Increased Plasma Homocysteine Concentrations Research Articles

СООТНОШЕНИЕ H2S/ГОМОЦИСТЕИН КАК ПОТЕНЦИАЛЬНЫЙ БИОМАРКЕР ПРОГНОЗИРОВАНИЯ ПРОГРЕССИРОВАНИЯ АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИИ У ДЕТЕЙ

Background. The H2S/homocysteine ratio is a potential biomarker for predicting the progression of cardiovascular diseases. The purpose. To establish the features of changes in the H2S/homocysteine ratio in children with arterial hypertension. Material and methods. A total of 111 children aged 14 to 18 years were examined. Based on the results of 24-hour blood pressure monitoring (n=81), two groups were formed: group 1 (n=51) – children with arterial hypertension (AH), group 2 (n=30) – children with high-normal blood pressure (HNBP). Group 3 included 30 healthy children. Plasma homocysteine level was determined by high-pressure liquid chromatography [Naumov A.V. et al., 2010]. The level of endogenous hydrogen sulfide was assessed by spectrophotometric method based on the reaction between sulfide anion and an acidic solution of the reagent N, N-dimethyl-p-phenylenediamine hydrochloride [Norris Eric J., 2011]. Results. A significant increase in plasma homocysteine concentration was revealed in patients with AH and HNBP compared with healthy children. The plasma levels of hydrogen sulfide in children with AH were significantly lower than in the comparison group. Hypertensive children in comparison to healthy children showed significantly lower plasma H2S/homocysteine ratio. Correlations have been established between the H2S/homocysteine ratio and plasma levels of homocysteine and hydrogen sulfide. Conclusions. Hypertensive children have a lower H2S/homocysteine ratio, which is due to the presence of hyperhomocysteinemia and reduced H2S levels. The H2S/homocysteine ratio can be used as a potential marker for predicting the progression of AH.

Changes in homocysteine and non-mercaptoalbumin levels after acute exercise: a crossover study

BackgroundAcute exercise is one factor that increases blood homocysteine levels, and elevated homocysteine levels cause oxidative stress. Albumin, which is abundant in blood, is an antioxidant, and the redox state of albumin is used as an index of oxidative stress in blood. This study aimed to assess the effect of acute exercise on plasma homocysteine levels and the blood non-mercaptoalbumin/mercaptoalbumin ratio as an oxidative stress marker.MethodsThis study used a crossover design with exercise and control conditions. Under exercise conditions, a bicycle ergometer was used to perform 40 min of transient constant-load exercise at 65% heart rate reserve. Under control conditions, participants rested for 40 min. Blood was collected before, 30 min after, and 90 min after exercise, and at the same time points under control conditions. Samples were analyzed for the homocysteine concentration and non-mercaptoalbumin/mercaptoalbumin ratio.ResultsThe results revealed that a 65% heart rate reserve and 40 min of acute exercise increased plasma homocysteine concentration and non-mercaptoalbumin ratio. In the intra-condition comparison, the plasma Hcy concentration was significantly increased at Post 30 min (+ 0.83 ± 0.70 µmol/L, P = 0.003) compared with that at Pre in the exercise condition. Furthermore, 90 min after exercise, the blood non-mercaptoalbumin ratio was significantly increased (+ 0.35 ± 0.71%, P = 0.030) compared to Pre.ConclusionThese results indicate that the plasma Hcy concentration first increased, and then the non-mercaptoalbumin/mercaptoalbumin ratio increased as the elevated state was maintained. This study revealed that 65% heart rate reserve, 40 min of acute exercise increased plasma Hcy concentration and non-mercaptoalbumin ratio.

607-P: Hyperhomocysteinemia Is Closely Associated with Macular Edema in Type 2 Diabetes

