. Effects of high-dose folic acid and pyridoxine on plasma and erythrocyte sulfur amino acids in hemodialysis patients.

Suliman ME, Divino Filho JC, Barany P, Anderstam B, Lindholm B, Bergstrom J.

Department of Clinical Science, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden.

In this investigation, sulfur amino acids (sAA) and sulfhydryls were determined in the plasma and erythrocytes (RBC) of 10 uremic patients on regular hemodialysis (HD) treatment and 10 healthy subjects, before and after supplementation with 15 mg/d of folic acid and 200 mg/d of pyridoxine for 4 wk. The basal total plasma concentrations of homocysteine (Hcy), cysteine (Cys), cysteinylglycine (Cys-Gly), gamma-glutamylcysteine (gamma-Glu-Cys), glutathione (GSH), and free cysteinesulfinic acid (CSA) were significantly higher in HD patients when compared to healthy subjects, whereas methionine (Met) and taurine (Tau) concentrations were the same in the two groups. HD patients showed significantly higher RBC levels of Hcy and Cys-Gly, whereas the RBC concentrations of Met, Cys, Tau, and GSH were not different from those in the healthy subjects. The plasma concentrations of sAA and sulfhydryls differed compared with RBC levels in the healthy subjects and HD patients. In both groups, supplementation with high doses of folic acid and pyridoxine reduced the plasma Hcy concentration. In addition, increased plasma concentrations of Cys-Gly and GSH were found in the HD patients and of CSA in the healthy subjects. After vitamin supplementation, the RBC concentrations of Hcy, Cys, and GSH increased and that of Tau decreased in healthy subjects. The only significant finding in RBC of HD patients was an increase in GSH levels after supplementation. This study shows several RBC and plasma sAA and sulfhydryl abnormalities in HD patients, which confirms earlier findings that RBC and plasma pools play independent roles in interorgan amino acid transport and metabolism. Moreover, high-dose supplementation with folic acid and pyridoxine significantly reduced Hcy levels, but did not restore the sAA and sulfhydryl abnormalities to normal levels. The increase that was observed in GSH after vitamin supplementation may have a beneficial effect in improving blood antioxidant status in uremic patients. Finally, the findings of elevated plasma Cys levels correlating to the elevated plasma Hcy levels in the presence of elevated plasma CSA levels, both before and after vitamin supplementation, led to the hypothesis that a block in decarboxylation of CSA is linked to hyperhomocysteinemia in end-stage renal failure.

Pharmacol Toxicol. 1999 Jun;84(6):274-80.

Nicotinic acid and pyridoxine modulate arachidonic acid metabolism in vitro and ex vivo in man.

Saareks V, Mucha I, Sievi E, Riutta A.

Department of Pharmacological Sciences, University of Tampere, Finland.

The in vitro effects of nicotinic acid (10-1000 microM), pyridoxine (0.1-500 microM) and pyridoxal-5'-phosphate (0.1-500 microM) and the ex vivo effects of nicotinic acid (2500 mg orally during 12 h) and pyridoxine (600 mg orally daily for seven days) on arachidonic acid metabolism were investigated in calcium ionophore A23187 (calcimycin)-stimulated human whole blood. In vitro nicotinic acid stimulated prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis. Pyridoxine at all concentrations and pyridoxal-5'-phosphate at the highest concentration stimulated prostaglandin E2 and thromboxane B2 production, but had no effect on leukotriene E4 synthesis. Nicotinic acid treatment increased ex vivo prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis to 185%, 165% and 175% of the initial values, respectively. In the pyridoxine-treated subjects, ex vivo prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis was decreased after seven days to 75%, 65% and 45% of the initial values, respectively. In the present study the effects of nicotinic acid on the 5-lipoxygenase pathway in arachidonic acid metabolism were studied for the first time and the drug was found to stimulate this pathway in vitro and ex vivo. In vitro pyridoxine and pyridoxal-5'-phosphate had no effect on the 5-lipoxygenase pathway. The inhibition of leukotriene synthesis by pyridoxine ex vivo might be of therapeutic importance.

Rev Med Liege. 1999 Jun;54(6):541-7.

[Homocysteine and cardiovascular risk]

[Article in French]

Lutteri L, Chapelle JP, Gielen J.

Service de Chimie medicale, Universite de Liege.

