The aim of this thesis was to study the biomarker homocysteine and other novel potential vascular risk factors for dementia. In an out-patient based study of a cohort of 926 consecutive subjects referred to our Memory Unit during 1996―2000, serum-folate was lower and total plasma homocysteine (tHcy) and serum methyl malonate were higher in subjects being prescribed with B12. In the subgroup diagnosed with dementia and with a positive family history of dementia, tHcy was higher than in the subgroup diagnosed as non-demented. It is necessary to supplement subjects with vitamin B12 deficiency with B12, but our results indicate that it is not sufficient with B12 alone because this gives rise to intracellular folate deficiency. We also found indications of a genetic component in dementia because tHcy was higher in the group with a positive family history of dementia. These findings prompted further studies of homocysteine metabolism. The frequency of mutations in the gene for folate receptor-α (FOLR-1), and the fibrinolytic pattern in dementia and non-dementia were studied in the two cohorts DGM (n=300) and AS (n=389). The DGM cohort is a consecutive series of subjects attending our Memory Care Unit for investigation of suspected cognitive problems or dementia between 2003 - 2007. The AS (= active seniors) cohort comprises retired, apparently healthy subjects from central Sweden, actively participating in study circles. A rare haplotype in the FOLR-1, with mutations in two nearby loci, was discovered, possibly associated with lower serum-folate and higher tHcy concentrations and was more frequent in the DGM group. The transport of folate to the CSF was studied in the DGM-cohort. Dementia with a vascular component was associated with a lower CSF to serum folate ratio indicative of reduced transport of folate to the CSF and further to the brain. The vascular endothelial derived fibrinolytic markers tPA, tPA/PAI-1-complex, and vWF were not only higher in vascular dementia (VaD) but also in Alzheimer’s Disease (AD) when compared to the AS group. The impaired fibrinolytic activity in both vascular dementia and in AD is a novel finding, signifying a vascular component in the development of dementia. In conclusion we found that both hereditary and nutritional background factors were linked to dementia and furthermore that a dysregulated fibrinolysis was linked to both VaD and AD.

Eine erhöhte Konzentration von Homocystein im Plasma (Hyperhomocysteinämie) gilt als unabhängiger Risikoindikator für neuronale und kardiovaskuläre Erkrankungen. Der Präcursor des Homocysteins, Methionin, ist eine essentielle Aminosäure, die bei Fehlernährung übermäßig verzehrt werden kann. Es wurde untersucht, ob tatsächlich durch langfristigen erhöhten Methioninverzehr via Erhöhung des Homocysteinspiegels im Plasma ein reales Gesundheitsrisiko besteht. Als Modell wurde eine Füttterungsstudie an Ratten gewählt, deren Bedingungen bezüglich Fütterungsdauer und Methioningehalt der Diät (0,4 % Methionin für 4 Wochen) an eine mögliche Fehlernährung des Menschen angepasst waren. Bei diesen Ratten war die Plasmahomocystein-Konzentration ca. 2-fach höher, als bei