Macular edema that impairs central vision is one of leading causes of blindness related to diabetes. Hyperhomocysteinemia is more common in type 2 diabetes, which may damage endothelium by excessive sulphation of connective tissues. In this study, we for the first time explored the relation of plasma total homocysteine concentration to diabetic macular edema in patients with type 2 diabetes. We enrolled 176 type 2 diabetic patients and 115 healthy subjects in a cross-sectional hospital-based study. Using fundus photographs documented retina statuses and using fluorescence polarization immunoassay measured homocysteine concentration. Risk factors for diabetic macular edema were obtained from fasting blood samples and interviewer- questionnaire. We found that diabetic patients had increased plasma homocysteine compared with normal control, and plasma homocysteine levels were higher in subjects with diabetic macular edema than without ((11.4 ± 2.7) vs. (8.5 ± 1.9) (μmol/l), p = 0.000). The association of homocysteine with diabetic macular edema was independent of major risk factors for diabetic macular edema (duration of diabetes, HbA1c, lipid) and determinants of higher homocysteine concentration (age, gender, serum folate and vitamin B12, renal status, and biguanide use) (OR: 1.63 (1.02-2.14), p = 0.018). Furthermore, a 1 μmol/l increase in plasma homocysteine concentration was associated with a 0.5% to 2.2% increase of diabetic macular edema and per increase of 5.0 μmol/l plasma homocysteine was significantly related to macular edema (OR: 1.64 (1.04-2.16), p = 0.019) after adjusting for duration of diabetes per 5 year increase, HbA1c per 1% increase, serum folate per 10 nmol/l increase, serum B12 per 100 pmol/l increase, serum creatinine per 10 μmol/l increase and urinary ACR per 5 mg/g increase. We concluded that hyperhomocysteinemia is independently associated with occurrence of macular edema in type 2 diabetes. Future prospective studies are warranted to clarify the relationship. Disclosure J. Li: None. H. Zhang: None. Q. Lv: None. H. Lu: None. J. Zhou: None.

The Effects of Acute Exercise and Exercise Training on Plasma Homocysteine: A Meta-Analysis.

BackgroundAlthough studies have demonstrated that physical exercise alters homocysteine levels in the blood, meta-analyses of the effects of acute exercise and exercise training on homocysteine blood concentration have not been performed, especially regarding the duration and intensity of exercise, which could affect homocysteine levels differently.ObjectiveThe aim of this meta-analysis was to ascertain the effects of acute exercise and exercise training on homocysteine levels in the blood.MethodA review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using the online databases PubMed, SPORTDiscus, and SciELO to identify relevant studies published through June 2015. Review Manager was used to calculate the effect size of acute exercise and exercise training using the change in Hcy plasmaserum concentration from baseline to post-acute exercise and trained vs. sedentary control groups, respectively. Weighted mean differences were calculated using random effect models.ResultsGiven the abundance of studies, acute exercise trials were divided into two subgroups according to exercise volume and intensity, whereas the effects of exercise training were analyzed together. Overall, 22 studies with a total of 520 participants indicated increased plasma homocysteine concentration after acute exercise (1.18 μmol/L, 95% CI: 0.71 to 1.65, p < .01). Results of a subgroup analysis indicated that either long-term exercise of low-to-moderate intensity (1.39 μmol/L, 95% CI: 0.9 to 1.89, p < .01) or short-term exercise of high intensity (0.83 μmol/L, 95% CI: 0.19 to 1.40, p < .01) elevated homocysteine levels in the blood. Increased homocysteine induced by exercise was significantly associated with volume of exercise, but not intensity. By contrast, resistance training reduced plasma homocysteine concentration (-1.53 μmol/L, 95% CI: -2.77 to -0.28, p = .02), though aerobic training did not. The cumulative results of the seven studies with a total of 230 participants in exercise training analysis did not demonstrate a significant impact on homocysteine levels in the blood (-0.56 μmol/L, 95% CI: -1.61 to 0.50, p = .23).ConclusionsCurrent evidence demonstrates that acute exercise increases homocysteine levels in the blood independent of exercise duration and intensity. Resistance, but not aerobic training decreases plasma homocysteine levels.