Homocystinuria is an uncommon genetic disease characterized by a marked increase of serum homocysteine (HCY), an intermediate of methionine metabolism. In patients with homocystinuria, hyperhomocysteinemia promotes the development of atherosclerotic lesions and is responsible for premature coronary artery disease. Recently, several studies have also demonstrated that moderate hyperhomocysteinemia--not necessarily linked to an inborn metabolic defect--may also be considered as an independant risk factor for cardiovascular disease. The main mechanisms of HCY atherogenic action are thought to be LDL oxydation, inhibition of vascular endothelium growth combined with stimulation of smooth muscular cells proliferation, and interference with the coagulation and fibrinolytic systems. Cofactors of key enzymes in HCY metabolism, folic acid, vitamin B12 and vitamin B6, may be given, alone or in combination, for the treatment of hyperhomocysteinemia. Homocysteinemia can be assessed by basal plasma HCY concentration and/or by HCY levels measured after a methionine loading test. Mainly measured till now in specialized laboratories using rather complex techniques (HPLC, GCMS, amino acid analyser ...), HCY determination is today spreading widely owing to the development of automated immunoassays.

Vet Hum Toxicol. 1999 Jun;41(3):175-7.

Comment in: • Vet Hum Toxicol. 1999 Oct;41(5):342.

Seizures induced by theophylline and isoniazid in mice.

Bonner AB, Peterson SL, Weir MR.

Department of Pediatrics, Scott & White Clinic and Memorial Hospital, Scott, Sherwood and Brindley Foundation, Texas A&M University Health Science Center, College of Medicine, Temple 76502, USA.

Isoniazid-induced seizures respond poorly to anticonvulsants but well to pyridoxine (Vitamin B6); theophylline produces difficult-to-treat seizures with substantial morbidity and mortality. Theophylline therapy depresses plasma pyridoxal-5'-phosphate (PLP), the active metabolite of pyridoxine, suggesting that theophylline-induced seizures might be amenable to treatment with pyridoxine. Our study established the dose-response relationship for convulsions due to isoniazid and theophylline in mice and determined if pyridoxine antagonized such seizures. Female CD-1 outbred mice weighing 25 to 30 g were used. Clonic seizures had clonic activity lasting 5 sec; tonic seizures had loss of the righting reflex with tonic hindlimb extension. Groups of 10 mice received single doses of 50, 100, 150, 200, 250 or 300 mg aminophylline/kg i.p. or 100, 150, 200, 250, 300 or 350 mg isoniazid/kg i.p. and were observed for seizures or death. Pyridoxine or saline with aminophylline or isoniazid were administered simultaneously. The LD50 for aminophylline was 266 mg/kg; for isoniazid it was 160 mg/kg. Doses of 150 mg aminophylline/kg or 100 mg isoniazid/kg did not induce seizures. Pyridoxine with aminophylline or isoniazid did not alter the frequency or time of onset of seizures or death. This was unexpected because pyridoxine antagonizes theophylline-induced seizures in mice and reverses isoniazid-induced seizures in humans. We found no evidence that PLP depletion in mice is a mechanism for seizures induced by isoniazid or aminophylline in a fashion similar to isoniazid in humans.

BMJ. 1999 May 22;318(7195):1375-81.

Comment in: • ACP J Club. 1999 Nov-Dec;131(3):60. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review.

Wyatt KM, Dimmock PW, Jones PW, Shaughn O'Brien PM.

Academic Department of Obstetrics and Gynaecology, North Staffordshire Hospital, Stoke on Trent ST4 6QG.

OBJECTIVE: To evaluate the efficacy of vitamin B-6 in the treatment of premenstrual syndrome. DESIGN: Systematic review of published and unpublished randomised placebo controlled trials of the effectiveness of vitamin B-6 in the management of premenstrual syndrome. SUBJECTS: Nine published trials representing 940 patients with premenstrual syndrome. MAIN OUTCOME MEASURES: Proportion of women whose overall premenstrual symptoms showed an improvement over placebo. A secondary analysis was performed on the proportion of women whose premenstrual depressive symptoms showed an improvement over placebo. RESULTS: Odds ratio relative to placebo for an improvement in overall premenstrual symptoms was 2.32 (95% confidence interval 1.95 to 2.54). Odds ratio relative to placebo for an improvement in depressive symptoms was 1.69 (1.39 to 2.06) from four trials representing 541 patients. CONCLUSION: Conclusions are limited by the low quality of most of the trials included. Results suggest that doses of vitamin B-6 up to 100 mg/day are likely to be of benefit in treating premenstrual symptoms and premenstrual depression.

Int J Vitam Nutr Res. 1999 May;69(3):187-93.

Lowering of homocysteine concentrations in elderly men and women.

Bronstrup A, Hages M, Pietrzik K.

Department of Pathophysiology, University of Bonn, Germany.