Ratten, die im gleichen Zeitraum eine "normale" Diät mit einem 3-4 fach niedrigeren Methioningehalt bekamen. Neben der Auswirkung der Diät auf den Homocystein-Stoffwechsel wurde geprüft, welche der in der Literatur dargestellten potentiellen Pathomechanismen für Hyperhomocysteinämie-induzierte Schäden Anwendung in diesem Modell finden. Obwohl die Konzentration von Homocystein im Plasma verändert war, wurde keine Beeinträchtigung der Gefäßfunktion gefunden. Auch die Plasmakonzentration von asymmetrischem Dimethylarginin, einem weiteren Risikoindikator für Herz-Kreislauf-Erkrankungen blieb unverändert, obwohl dieser Parameter bei Hyperhomocysteinämie oftmals erhöht ist. Eine Konzentrationsverdoppelung von Homocystein durch erhöhte alimentäre Methioninzufuhr ohne gleichzeitige Erhöhung von ADMA scheint also keine Verschlechterung der Gefäßfunktion bei Ratten zu bewirken. In diesem Punkt kann man von in anderen Modellen der Hyperhomocysteinämie gefundenen Resultaten keine Rückschlüsse auf die durch alimentäres Methionin verursachte Hyperhomocysteinämie ziehen. Andere Modelle zur Induktion einer Hyperhomocysteinämie ist Homocyst(e)in-Fütterung. In weiteren Rattenstudien wurden Effekte homocystin- und methioninreiche Diät verglichen. In diesen Studien zeigte sich, dass bei ähnlichen applizierten Dosen (tägliche Aufnahme ca. 1,0 bzw. 1,4 g/kg Körpergewicht) methionin- und homocystinreiche Diät bei Ratten zu vergleichbaren Plasma-Homocysteinspiegeln führen (methioninreich: 27,32 ± 2,80 µmol/l; homocystinreich: 40,61 ± 2,22 µmol/l). Als Vergleichsparameter zur Beurteilung pathophysiologischer Veränderungen diente zum einen der Gewebsgehalt an Homocystein, zum anderen wurden die intrazellulären Konzentrationen von S-Adenosyl-Methionin (SAM) und S-Adenosyl-Homocystein (SAH) betrachtet. Es zeigten sich besonders in Leber und Niere signifikante Unterschiede zwischen einer methioninreichen und einer homocystinreichen Diät bei Ratten. Dies ist eine mögliche Erklärung dafür, dass die bei vierwöchiger methioninreicher Diät gefundenen Ergebnisse nicht mit Literaturdaten übereinstimmen. Abschließend wurde der Frage nachgegangen, ob eine homocytinreiche Ernährung, wie in der vorherigen Studie angewandt, überhaupt möglich ist. Da zwar die Gehalte von Methionin in fast allen Lebensmitteln bekannt sind, nicht aber die von Homocystein, wurde untersucht, in welchen Konzentrationen Homocystein in Lebensmitteln enthalten ist. In Schwarzbier (0,03 mg/l), Weißbrot (0,95 mg/kg), Roquefort-Käse (0,50 mg/kg), Thunfisch (0,25 mg/kg) und Schweineleber (0,31 mg/kg) konnte Homocystein bestimmt werden. Da die Homocysteinkonzentrationen in diesen Beispiellebensmitteln mindestens um den Faktor 105 geringer waren als die Methioninkonzentrationen ist ein Einfluss von alimentärem Homocystein auf den Plasmaspiegel sehr unwahrscheinlich. Es wurde weiterhin geprüft, ob durch Darmbakterien ein Teil des alimentär aufgenommenen Methionins bereits im Dünndarm in Homocyt(e)in umgewandelt werden könnte. Dabei wurde eine vermehrte Homocysteinproduktion nach Methionin-Zugabe zu Dünndarmisolaten gefunden. Quantitativ kommt dieser Homocysteinquelle eine untergeordnete Bedeutung zu.