Teenaged Siblings with Progressive Neurocognitive Disease

Two siblings were referred for workup for progressive neurological deterioration. The elder sibling was a 16- year-old boy who had been asymptomatic until 9 years of age when he developed walking difficulty that progressed to a bed-bound state followed by regression of cognitive function and generalized tonic clonic seizures. The younger sibling was a 14-year-old girl with onset of similar symptoms at the age of 6 years. The siblings were the eldest of 6 children from a family with no history of consanguinity. Both children principally ate a high-carbohydrate (maize)-based diet with sporadic access to fresh produce and animal protein. They had reached normal developmental milestones until the onset of symptoms. Both children had been treated unsuccessfully with sodium valproate. On examination, they demonstrated minimal communication skills and severe cognitive impairment. They had spastic paralysis of all extremities. Electroencephalography in the elder sibling revealed generalized, highly potentially epileptogenic foci, and a brain computed tomography scan demonstrated marked cerebral atrophy with minimal white matter. Initial laboratory investigations, including a complete blood count, measurement of electrolytes and urea, and thyroid and liver function tests, were all within reference intervals. Syphilis serology was negative. Screening for inherited metabolic diseases included measurements of plasma amino acids and urine organic acids. Selected laboratory results of the elder boy are provided in Table 1. View this table: Table 1. Selected laboratory results for the elder boy. ### QUESTIONS TO CONSIDER 1. What is the most common cause of a highly increased (>50 μmol/l) homocysteine? 2. Which nutrient deficiencies are associated with increased homocysteine concentrations? 3. What are the deleterious effects of increased plasma homocysteine concentrations? ### HOMOCYSTEINE Homocysteine is a nonessential, non–protein-forming, thiol-containing amino acid that is readily oxidized in the blood to homocystine and other disulfides. Only 1% is found in its free reduced form. The single source of homocysteine in humans is the demethylation of the essential amino acid, methionine, via 2 intermediate compounds, …

Frequency of MTHFR G1793A polymorphism in individuals with early coronary artery disease: cross-sectional study.

Atherosclerotic disease is the leading cause of death in Brazil. It is a complex disease and its prevention involves identification and control of risk factors. Moderately increased plasma homocysteine concentration (hyperhomocysteinemia) has been considered to be a risk factor for several vascular diseases. Mutations in the methylenetetrahydrofolate reductase (MTHFR) enzyme, which is involved in homocysteine metabolism, have been investigated as potential vascular disease risk factors. G1793A polymorphism was described in 2002 and there are few studies analyzing its involvement in diseases. The objective of this study was to investigate the prevalence of G1793A polymorphism in subjects with early coronary artery disease (CAD). Cross-sectional study with control group conducted at a private cardiology clinic and a molecular biology laboratory (Universidade do Vale do Itajaí). We studied 74 early-onset CAD+ patients and 40 CAD- individuals with normal angiography results. DNA was extracted from blood samples. Molecular data were obtained via PCR/RFLP and agarose gel electrophoresis. The occurrence of G1793A heterozygotes was similar in the control (5%) and test (6.25%) groups, thus showing that in the population studied there was no correlation between the marker and occurrences of early CAD. There was also no association between the polymorphism and the risk factors for atherosclerosis. The frequency of the 1793A allele in the test group (3.4%) was similar to what was found in the control individuals (2.5%). There was no correlation between G1793A polymorphism and occurrences of early CAD in this population.

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Folate, Vitamin B12, Vitamin B6 and homocysteine: impact on pregnancy outcome

Good clinical practice recommends folic acid supplementation 1 month prior to pregnancy and during the first trimester to prevent congenital malformations. However, high rates of fetal growth and development in later pregnancy may increase the demand for folate. Folate and vitamins B12 and B6 are required for DNA synthesis and cell growth, and are involved in homocysteine metabolism. The primary aim of this study was to determine if maternal folate, vitamin B12, vitamin B6 and homocysteine concentrations at 18-20 weeks gestation are associated with subsequent adverse pregnancy outcomes, including pre-eclampsia and intrauterine growth restriction (IUGR). The secondary aim was to investigate maternal B vitamin concentrations with DNA damage markers in maternal lymphocytes. A prospective observational study was conducted at the Women's and Children's Hospital, Adelaide, South Australia. One hundred and thirty-seven subjects were identified prior to 20 weeks gestation as at high or low risk for subsequent adverse pregnancy outcome by senior obstetricians. Clinical status, dietary information, circulating micronutrients and genome damage biomarkers were assessed at 18-20 weeks gestation. Women who developed IUGR had reduced red blood cell (RBC) folate (P < 0.001) and increased plasma homocysteine concentrations (P < 0.001) compared with controls. Maternal DNA damage, represented by micronucleus frequency and nucleoplasmic bridges in lymphocytes, was positively correlated with homocysteine (r = 0.179, P = 0.038 and r = 0.171, P = 0.047, respectively). Multivariate regression analysis revealed RBC folate was a strong predictor of IUGR (P = 0.006). This study suggests that low maternal RBC folate and high homocysteine values in mid pregnancy are associated with subsequent reduced fetal growth.