B-vitamin supplementation has previously been shown to lower the concentration of plasma total homocysteine, a risk factor for cardiovascular disease. Little is known about the homocysteine-lowering effects of low-dose B-vitamins in elderly individuals, who are prone to higher homocysteine levels due to advanced age and a greater frequency of impaired vitamin status. We aimed to identify if and to what extent B-vitamins lower total homocysteine and its subfractions in elderly individuals. Men and women (> or = 60 years) received either B-vitamins (400 micrograms folic acid + 1.65 mg pyridoxine + 3 micrograms cyanocobalamin) or a placebo daily for 4 weeks. Subjects in the vitamin group showed a significant decrease in plasma total homocysteine during the first 2 weeks; thereafter, total homocysteine only slightly decreased further resulting in a geometric mean reduction of -16.3% (95% CI: -11.3% to -21.0%) over the entire treatment period. Free homocysteine decreased as well. However, the observed higher ratio of free/total homocysteine after 4 weeks of supplementation suggest a more pronounced reduction in protein-bound homocysteine. Low-dose B-vitamin supplementation is effective in lowering homocysteine in elderly individuals. Further studies are needed to be able to depict the effect of B-vitamin supplementation on different homocysteine sub-fractions in plasma.

Rev Port Cardiol. 1999 May;18(5):507-14.

[Homocysteinemia and vascular disease--a new risk factor is born]

[Article in Portuguese]

Reis RP, Luis AS.

Hospital Pulido Valente, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa.

In recent years there has been growing evidence that high levels of plasmatic homocysteine constitute an independent risk factor for early cardiovascular disease. In this article we review the main theories of atherosclerosis which take into account the proteins, namely homocysteine, homocysteine metabolism, the cause that may be responsible for high levels of homocysteinemia, the pathophysiologic mechanisms of vascular lesion induced by hyperhomocysteinemia, the clinical evidence that homocysteinemia constitutes a vascular risk factor and finally, the evidence that it is possible to control homocysteinemia with supplementation of co-factors of homocysteine metabolism, namely vitamin B6, B12 or folic acid.

Vopr Med Khim. 1999 May-Jun;45(3):246-9.

[Effect of mexidol and its structural components on carbohydrate level and lipid peroxidation in acute stress]

[Article in Russian]

Deviatkina TA, Lutsenko RV, Vazhnichaia EM, Smirnov LD.

Ukraine Medical Stomatological Academy, Poltava.

The influence of mexidol (3-hydroxy-6-methyl-2-ethylpyridine succinate) and its structural components (3-hydroxy-6-methyl-2-ethylpyridine and sodium succinate) and pyridoxine hydrochloride on carbohydrate content and lipid peroxidation was studied in the mouse liver under conditions of stress. Under stress conditions mexidol and pyridoxine exerted positive effects on peroxidation processes; mexidol also normalised glycogen content in the liver.

Am J Epidemiol. 1999 Apr 15;149(8):717-25.

Nausea during pregnancy and congenital heart defects: a population-based case-control study.

Boneva RS, Moore CA, Botto L, Wong LY, Erickson JD.

Epidemic Intelligence Service, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, GA, USA.

The authors investigated the possible association between a mother's nausea during pregnancy and her child's risk for a congenital heart defect using data from the population-based Atlanta Birth Defects Case-Control Study conducted in 1982-1983. Case infants (n = 998) had nonsyndromic congenital heart defects and control infants (n = 3,029) had no congenital defects. Nausea during pregnancy (NP) was graded in eight levels of "severity" based on its onset, frequency, and duration. Level 1, the most severe NP, was associated with a lower risk for a congenital heart defect in the child (odds ratio (OR) = 0.81, 95% confidence interval (CI) 0.67-0.99) compared with no nausea. The lower risk tended to disappear with less severe levels of nausea, and the trend was statistically significant. Overall, early NP (levels 1 to 4 combined) with use of antinausea medication, particularly Bendectin (doxylamine, dicyclomine (dropped from the formulation in 1976), pyridoxine (vitamin B6)), was associated with a lower risk for congenital heart defects compared with: 1) absence of nausea (OR = 0.67, 95% CI 0.50-0.92), and 2) nausea without medication use (OR = 0.70, 95% CI 0.50-0.94). The results suggest that pregnancy hormones and factors or, alternatively, a component of Bendectin (most probably pyridoxine) may be important for normal heart development. These findings outline potential areas for future research on and prevention of congenital heart defects.

Ned Tijdschr Geneeskd. 1999 Apr 3;143(14):705-8.

[Obstetric problems followed by stroke]

[Article in Dutch]

Lubbers MF, Aarnoudse JG, van Doormaal JJ.

Rijksuniversiteit, faculteit der Medische Wetenschappen, Groningen.

