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Sample records for homocysteine levels fibrinogen

  1. Association of serum calcium concentrations with fibrinogen and homocysteine in nondiabetic Korean subjects.

    PubMed

    Cho, Hyun Sun; Lee, Sung Won; Shin, Juyoung; Moon, Sung Dae; Han, Je Ho; Cha, Bong Yun; Kim, Eun Sook

    2016-06-01

    Considerable evidence shows that increased serum calcium levels are associated with metabolic disorders, cardiovascular disease, and increased mortality. This study investigated whether serum calcium, within a normal range, is significantly associated with serum fibrinogen and homocysteine, markers of increased cardiovascular disease risk in nondiabetic Korean subjects.A cross-sectional analysis was performed on 1096 subjects (mean age, 55.1 ± 11.1 years; 36.1% women) undergoing a general health checkup. Serum biochemistry was analyzed including serum albumin-corrected calcium (Cac), insulin resistance (IR, using homeostasis model assessment [HOMA]), fibrinogen, and homocysteine.Compared with patients within the lowest Cac quartile, those with higher Cac levels had increased fibrinogen and homocysteine levels as well as an increased proportion of smoking, dyslipidemia, and HOMA-IR. Correlation analyses revealed linear relationships for Cac with fibrinogen and homocysteine in both genders. After adjustment for confounding factors, serum Cac was significantly associated with high fibrinogen (odds ratio [OR] for the highest vs the lowest quartile = 1.76, 95% confidence interval [CI] = 1.09-2.83, P = 0.02) and homocysteine (OR = 1.83, 95% CI = 1.07-3.11, P = 0.027). Multivariate regression models showed that Cac was linearly associated with fibrinogen (standardized β = 0.14, P < 0.001) and homocysteine (standardized β = 0.07, P = 0.009).High normal calcium concentrations were independently associated with increased levels of fibrinogen and homocysteine. Further investigation is needed to validate whether slightly increased calcium levels within the normal range indicate a higher risk of cardiovascular disease.

  2. Homocysteine and its thiolactone-mediated modification of fibrinogen affect blood platelet adhesion.

    PubMed

    Malinowska, Joanna; Olas, Beata

    2012-01-01

    Homocysteine (Hcys) and homocysteine thiolactone (HTL) concentrations in organism are correlated with a number of serious pathologies. In the literature, there are few papers describing studies on the effects of homocysteine on proteins that participate in blood coagulation and fibrinolysis in human. However, mechanisms involved in the relationship between hyperhomocysteinemia and hemostatic process are still unclear. The role of N- or S-homocysteinylation (induced by Hcys and its derivatives) of different hemostatic proteins, including fibrinogen is also still poorly known. The aim of this study was to establish the functional changes of the fibrinogen molecule induced by Hcys (at final doses of 10-100 µM) and the most reactive form of Hcys - its cyclic thioester, homocysteine thiolactone (0.1-1 µM), and to examine the effects of these changes on the capability of fibrinogen to interact with human blood platelets (by measuring the platelet adhesion). Our present results demonstrated that Hcys-treated fibrinogen in comparison with native molecule had a distinct capability to mediate platelet adhesion. Both, unstimulated and thrombin-activated platelets showed a reduced ability to adhere to Hcys-mediated fibrinogen. HTL (at all tested concentrations) had similar properties when we used thrombin-activated platelets. In conclusion, the results reported in this study could be useful for a better understanding of changes in hemostasis during hyperhomocysteinemia.

  3. Homocysteine influences blood clot properties alone and in combination with total fibrinogen but not with fibrinogen γ' in Africans.