Effect of entacapone on plasma homocysteine levels in Parkinson’s disease patients

Peripheral metabolism of L-DOPA via enzyme catechol-O-methyltransferase (COMT) is one of the possible sources of homocysteine (HCY). The aim of this study was to assess plasma HCY levels in L-DOPA-treated Parkinson's disease (PD) patients and its influence by adding the inhibitor COMT (entacapone). Patients were divided into two groups: (1) patients long term treated with L-DOPA but were naïve to entacapone, (2) L-DOPA naïve patients, in whom a combined treatment with L-DOPA and entacapone was started. The HCY levels were higher in Group 1 than in Group 2. No statistically significant changes of HCY concentrations were found in both patient groups after adding entacapone to their L-DOPA treatments. Results of this study confirm that patients treated with L-DOPA for a long term have increased plasma HCY concentrations. We believe combined L-DOPA and entacapone therapy could be a possible protective mechanism against hyperhomocysteinemia in early PD.

High Casein Diet Decreases Plasma Homocysteine Concentration in Rats

Experiments were conducted to clarify the relationship between dietary protein level and plasma homocysteine concentration in rats. Male Wistar rats were fed diets differing in casein level from 5 to 50% for 14 d (Expt. 1). Plasma total homocysteine concentration was positively correlated with dietary casein level in the range of 5 to 10% but inversely correlated with dietary casein level in the range of 10 to 50%. Hepatic cystathionine beta-synthase (CBS) and betaine-homocysteine S-methyltransferase (BHMT) activities and renal CBS activity increased in response to dietary casein level in the range of 10 to 50%, whereas hepatic serine and betaine concentrations decreased with increasing dietary casein levels. When rats were fed the 10% casein diet or 10% casein+17.2% amino acid mixture diet for 14 d, plasma homocysteine concentration was significantly lower in rats fed the amino acid mixture-added diet than in rats fed the 10% casein diet (Expt. 2), indicating that the hypohomocysteinemic effect of high casein diets was elicited by amino acids, not by casein contaminants. The degree of increase in plasma homocysteine concentration caused by dietary supplementation with 0.75% L-methionine was significantly lower in rats fed the 40% casein diet than in rats fed the 10% casein diet (Expt. 3). These results indicate that high casein diets do not increase but rather decrease plasma homocysteine concentration and cause resistance to hyperhomocysteinemic treatment, and suggest that such effects of high casein diets are mediated at least by increased activities of CBS and BHMT.

B-Vitamin and Homocysteine Status Determines Ovarian Response to Gonadotropin Treatment in Sheep1

Maternal B-vitamin status and homocysteinemia can affect fertility and pregnancy establishment, although the direct effects on ovarian follicle and oocyte development are not known. We report on the effects of restricting the supply of vitamin B(12) and methionine from the diet of mature female sheep on ovarian folliculogenesis following follicle-stimulating hormone (FSH) stimulation. The study was split into three batches and involved 76 animals. Surprisingly, the number of growing, estrogen-active antral follicles following FSH treatment was enhanced (P = 0.005) following this dietary intervention. This increase occurred even in the presence of modest live-weight loss (batch 1 only) and depressed plasma insulin concentrations, suggesting a breakdown in the regulation of follicular responsiveness to FSH. This dietary intervention also increased plasma homocysteine concentrations. Physiological concentrations of homocysteine increased granulosa cell proliferation (P < 0.001), estradiol production (P = 0.05), and FSHR transcript expression (P = 0.017) during culture. Transcript levels for growth differentiation factor 9 and bone morphogenetic protein 15 in oocytes from treated ewes were increased (P < 0.05) in the first two batches. Furthermore, regression of BMP receptor 2 (BMPR2) transcript expression and diet on follicle number revealed a significant interaction (P = 0.01); BMPR2 transcript expression was associated with follicle number only in vitamin B(12)/methionine-restricted animals. Because FSHR transcript expression also was positively (P = 0.007) related to follicle number, the effects of diet may have arisen through enhanced FSH and BMP signaling. Although this remains to be confirmed, the data support an intraovarian impact of vitamin B(12)/methionine-deficient diets.