Background: Preeclampsia, small for gestational age (SGA), placental abruption, and fetal death are pregnancy complications linked to the utero-placental vasculature with serious consequences for maternal and infant well-being. Elevated homocysteine, a marker of cardiovascular disease risk, is postulated to play a role in placenta-mediated complications, but epidemiologic studies have reported inconsistent findings. The two primary objectives of this thesis were to 1: comprehensively investigate the association of homocysteine with placenta-mediated complications and examine modifying effects of pre-specified factors on this association, and 2: comprehensively investigate determinants of maternal homocysteine during pregnancy. Methods: A systematic review and meta-analysis of prospective studies was conducted to address thesis objective 1. The Ottawa and Kingston (OaK) Birth Cohort, a prospective cohort study that recruited pregnant women between 2002 and 2009, was used to address thesis objectives 1 and 2. Homocysteine concentration was measured between 12 and 20 weeks gestation. Analyses based on the OaK Birth Cohort consisted of multivariable regressions using restricted cubic splines to model associations with continuously distributed variables. Results: Objective 1: In an analysis of 7587 participants, a significant association between homocysteine concentration and a composite outcome of any placenta-mediated complication was observed (odds ratio (OR) for a 5 µmol/L increase: 1.63, 95% Confidence Interval (CI) 1.23-2.16) and SGA (OR 1.76, 95% CI 1.25-2.46), with potential modifying effects of the methylene tetrahydrofolate reductase (MTHFR) 677C>T variant (SGA) and high-risk pregnancy (preeclampsia). In the systematic review identifying 30 prospective cohort or nested case-control studies, a random effects meta-analysis of pooled mean differences in homocysteine between cases and controls in 28 studies revealed significantly higher means for SGA: 0.35 µmol/L (95% CI 0.19 to 0.51, I2=33%); and preeclampsia: 0.87 µmol/L (95% CI 0.52 to 1.21, I2=92%). Significant sources of heterogeneity were study region (SGA and preeclampsia), adjusting for covariates (preeclampsia), folate status (preeclampsia), and severity (preeclampsia). Objective 2: In 7587 OaK participants, factors related to favourable health status were associated with lower maternal homocysteine concentrations. Folic acid supplementation during pregnancy of >1 mg/day did not substantially increase serum folate concentration. Conclusion: This thesis suggests an independent effect of slightly higher homocysteine concentration in the early to mid-second trimester on the risk of any placenta-mediated complication, SGA, and preeclampsia. Modifying effects explain some of the variability in previous studies. Favourable preconception health status was associated with lower maternal homocysteine.

Sulfur amino acids have critical function as intracellular redox buffers and maintain homeostasis in the external milieu by combating oxidative stress. Synthesis of glutathione (GSH) is regulated at a substrate level by cysteine, which is synthesized by homocysteine via the transsulfuration pathway. Oxidative stress and diminished glutathione pools play a sustained role in the pathogenesis of acute pancreatitis. One of the aims of this study was to experimentally address the temporal relationship between plasma sulfur amino acid levels in patients suffering from acute pancreatitis. The data indicated low concentration of cysteine initially, at levels similar to those of healthy controls. Glutathione was found reduced whilst cysteinyl-glycine and ¿- glutamyl transpeptidase activity were increased in both mild and severe attacks. As the disease progressed, glutathione and cysteinyl-glycine were further increased in mild attacks and cysteine levels correlated with homocysteine and ¿-glutamyl transpeptidase activity. The progress of severe attacks was associated with glutathione depletion, reduced ¿-glutamyl transpeptidase activity and increased cysteinyl-glycine, that correlated with glutathione depletion. The corollary that ample supply of cysteine and cysteinly-glycine does not contribute towards glutathione synthesis in acute pancreatitis poses an important issue that merits resolution. Heightened oxidative stress and depletion of glutathione rationalized the progression of disease in severe attacks. An upsurge that reactive oxygen species can shift redox state of cells is determined by the ratio of the abundant redox couples reduced and oxidized glutathione (GSH: GSSG) in cell. The study reported a novel methodology for quantification of total oxidized glutathione (tGSSG) and total glutathione (tGSH) in whole blood using reverse phase high performance liquid chromatography. The novelty of the method is ascertained by the use of a mercaptan scavenger 1, methyl-2-vinyl-pyridinium trifluromethanesulfonate for the total oxidized glutathione determination. The results reported permit quantitation of tGSSG and tGSH and was applied to a control group. Finally, the study was also focussed in developing a liquid chromatography-mass spectrometric method to evaluate free and conjugated bile acids in patients suffering from various degrees of cholestatic-hepatobiliary disorders. The study reported low levels of ursodeoxycholic acid (UDCA) and slightly high levels of lithocholic acid (LCA). All the primary bile acids seem to be conjugated with glycine and taurine amino acid.