Obstetrical problems sometimes portend manifestations of atherosclerosis, as illustrated by two case reports. The first patient had the combination of hyperhomocysteinaemia due to chronic vitamin deficiencies in the diet, and smoking. The second was also a smoker and had a genetically determined mild hyperhomocysteinaemia, aggravated by chronic vitamin deficiencies resulting from poor dietary habits; she also had an increased folic acid requirement because of use of anti-epileptic drugs in combination with a familial predisposition for premature atherosclerotic manifestations. The first patient had four pregnancies, two of which ended in intrauterine foetal death due to placental infarction, and one in the birth of a dysmature boy. The second patient's four pregnancies ended twice in abortion and twice in the birth of a dysmature child; in one of the latter cases placental infarction was observed. Both women subsequently suffered cerebrovascular accidents while in addition, older cerebral infarctions were found to be present. Women with recurrent abortion, pre-eclampsia, placental infarction, placental detachment and foetal growth retardation should be examined, even if other risk factors are also present, for (mild) hyperhomocysteinaemia, and treated for it with vitamin suppletion (folic acid, vitamins B6 and B12), even although admittedly more research is necessary to make certain that such treatment has a preventive effect on the manifestations of this disorder.

Can J Cardiol. 1999 Apr;15 Suppl B:35B-38B.

Hyperhomocyst(e)inemia--determining factors and treatment.

Genest J Jr.

Clinical Research Institute of Montreal, Montreal, Canada. genesti@ircm.qc.ca

Elevated homocyst(e)ine levels are associated with an increased risk of vascular disease, particularly aorto-iliac, coronary and cerebrovascular disease. In patients with confirmed disease, plasma homocyst(e)ine is a strong predictor of death. In addition to B vitamins, folic acid and certain genotypes, renal function is an independent determinant of plasma homocyst(e)ine level. There also may be a polygenic component contributing to elevated homocyst(e)ine levels in confirmed vascular disease. Possible mechanisms of homocyst(e)ine-induced vascular change include proliferation of vascular smooth muscle cells, endothelial cell dysfunction and a procoagulant state. The definition of hyperhomocyst(e)inemia is based on arbitrary cut-points (eg, the 90th percentile). In most populations, this is approximately 15 microM/L. Patients with hyperhomocyst(e)inemia should be treated with at least 400 micrograms of folic acid per day. Alternative treatments are vitamin B6 and B12 supplementation, although optimal doses have yet to be identified.

Can J Cardiol. 1999 Apr;15 Suppl B:31B-34B.

Homocyst(e)ine, vitamins and genetic interactions in vascular disease.

Malinow MR.

Oregon Health Sciences University, Portland, Oregon, USA. malinowr@ohsu.edu

Blood homocyst(e)ine levels are an important, independent and frequent risk factor for clinical atherosclerosis and venous thrombosis. Folic acid, vitamins B6 and B12, renal and thyroid functions, certain medications and certain genotypes are known to modulate plasma homocyst(e)ine levels. Intake of B vitamins through diet, supplementation and fortified foods effectively reduces homocyst(e)ine concentration and thus may reduce the risk of cardiovascular disease. This is true even in individuals who are genetically predisposed to hyperhomocyst(e)inemia. Randomized clinical trials are needed to investigate these effects further.

Clin Nutr. 1999 Apr;18(2):87-91.

The thiamin, riboflavin and pyridoxine status of patients on emergency admission to hospital.

Jamieson CP, Obeid OA, Powell-Tuck J.

Department of Human Nutrition, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, Whitechapel, E1 1BB, U.K.

The aim of this study was to assess the prevalence of thiamin, riboflavin and pyridoxine deficiencies at admission to an acute hospital. One hundred and twenty adult patients were selected at random from those admitted via the Accident and Emergency department over 3 days. Comparisons were made with a group of 80 healthy blood donors sequentially attending a local transfusion centre. The alcohol intake of 500 patients admitted sequentially via the same Accident and Emergency department was also assessed. Erythrocyte transketolase (ETK), glutathione reductase (EGR) and aspartate aminotransferase (EAA) coenzyme activation assays were used to determine thiamin, riboflavin and pyridoxine deficiencies. The prevalences of deficiency states in the inpatient group were 21, 2.7 and 32% for thiamin, riboflavin and pyridoxine deficiencies respectively with 49.2% being deficient in one or more vitamin. The mean alcohol intake in the group of patients in whom this was assessed was 9.7 units per week compared with 10 units per week amongst blood donors. Copyright 1999 Harcourt Publishers Ltd.

Epidemiol Mikrobiol Imunol. 1999 Apr;48(2):71-5.