Influences of Acute and Chronic Aerobic Exercise on the Plasma Homocysteine Level

Background and Aims: Elevated plasma homocysteine (PH) levels have been identified as a risk factor for cardiovascular diseases. The aims of this study were to investigate the influences of submaximal acute aerobic exercise and aerobic training on PH levels and lipid profiles. Methods: 69 volunteersubjects (21.12 ± 2.08 years) were randomized to three groups as acute, training and control groups. Examination and blood samples were collected before and immediately after exercise in the acute group and before and 6 weeks later in the training and control groups. Results: A significant increase in PH concentration was recorded immediately after aerobic exercise, compared with baseline values (p = 0.001). Although, in the training group, total cholesterol (p = 0.00) and LDL cholesterol (p = 0.001) decreased significantly after training, no significant changes in PH concentration, HDL cholesterol (p = 0.087) and triglyceride (p = 194) levels were found. Conclusions: It can be said that the PH level increases following submaximal acute aerobic exercise, but does not alter after submaximal aerobic training due to training duration or intensity. Therefore, submaximal aerobic training decreases lipid profiles independent of the PH level.

Dietary eritadenine suppresses guanidinoacetic Acid-induced hyperhomocysteinemia in rats.

We assessed the effect of eritadenine, a hypocholesterolemic factor isolated from the edible mushroom Lentinus edodes, on plasma homocysteine concentration using methyl-group acceptor-induced hyperhomocysteinemic rats. Male Wistar rats were fed a control diet or diets supplemented with a methyl-group acceptor or a precursor of methyl-group acceptor. Diets were supplemented with guanidinoacetic acid (GAA) at 2.5, 5, 7.5, and 10 g/kg, nicotinic acid (NiA) or ethanolamine (EA) at 5 and 10 g/kg, or glycine at 25 and 50 g/kg, and the rats were fed for 10 d (Expt. 1). Plasma total homocysteine concentration was increased 255 and 421% by 5 and 10 g/kg GAA, respectively, and 39 and 58% by 5 and 10 g/kg NiA, respectively, but not by EA or glycine. GAA supplementation dose-dependently decreased the hepatic S-adenosylmethionine (SAM) concentration and the activity of cystathionine beta-synthase (CBS) and increased the hepatic S-adenosylhomocysteine (SAH) and homocysteine concentrations. In another study in which rats were fed 5 g/kg GAA-supplemented diet for 1-10 d, plasma homocysteine and the other variables affected in Expt. 1 were affected in rats fed the GAA-supplemented diet (Expt. 2). We investigated the effect of supplementation of 5 g/kg GAA-supplemented diet with eritadenine (50 mg/kg) on plasma homocysteine concentration (Expt. 3). Eritadenine supplementation significantly suppressed the GAA-induced increase in plasma homocysteine concentration. Eritadenine also restored the decreased SAM concentration and CBS activity in the liver, whereas it further increased hepatic SAH concentration, suggesting that eritadenine might elicit its effect by both slowing homocysteine production and increasing cystathionine formation. The results confirm that GAA is a useful compound to induce experimental hyperhomocysteinemia and indicate that eritadenine can effectively counteract the hyperhomocysteinemic effect of GAA.

Homocysteine: Clinical Significance and Laboratory Measurement

Increased plasma homocysteine concentrations are associated with increased risks of myocardial infarction, stroke, and venous thrombosis. Potential benefits of homocysteine-lowering therapy are stimulating clinical interest in measuring homocysteine. Many methods are now available including some new options. However, homocysteine testing and interpretation present challenges to clinical laboratories. Future demand for homocysteine testing likely will depend on the outcome of ongoing trials of homocysteine-lowering therapy.

Homocysteine: Clinical Significance and Laboratory Measurement

Increased plasma homocysteine concentrations are associated with increased risks of myocardial infarction, stroke, and venous thrombosis. Potential benefits of homocysteine-lowering therapy are stimulating clinical interest in measuring homocysteine. Many methods are now available including some new options. However, homocysteine testing and interpretation present challenges to clinical laboratories. Future demand for homocysteine testing likely will depend on the outcome of ongoing trials of homocysteine-lowering therapy.

Suppression of Methionine-Induced Hyperhomocysteinemia by Dietary Eritadenine in Rats

The effect of dietary eritadenine on the plasma homocysteine concentration was investigated in methionine-induced hyperhomocysteinemic rats. The rats were fed on the control or eritadenine-supplemented (50 mg/kg) diet for 10 d. The animals were then injected with saline or methionine at a level of 100 or 300 mg/kg of body weight, and sacrificed 2 h or a more appropriate time after injection. The methionine injection increased the post-2 h concentration of plasma homocysteine in a dose-dependent manner in the control rats, this increase being significantly suppressed in the eritadenine-fed rats. This effect persisted up to 8 h after the methionine injection. The hepatic concentrations of S-adenosylmethionine and S-adenosylhomocysteine were increased by eritadenine, whereas the hepatic homocysteine concentration was inversely decreased. The cystathionine beta-synthase activity in the liver was increased by eritadenine. It is suggested from these results that eritadenine might suppress the methionine-induced increase in plasma homocysteine concentration by dual mechanisms: slowing the homocysteine production from S-adenosylhomocysteine and increasing the removal of homocysteine due to the enhanced activity of cystathionine beta-synthase.