Thesis (MPath)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Major Depressive Disorder (MDD) is a severe debilitating medical condition that may lead to suicide. Due to a poor understanding of the biological mechanisms underlying the disease process therapeutic decisions are usually taken using a ‘trial and error’ approach. This is not ideal since many treatments do not work as expected for all individuals. Studies have shown that only half of MDD patients receive the appropriate treatment, whereas many patients have adverse response to anti-depressants. These may include weight gain and raised homocysteine levels that may further compromise the health status of MDD patients and may partly explain the link with cardiovascular disease. The objective of the study was to identify genetic risk factors interacting with environmental factors implicated in MDD that may be of relevance to the South African population. Polymorphisms in the MTHFR (677 C>T, rs1801133 and 1298 A>C, rs1801131), COMT (472G>A, rs4680), CYP2D6 (6937G>A, rs3892097), ASMT (24436 G>A, rs4446909) and SLC6A4 (43 bp ins/del, rs4795541) genes were genotyped in 86 MDD patients and 97 population-matched controls. The specific aims were 1) to analytically validate high throughput real-time polymerase chain reaction (RT-PCR) genotyping assays for the selected SNPs against direct sequencing as the gold standard for 2) possible integration into a pathology-supported genetic testing strategy aimed at improved clinical management of MDD. A total of 183 unrelated Caucasians participated in the study, including 69 females and 17 males with MDD and 57 female and 40 male controls without a personal and family medical history of overlapping stress/anxiety and depressive disorders. All study participants were genotyped for the six selected SNPs considered clinically useful based on international data. The allelic distribution of the SNPs, single or combined into a genotype risk score after counting their minor alleles, did not differ between MDD patients and controls. Homocysteine levels were determined and correlated with body mass index (BMI) and other variables known to influence these phenotypes. The folate score assessed with use of the study questionnaire was significantly lower in the patient group compared with controls (p=0.003) and correlated significantly with BMI, particularly in females (p=0.009). BMI was on average 8% higher in the MDD patients compared with controls (p=0.015) after adjustment for age and sex. The MTHFR rs1801133 677 T-allele was associated with a 14% increase in BMI in MDD patients but not controls (p=0.032), which in turn was associated with significantly increased homocysteine levels (p<0.05). The aims of the study were successfully achieved. Identification of the MTHFR rs1801133 677 T-allele reinforces the importance of adequate folate intake in the diet due to increased risk of obesity and depression found to be associated with low dietary intake. Evidence of shared genetic vulnerability for many chronic diseases and drug response mediated by the MTHFR 677 T-allele support the clinical relevance of this low-penetrance mutation. / AFRIKAANSE OPSOMMING: Major depressie (MD) is ‘n aftakelende siektetoestand wat tot selfdood kan lei. Onkunde oor die siekte se onderliggende biologiese meganismes lei dikwels tot ‘n lukrake terapeutiese benadering. Dit is ‘n onbevredigende situasie aangesien indiwidue verskillend reageer op die middels wat voorgeskryf word. Navorsing toon dat slegs ongeveer die helfte van MD pasiënte toepaslike behandeling kry, terwyl anti-depressante ‘n nadelige uitwerking het op baie pasiënte. Dit sluit massatoename en verhoogde homosisteïenvlakke in wat MD pasiënte se gesondheid bykomend nadelig kan beïnvloed en die verband met kardiovaskulêre siekte gedeeltelik kan verklaar. Hierdie studie poog om MD verwante genetiese risikofaktore en omgewingsfaktore wat mekaar beïnvloed en moontlik op die Suid Afrikaanse bevolking betrekking het, te identifiseer. Polimorfismes in die MTHFR (677 C>T, rs1801133 en 1298 A>C, rs1801131), COMT (472G>A, rs4680), CYP2D6 (6937G>A, rs3892097), ASMT (24436 G>A, rs4446909) en SLC6A4 (43 bp ins/del, rs4795541) gene is geanaliseer in 86 