[Determination of tobacco mosaic viruses and tar carcinogens using electromagnetic resonance in smokers]

[Article in Czech]

Bradna J.

Nemocnice s ambulanci, Kutna Hora.

Distance monitoring of viral diseases in the zone of MHz frequencies makes rapid non-contact investigation of the presence of tobacco mosaic viruses (VTM) in cigarettes and secretions of smokers possible by using electromagnetic resonance. The incidence of VTM in common cigarettes was assessed as well as in several smokers, in dermatitis, arthralgias and in tumours (of the large intestiner, in mastopathy). Also in neuritis of the optic nerve, in suspected sclerosis multiplex of smokers. After sanation of VTM by resonance therapy with Sanator (Bradna AO 272,361) VTM disappeared as well as symptoms of this viral mosaic disease. Electromagnetic resonance with tar made it possible to make this investigation in cigarettes filters after smoking as well as in the secretions of smokers. The authors proved the hastening effect of cigarette smoke with tar on the growth of VTM on cultivation as well as an increase of the bioelectric activity of tumours. It proved possible to abolish the electromagnetic distance action of tar by interaction with pyridsoxine similarly as in foods containing tar (smoked meat, fish, frankfurters, black coffee, cocoa). Filters with pyridoxine proved useful. VTM monitoring was quick, in tumours it was possible to follow the accompanying viral agent as well as the action of cancerogens on their bioelectromagnetic activity. It also made it possible to follow up disintegrating action of MHz resonance frequencies of the Sanator.

J Am Coll Nutr. 1999 Apr;18(2):144-51. The influence of dietary restriction on vitamin B-6 vitamer distribution and on vitamin B-6 metabolizing enzymes in rats.

Wei IL.

Laboratory of Nutrition, School of Nursing, National Yang-Ming University, Taipei, Taiwan.

OBJECTIVE: The purpose of this study was to assess the effect of dietary restriction on tissue distribution of vitamin B-6 vitamers and activities of vitamin B-6 metabolizing enzymes in rats. METHODS: Male rats were subjected to a 40% dietary restriction for 10, 20 or 40 weeks. The tissue vitamin B-6 vitamer concentrations and activities of the vitamin B-6 metabolizing enzymes of the animals were determined. RESULTS: The plasma pyridoxal 5'-phosphate (PLP) concentrations of the diet-restricted (DR) rats were comparable to those of the control group at week ten but were significantly lower at weeks 20 and 40. These significantly lower levels of plasma PLP in DR rats might in part be related to lower hepatic pyridoxal kinase and pyridoxamine (pyridoxine) 5'-phosphate oxidase activities. The urinary 4-pyridoxic acid excretion of the DR groups responded to the reduced food intake and were lower at weeks 10 and 20. Tissue levels of PLP were not affected by dietary restriction. In contrast, greater levels of pyridoxamine 5'-phosphate were found in liver, kidney and heart of the DR animals. CONCLUSION: The duration of dietary restriction influenced the distribution of vitamin B-6 vitamers. When plasma PLP is used to evaluate vitamin B-6 status, the length of dietary restriction should be considered.

J Am Soc Nephrol. 1999 Apr;10(4):840-5. Intake of vitamins B6 and C and the risk of kidney stones in women.

Curhan GC, Willett WC, Speizer FE, Stampfer MJ.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. gary.curhan@channing.harvard.edu

Urinary oxalate is an important determinant of calcium oxalate kidney stone formation. High doses of vitamin B6 may decrease oxalate production, whereas vitamin C can be metabolized to oxalate. This study was conducted to examine the association between the intakes of vitamins B6 and C and risk of kidney stone formation in women. The relation between the intake of vitamins B6 and C and the risk of symptomatic kidney stones were prospectively studied in a cohort of 85,557 women with no history of kidney stones. Semiquantitative food-frequency questionnaires were used to assess vitamin consumption from both foods and supplements. A total of 1078 incident cases of kidney stones was documented during the 14-yr follow-up period. A high intake of vitamin B6 was inversely associated with risk of stone formation. After adjusting for other dietary factors, the relative risk of incident stone formation for women in the highest category of B6 intake (> or =40 mg/d) compared with the lowest category (<3 mg/d) was 0.66 (95% confidence interval, 0.44 to 0.98). In contrast, vitamin C intake was not associated with risk. The multivariate relative risk for women in the highest category of vitamin C intake (> or =1500 mg/d) compared with the lowest category (<250 mg/d) was 1.06 (95% confidence interval, 0.69 to 1.64). Large doses of vitamin B6 may reduce the risk of kidney stone formation in women. Routine restriction of vitamin C to prevent stone formation appears unwarranted.