Methylenetetrahydrofolate reductase polymorphism associated with moderate hyperhomocysteinaemia in a patient with livedo vasculopathy: treatment with vitamin supplementation and low molecular weight heparin

Conflicts of interest: none declared. Sir, Livedo vasculopathy, a distinct form of thrombogenic vasculopathy, is characterized by recurrent painful ulcers of the lower extremity with persistent livedo racemosa.1 High levels of homocysteine are an independent risk factor for arterial occlusive diseases and deep vein thrombosis.2 One study demonstrated a possible association between plasma homocysteine levels and livedo vasculopathy.3, 4 The key enzyme controlling remethylation of homocysteine is 5,10‐methylenetetrahydrofolate reductase (MTHFR). An alanine/valine gene polymorphism caused through a C to T substitution at nucleotide 677 is responsible for a reduced MTHFR activity and increased thermolability of this enzyme in homozygous individuals, resulting in increased plasma homocysteine concentrations, particularly under conditions of low dietary folate intake. We report livedo vasculopathy in a patient with moderate hyperhomocysteinaemia due to homozygous MTHFR gene mutation. A 42‐year‐old woman presented with livedo racemosa and several small bizarrely shaped ulcers and atrophie blanche on the dorsal aspect of both feet and ankles (Fig. 1). Dorsal arteries of both feet were palpable. Colour‐coded duplex sonography and Doppler sonography revealed no signs of venous insufficiency. Ulcers had previously occurred during the summer months and healed with ivory‐coloured scars. The patient denied other medical problems, intake of medications, vitamin supplements, alcohol or drugs, but smoked five cigarettes per day.

Increased levels of C‐reactive protein and interleukin‐6 in hyperhomocysteinemic subjects

Objective. Elevated plasma homocysteine concentration is considered to be an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia are related to vascular disease are unclear. High‐sensitivity C‐reactive protein (CRP), a marker of inflammation, has been reported to be an independent predictor of future myocardial infarction among clinically healthy individuals. Interleukin (IL)‐6 is a regulator of CRP and has a key role in initiation of inflammation. The aim of this study was to investigate whether individuals with increased plasma homocysteine concentrations have altered levels of serum CRP and IL‐6. Material and methods. Serum concentrations of CRP and IL‐6 were measured in 39 individuals with hyperhomocysteinemia and in 39 control subjects matched for gender, age and body mass index (BMI). In addition, the inflammatory effect of IL‐6 on peripheral blood mononuclear cells was measured. Results. Compared to controls, hyperhomocysteinemic subjects have elevated serum levels of CRP and IL‐6 (p⩽0.001 and p<0.005, respectively). Importantly, this raised level of IL‐6 was also seen in hyperhomocysteinemic individuals without accompanying hypercholesterolemia or cardiovascular disease. IL‐6 increased the release of monocyte chemoattractant protein‐1 from peripheral blood mononuclear cells, with particularly enhancing effects in cells from patients with hyperhomocysteinemia. Conclusions. These data suggest that enhanced inflammation may be associated with homocysteine‐related cardiovascular disease, possibly involving IL‐6‐related mechanisms.

Differences in plasma homocysteine levels between Zucker fatty and Zucker diabetic fatty rats following 3 weeks oral administration of organic vanadium compounds