MD pasiënte en 97 kontroles geselekteer van dieselfde populasie. Die spesifieke doelwitte was om 1) hoë deurset direkte polimerase kettingreaksie (RT-PCR) genotiperingstoetse vir die 6 gekose polimorfismes met direkte volgordebepaling as maatstaf analities te valideer vir 2) moontlike insluiting in ‘n patologie-ondersteunde genetiese toetsstrategie met die oog op beter kliniese hantering van MD. Altesaam 183 Kaukasiërs het aan die studie deelgeneem. Die MD pasiënte het uit 69 vroue en 17 mans bestaan. Die kontroles (57 vroue en 40 mans) het geen mediese geskiedenis (persoonlik of familie) van oorvleuelende stress/angstigheid of depressie gehad nie. Gebaseer op internasionale data, is al die deelnemers vir die 6 gekose, potensieel klinies-bruikbare polimorfismes getoets. Die alleliese verspreiding van die polimorfismes enkel of gekombineer (uitgedruk as ‘n genotipe-risiko-syfer nadat minor allele getel is), was dieselfde in MD-pasiënte en kontroles. Homosisteïenvlakke is bepaal en gekorreleer met die liggaamsmassa-indeks (BMI) en ander veranderlikes wat bekend is vir hulle invloed op hierdie fenotipes. In teenstelling met die kontroles, was die folaat telling, soos bepaal met die studievraelys, betekenisvol laer in die pasiënte (p=0.003). Die korrelasie met die liggaamsmassa-indeks, spesifiek by vroue, was ook betekenisvol (p=0.009). Na aanpassings vir ouderdom en geslag, is gevind dat die liggaamsmassa-indeks gemiddeld 8% hoër was in die die MD pasiënte teenoor die kontroles. By MD-pasiënte, maar nie by die kontroles nie, is die MTHFR rs1801133 677 T-alleel geassosieer met ‘n 14% toename in liggaamsmassa-indeks (p=0.032), wat ook geassosieer was met betekenisvolle verhoogde homosisteïenvlakke (p<0.05). Die doelwitte van die studie is bereik. Identifisering van die MTHFR rs1801133 677 T-alleel beklemtoon hoe belangrik dit is om voldoende folaat in te neem, veral omdat ‘n verhoogde risiko vir vetsug en depressie met ‘n lae folaatinname in die diet geassosieer word. Die kliniese belang van die MTHFR 677 T-alleel word beklemtoon deur toenemende bewyse wat daarop dui dat gedeelde genetiese vatbaarheid vir ‘n verskeidenheid van kroniese siektes asook middelrespons aan bemiddeling deur hierdie lae penetrasie mutasie toegeskryf kan word. / Winetech / Technology for Human Resources and Industry Program (THRIP).

This research work has investigated the electrochemistry of glutathione (GSH)and homocysteine (HCSH) in order to develop sensors for these biological thiols.Ru(bpy)33+ and IrCl62− have been used as mediators for the electrooxidation of GSH andHCSH because direct oxidation of these thiols is slow at most conventional electrodes.The electrochemical detection of GSH and HCSH has been pursued because of their biological roles. Concerted proton electron transfer (CPET) and stepwise proton electron transfer(PT/ET) pathways have been observed in the electrooxidation of GSH and HCSH.Oxidation of GSH by Ru(bpy)33+ carried out in deuterated and undeuterated buffered (pH= pD = 5.0) and unbuffered solutions (pH = pD 5.0−9.0) indicates a CPET pathway. AtpH 7.0 buffered solution, the involvement of the buffer was obvious, with rate increasing as the buffer concentration increases − an indication of a general base catalysis. The oxidation of GSH by IrCl62− follows through CPET at pH 7.0 when the optimum concentration of the buffer is established. The plot of the rate vs. buffer concentration gave a curvature at lower buffer concentration and then a plateau at higher concentration,which implies a change in the rate determining step as the buffer concentration increases.At lower buffer concentration, proton transfer was seen to be the rate determining step asthe reduction current increases upon scan rate increase. In the oxidation of HCSH by IrCl62−, CPET was observed at pH = pD values of7.0 and 8.0, whereas PT/ET was seen at pH = pD values of 9.0 and 10. Increase in the buffer concentration at pH 7.0 revealed the contribution of the buffer, in that, the oxidation proceeds more efficiently, seeing that the catalytic peak current shifts more negatively and the peak broadness diminishes. Increase in the temperature for the electrooxidation of HCSH resulted in increase in the rate.