    PubMed

    Nienaber-Rousseau, Cornelie; de Lange, Zelda; Pieters, Marlien

    2015-06-01

    Simultaneously increased fibrinogen and homocysteine (Hcy) in blood are believed to elevate the risk of cardiovascular disease mortality. However, the pathophysiological mechanisms involved are unknown. We sought to determine whether Hcy or its genetic determinants influence blood clot properties alone or in combination with fibrinogen. In addition, we investigated, for the first time, the gamma prime (γ') isoform of fibrinogen with Hcy in relation to clot architecture and lysis. Single-nucleotide polymorphisms, Hcy and hemostatic variables, including clot lysis, determined with a global fibrinolytic assay [giving lag time, slope, maximum absorbance and clot lysis time (CLT)], were measured in 1867 healthy black South Africans and cross-sectionally analyzed. Increasing Hcy did not affect fiber cross-sectional area (maximum absorbance). However, it decreased the time needed to initiate the coagulation cascade and for fibrin fibers to grow (lag time), it increased the tempo of lateral aggregation (slope) and reduced CLT. None of the single-nucleotide polymorphisms measured had effects on clot properties. Combined effects were observed between Hcy and total fibrinogen in predicting CLT. Fibrinogen γ', which affected markers of the fibrinolytic assay, did not have conjoint effects with Hcy. We believe that there is value in recognizing the combined effects of Hcy and fibrinogen, but not its γ' isoform in relation to clot structure and lysis. The enhanced fibrinolysis rate observed in patients with low fibrinogen and high Hcy may have adverse consequences for health if it disturbs hemostasis and results in a bleeding tendency.

  4. Homocysteine levels in Turkish children.

    PubMed

    Altuntaş, Nilgün; Soylu, Kazım; Suskan, Emine; Akar, Nejat

    2004-06-05

    Hyperhomocysteinemia is a known risk factor for cerebrovascular, peripheral vascular, coronary heart disease, and thrombosis. Several data related to total homocysteine concentrations for children and adolescents were reported from different populations. But no data are available comparing homocysteine levels analyzing according to age ranges in Turkish children. So, we aimed to achieve a reference range for total homocysteine in Turkish children. Plasma total homocysteine concentrations were measured in 177 healthy children within three groups according to age range (1-6, 7-11, 12-17 y). Mean tHcy concentrations were determined (7.77 ± 4.13 μmol/L). Homocysteine were lowest in younger children and increased with age: 1-6 y (3.87 ± 1.44 μmol/L), 7-11 y (8.70 ± 1.40 μmol/L), and 12-17 y (13.54 ± 1.49 μmol/L). We observed no significant differences in tHcy values between girls and boys in all groups. We suggest that total homocysteine levels must be evaluated in children according to age.

  5. Circulating levels of homocysteine in preeclamptic women.

    PubMed

    Khosrowbeygi, A; Ahmadvand, H

    2011-12-01

    It has been hypothesized that maternal hyperhomocysteinemia to be associated with preeclampsia. The aims of the present study were to examine maternal serum levels of total homocysteine in preeclamptic women and its association with the severity of the disease. The study population consisted of 30 preeclamptic patients and 30 matched healthy pregnant women. Serum levels of total homocysteine were assessed using enzyme immunoassay method. Maternal serum levels of total homocysteine were significantly higher in preeclamptic group than in normal pregnant women. Women with severe preeclampsia had higher serum levels of total homocysteine than mild preeclamptic patients. Levels of total homocysteine correlated positively with systolic blood pressure values in preeclamptic women. In summary, maternal serum levels of total homocysteine were increased in preeclamptic women and hyperhomocysteinemia was associated with severity of preeclampsia.

  6. Folate and homocysteine levels in pregnancy.

    PubMed

    Megahed, M A; Taher, I M

    2004-01-01

    This study aims to determine serum folate and plasma homocysteine levels in healthy pregnant women following a live birth and compare them with healthy non-pregnant women. Fifty healthy gravid multiparous women are included in the study and 25 normal non-pregnant female subjects act as controls (group I). The pregnant women are divided into two groups according to interpregnancy interval: group II (six months or less); group III (18-24 months). Venous blood samples are analysed for red blood cell folate and homocysteine, vitamin B12, serum folate and albumin, and serum aminotransferases (ALT and AST). There was a significant decrease in red cell folate and serum folate in group II compared to the control group (P<0.001). Serum vitamin B12 showed no significant difference. Plasma homocysteine and serum albumin showed significant decreases in both groups II and III compared to the control group. (P<0.001) There was significant positive correlation between homocysteine and serum albumin in the three studied groups. (r=0.42, P<0.001; r=0.45, P<0.001; r=0.51, P<0.001, respectively). There was significant negative correlation between red cell folate and homocysteine in the three studied groups. (r=-0.48, P<0.001; r=-0.53, P<0.001; r=-0.49, P<0.001, respectively). Two cases in group II showed signs of intrauterine growth retardation. The results suggest that pregnant females with short interpregnancy intervals are more likely to develop folate deficiency. Educational strategies are required to increase folate awareness among women to promote the benefits of folic acid supplementation. Mandatory folate fortification of foods should be defined and monitored.