Purpose: Recently, our laboratory group has reported that rats with Type 1 diabetes have decreased plasma homocysteine and cysteine levels compared to non-diabetic controls and that organic vanadium treatment increased plasma homocysteine concentrations to non-diabetic concentrations. However, to date, no studies have been done investigating the effects of organic vanadium compounds on plasma homocysteine and its metabolites in Type 2 diabetic animal model. These studies examined the effect of organic vanadium compounds [bis(maltolato)oxovanadium(IV) and bis(ethylmaltolato)oxovanadium(IV); BMOV and BEOV] administered orally on plasma concentrations of homocysteine and its metabolites (cysteine and cysteinylglycine) in lean, Zucker fatty (ZF) and Zucker diabetic fatty (ZDF) rats. ZF rats are a model of pre-diabetic Type 2 diabetes characterized by hyperinsulinemia and normoglycemia. The ZDF rat is a model of Type 2 diabetes characterized by relative hypoinsulinemia and hyperglycemia. Methods: Zucker lean and ZF rats received BMOV in the drinking water at a dose of 0.19±0.02 mmol/kg/day. Lean and ZDF rats received BEOV by oral gavage daily at dose of 0.1 mmol/kg. The treatment period for both studies was 21 days. At termination, animals were fasted overnight (∼16 h) and blood samples were collected by cardiac puncture for determination of plasma glucose, insulin and homocysteine levels. Plasma homocysteine and its metabolites levels were determined using high-pressure liquid chromatography. Plasma glucose was determined using a Glucose Analyzer 2. Plasma insulin levels were determined by radioimmunoassay. Plasma triglycerides were determined by an enzymatic assay methodology. Results: ZF ( n = 4 ) and ZDF ( n = 1 0 ) rats had significantly lower plasma homocysteine as compared to their respective lean groups (ZF 0.78±0.1 μmol/L vs. Zucker lean 2.19±0.7 μmol/L; ZDF 1.71±0.2 μmol/L vs. Zucker lean 3.02±0.3 μmol/L; p < 0.0 5 ). BMOV treatment in ZF rats restored plasma homocysteine levels to those observed in lean untreated rats (ZF treated: 2.04±0.2 μmol/L; lean 2.19±0.7 μmol/L). There was a modest effect of BMOV treatment on plasma glucose levels in ZF rats. BEOV treatment significantly decreased the elevated plasma glucose levels in the ZDF rats (lean 7.9±0.1 mmol/L; lean+vanadium 7.7±0.2 mmol/L; ZDF 29.9±0.4 mmol/L; ZDF+vanadium 17.4±0.3 mmol/L, p < 0.0 5 ). Organic vanadium treatment reduced cysteine levels in both ZF and ZDF rats. No differences in total plasma cysteinylglycine concentrations were observed. Conclusion: Plasma homocysteine levels are significantly reduced in a pre-diabetic model of Type 2 diabetes, which was restored to lean levels upon vanadium treatment; however, this restoration of plasma homocysteine levels was not seen in ZDF Type 2 diabetic rats following vanadium treatment. In the latter case vanadium treatment may not have totally overcome the insulin resistance seen in these animals.

Thrombophilia and Preeclampsia: The Evidence So Far

The Role of Thrombophilias Pregnancy is a hypercoagulable state. The field of thrombophilia, the tendency to thrombosis, has been developed rapidly and has been linked to many aspects of pregnancy. Recently, it has been determined that severe pregnancy complications such as severe preeclampsia intrauterine growth retardation (IUGR), abruptio placentae, and intrauterine fetal death (IUFD) are associated with thrombophilia. Thrombophilias are inherited or acquired conditions that predispose an individual to thromboembolism. Deficiencies of protein S, C, and antithrombin are rare and each of them is found in approximately 3% of patients with thrombosis. Three important inherited thrombophilias were discovered, which are responsible of the majority of thromboembolic events in patients with no otherwise apparent risk for thrombosis. Resistance to activated protein C caused by an adenine 506 guanine (A506G) mutation in factor V (factor V Leiden) has been linked with an increased risk for venous thromboembolism. Heterozygosity for the factor V (FV) Leiden mutation is found in approximately 5% of the population and the mutation is responsible for 20% to 30% of venous thromboembolism events. A recently described guanine 20210 adenine mutation in prothrombin is associated with higher plasma prothrombin concentrations and increased risk for venous thromboembolism and cerebral vein thrombosis. Homozygosity for the cytosine 677 thymine (C677T) mutation in methylenetetrahydrofolate reductase (MTHFR) results in decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of homocysteine to methionine, and the resulting increase in plasma homocysteine concentrations is a risk factor for thrombosis. The mutation is responsible for reduced MTHFR activity and is the most frequent cause of mild hyperhomocystinemia and can be found in 5% to 15% of the population. Homocysteine is an independent risk Correspondence: Michael J. Kupferminc, MD, Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. E-mail: tmcobgyn@tasmc.health. gov.il