<p>Prema podacima iz 2011 godine, u Srbiji je približno 630 000 ljudi (8,6%) obolelo od dijabetes melitus-a, a procenjuje se da će taj broj porasti na 730 000 (10,2%) do 2030 godine. Preko 90% obolelih ima tip 2 dijabetes melitus (T2DM). Prva linija medikamentne terapije predstavljaju bigvanidi čiji je najznačajniji predstavnik metformin. Prema literaturnim podacima, u oko 10-30% sluĉajeva, kontinuirana upotreba metformina ima za posledicu smanjenu intestinalnu apsorpciju vitamina B12. Tačan patofiziolo&scaron;ki mehanizam koji dovodi do metforminom indukovane malapsorpcije vitamina B12 nije u potpunosti ispitan i poznat i postoji nekoliko aktuelnih teorija s ciljem obja&scaron;njenja ovog kompleksnog problema. Cilj rada je bio utvrđivanje nivoa, dinamike, trenda i učestalosti promena vitamina B12, holotranskobalamina (B12 aktiv), homocisteina i folne kiseline tokom kontinuirane primene metformina tokom godinu dana. Studija praćenja je sprovedena u Centru za laboratorijsku medicinu a u saradnji sa Klinikom za endokrinologiju, dijabetes i bolesti metabolizma, Kliničkog centra Vojvodine. Ovom studijom je obuhvaćeno 50 ispitanika obolelih od T2DM a u momentu uvođenja metformina. Svim ispitanicima je određivana koncentracija vitamina B12, B12 aktiva, homocisteina i folne kiseline, u momentu uvođenja terapije kao i nakon 4, 8 i 12 meseci primene metformina. Za dvanaest meseci kontinuirane primene metformina, utvrđen je kontinuirani pad i redukcija vrednosti ukupnog vitamina B12 za 25.29 %, odnosno vrednosti B12 aktiva za 23.26 %. U toku ispitivanja, utvrđen je kontinuirani trend porasta vrednosti homocisteina u krvi, s statistički značajnim porastom vrednosti homocisteina nakon osam meseci primene metformina. Po&scaron;av&scaron;i od predpostavki da metformin istovremeno blokira apsorpciju vitamina B12 u gastrointestinalnom traktu kao i raspoloživost iz postojećih, tkivnih rezervi, zatečene količine ovog vitamina u ciljnim ćelijama se postepeno redukuju i tro&scaron;e, rezultujući krajnjem snižavanju nivoa metabolički aktivnih oblika kobalamina, te posledičnoj akumulaciji homocisteina kako u ćelijskom, tako i u vanćelijskom prostoru. Na osnovu dobijenih rezultata ispitivanja može se predložiti opservacija nivoa ukupnog vitamina B12 i homocisteina u krvi pre uvođenja metformina u terapiju tipa 2 dijabetes melitusa kao i dvanaest meseci nakon toga. Na osnovu nivoa jednogodi&scaron;njeg pada koncentracija ukupnog vitamina B12, porasta koncentracija homocisteina, kao i drugih kliničkih i laboratorijskih parametara, može se razmatrati opcija uvođenja supstitucione terapije vitaminom B12 ili dalja opservacija nivoa vitamin B12 u krvi i ćelijskom prostoru.</p> / <p>According to data from 2011, in Serbia, approximately 630.000 people (8.6%) were diagnosed with diabetes mellitus, and it is estimated that this number will increase to 730.000 (10.2%) by 2030. Over 90% are type 2 diabetes mellitus (T2DM) patients. The first line of medication therapy is metformin. According to the literature data, in about 10-30% of cases, continuous use of metformin causes impared intestinal absorption of vitamin B12. The exact pathophysiological mechanism leading to metformin induced malabsorption of vitamin B12 has not been fully known, and there are several current theories to explain this complex problem. The aim of this study was to determine the level, dynamics, trend and frequency of changes in blood levels of total vitamin B12, holotranscobalamin (B12 active), homocysteine and folic acid during continuous application of metformin, over a year. The study was carried out at the Center of Laboratory Medicine in cooperation with the Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Vojvodina. This study included 50 T2DM patients at the time of the introduction of metformin therapy. Levels of vitamin B12, holotranscobalamin, homocysteine and folic acid are determined before and after 4, 8 and 12 months of metformin administration, to all subjects. After a year of metformin use, the level of total vitamin B12 has been reduced by 25.29%, as well as holotranskobalamin by 23.26%. During the study, a continuous elevation of homocysteine levels was determined, with statistically significant increase in homocysteine values after eight months of metformin administration. Starting from the assumption that metformin blocks the absorption of vitamin B12 in the gastrointestinal tract as well as the availability of existing tissue reserves, the amount of this vitamin in the target cells is gradually reduced, resulting in an extremely low level of metabolically active forms of this vitamin and the consequent accumulation of homocysteine in intracellular and extracellular space. On the basis of the obtained test results, it may suggest observation of the level of total vitamin B12 and homocysteine prior to the introduction of metformin in T2DM therapy and after one year thereafter. Based on the level of one-year decline of total vitamin B12 and the increase of homocysteine concentrations, as well as other clinical and laboratory parameters, substitution therapy with vitamin B12 or further monitoring of laboratory parameters of vitamin B12 metabolism may be proposed.</p>

A homocisteína plasmática é considerada marcador de risco para doenças cardiovasculares e sua associação com a hipertensão arterial essencial parece ser importante no agravamento desta doença. O exercício físico tem mostrado eficácia na redução da pressão arterial e o ácido fólico suplementar a dieta como a melhor conduta para a redução da homocisteinemia. O objetivo deste trabalho foi verificar o efeito da suplementação de ácido fólico e/ou do exercício físico sobre as concentrações plasmáticas de homocisteína em hipertensos essenciais medicados. Para tanto foram estudados 69 hipertensos (57&#177;10 anos), sendo 22 do sexo masculino e 47 do sexo feminino, divididos em dois grupos: grupo 1 medicado com diurético e grupo 2 medicado sem diurético, sendo o tiazídico o diurético mais utilizado (80%). Foram realizadas avaliações médica, antropométrica, dietética, pressórica, bioquímica e o teste de aptidão cardiorrespiratória. Os indivíduos receberam suplementação com 500 &#181;g/dia de ácido fólico, em estudo do tipo cruzado, e foram submetidos a treinamento com exercícios físicos supervisionados, sendo reavaliados a cada dois meses até o final do estudo. Os grupos foram homogêneos em relação a todas as variáveis estudadas exceto a homocisteína plasmática que foi maior significativamente no grupo 1. Não houve diferença significativa entre os sexos para todas as variáveis estudadas. Os hipertensos eram em sua maioria (62%) não controlados e portadores de síndrome metabólica (77%). O exercício físico apresentou efeito benéfico na reclassificação dos hipertensos leves e moderados para a classe de limítrofes sem normalizar a pressão arterial. Não houve efeito do exercício na composição corporal e na homocisteinemia. A suplementação de ácido fólico reduziu a hiperhomocisteinemia em 11% no grupo 1 e 19% no grupo 2 frente a aumentos similares na folacemia. Em relação à pressão arterial houve normalização da homocisteinemia apenas nos hipertensos com pressão arterial normalizada. Os hipertensos limítrofes e leves apresentaram reclassificação da hiperhomocisteinemia limítrofe para moderada. A presença de diurético potencializou a normalização da pressão pelo exercício físico e indiretamente influenciou, nesses casos, a normalização da homocisteína. Entretanto, a maior redução das concentrações médias de homocisteína ocorreu coma oferta de ácido fólico na ausência de diurético. Desta forma, recomenda-se a adequação dietética do folato como adjuvante terapêutico da hipertensão arterial associadamente ao exercício físico e/ou medicamentos / The plasma homocysteine is considered to be a risk indicator for cardiovascular diseases and its association with essential hypertension seems to be important to the worsening of this disease. Physical exercises are efficient to reduce blood pressure and the dietary supplements of folic acid are considered the best way to decrease homocysteine. The aim of this study was investigate the effect of acid folic supplementation and physical exercises on plasmatic levels of homocysteine in essential hypertensive medicated individuals. In order to that, 69 hypertensive subjects were studied (22 men and 47 women) divided in two groups: group 1 medicated with diuretic and group 2 medicated without diuretic. Medical, anthropometrical, dietetic, blood pressure, biochemistry and cardio-respiratory capacity evaluations were performed. These individuals received 500 &#181;g/dia of folic acid supplementation in a cross-over design and were submitted to daily supervisioned physical exercise. They were evaluated every two months until the end of the study. The groups were similar for all variables except for the homocysteine which was significantly greater in the group 1. There were no difference for the gender to all variables. The high blood pressure was not controlled (62%) and 77% of the patients showed metabolic syndrome. The physical exercise showed benefit on the reclassification of slight and moderated hypertensives to border-line hypertension, however, it did not normalize the blood pressure. There were no effects on the body composition and on homocysteine values . Folic acid supplementation decreased 11% of hyperhomocysteinemia in the group 1 and 19% in group 2 face to similar increases in folate. Regarding to high blood pressure subjects the homocysteine normalization occurred only in hypertensive subjects with normalized blood pressure. The border and slightly hypertensive individuals had border-line hyperhomocysteine wich were reclassificated to moderated c1ass. The use of diuretic enhanced blood pressure normalization with the physical exercise and indirectly influenced the plasma homocysteine normalization. However the greater decreasing mean homocysteine concentration occurred with folic acid but in the diuretic absence. So we strong recommend an adequate folate intake as a terapheutical adjuvant to arterial hypertension treatments either with physical exercise and/or antihipertensive drugs.

A metionina sintase redutase (MTRR) catalisa a redução da cobalamina (Cbl) oxidada a metilcobalamina. Em presença de folato, a metionina sintase (MTR) utiliza a metilcobalamina como cofator na metilação da homocisteína (tHcy) a metionina. O objetivo deste estudo foi avaliar os efeitos dos polimorfismos MTR A2756G e MTRR A66G nas concentrações dos metabólitos marcadores de deficiência de Cbl e folato em gestantes e neonatos. Os genótipos dos polimorfismos MTR A2756G e MTRR A66G foram obtidos por PCR-RFLP. O genótipo MTR 2756AA foi relacionado aos maiores valores de tHcy em gestantes e MMA em neonatos. Gestantes com genótipos MTRR 66AG e GG e com menores concentrações de Cbl apresentaram maior risco de apresentar concentrações elevadas de tHcy. Neonatos com genótipos com MTRR 66AG e GG apresentaram menores valores de SAM. Os polimorfismos MTR A2756G e MTRR A66G interferem nas reações dependentes de Cbl e folato em gestantes e neonatos. / Methionine synthase reductase (MTRR) catalyzes the reductive reaction of oxidized cobalamin to methylcobalamin. When folate is present, methionine synthase (MTR) uses methylcobalamin cofactor at homocysteine to methionine methylation process. The aim of this study was to evaluate the effects of MTR A2756G and MTRR A66G polymorphisms on total homocysteine (tHcy), methylmalonic acid (MMA), S-adenosylmethionine (SAM) concentrations and SAM/SAH ratio in Brazilian pregnant women and their newborns. Genotypes of two polymorphisms were determined by PCR-RFLP. MTR 2756AA genotype was associated with higher tHcy and MMA levels in mothers and babies, respectivelly. Lower cobalamin concentrations associated with MTRR 66AG and GG genotypes increased risk to elevated tHcy levels in pregnant women. The SAM levels were lower in neonates with MTRR 66AG e GG genotypes. The polymorphisms MTR A2756G and MTRR A66G could affect cobalamin and folate dependent reactions in pregnant women and newborns.

No description available.