  7. Homocysteine levels in vegetarians versus omnivores.

    PubMed

    Krajcovicová-Kudlácková, M; Blazícek, P; Kopcová, J; Béderová, A; Babinská, K

    2000-01-01

    Vitamin B(12), folate, and vitamin B(6) are the main determinants of homocysteinemia. The vegan diet provides no vitamin B(12), but also less strict forms of alternative nutrition may suffer from a deficit of this vitamin. The plasma homocysteine level was measured in alternative nutrition groups of adults (lacto- and lactoovovegetarians, n = 62; vegans, n = 32) and compared with the levels in a group consuming traditional diet (n = 59), omnivores). In the group of vegetarians the average homocysteine level is 13.18 vs. 10.19 micromol/l in omnivores; the frequency of hyperhomocysteinemia is 29 vs. 5% in omnivores. In the group of vegans the average homocysteine value is 15.79 micromol/l (53% of the individual values exceeded 15 micromol/l). Omnivores consume the recommended amount of methionine; however, in individuals consuming an alternative diet, the intake of methionine is deficient (assessed by food frequency questionnaire; lower content of methionine in plant proteins). Under conditions of lower methionine availability the remethylation pathway prevails; therefore, vitamin B(12) and folate were evaluated in relation to the homocysteine level. The serum vitamin B(12) levels are significantly lower in the alternative nutrition groups (214.8 pmol/l in vegetarians, 140.1 pmol/l in vegans vs. 344.7 pmol/l in omnivores); a deficit (<179.0 pmol/l) was found in 26% of the vegetarians and in 78% of the vegans vs. 0% in omnivores. The serum folate levels were within the range of reference values in all groups; however, they were significantly lower in omnivores. The results show that the mild hyperhomocysteinemia in alternative nutrition is a consequence of vitamin B(12) deficiency.

  8. Homocysteine level in urine of autistic and healthy children.

    PubMed

    Kałużna-Czaplińska, Joanna; Michalska, Monika; Rynkowski, Jacek

    2011-01-01

    Homocysteine is an amino acid which plays several important roles in human physiology and is an important biomarker for possible deficiencies of various vitamins (vitamin B₆ and B₁₂, folic acid). In this work GC-MS method was used to determine the levels of homocysteine in the urine of autistic and healthy children. The levels of homocysteine in urine samples from 34 autistic and 21 healthy children were 2.36 ± 1.24 and 0.76 ± 0.31 (mmol∙mol⁻¹ creatinine), respectively. The higher level of homocysteine in autistic children may indicate deficiencies of folic acid and vitamins B₆ and B₁₂ in nutrition of these children. The results of this work were taken into consideration in the nutrition of autistic children treated in the Navicula Centre of Diagnosis and Therapy of Autism in Łódź (Poland).

  9. [Serum homocysteine levels in pregnant women with preeclampsia].

    PubMed

    Stoĭkova, V; Ivanov, S; Mazneĭkova, V; Tsoncheva, A

    2005-01-01

    Preeclampsia is one of the most common and severe pregnancy complications, which ethiology remains unclear. It is certain that endothelial dysfunction plays a key role in the development of preeclampsia. Homocysteine is an important independent cardiovascular risk factor, which might induce the endothelial dysfunction observed in preeclampsia. 26 pregnant women--14 with preeclampsia (group 1) and 12 healthy term pregnant controls (group 2) were enrolled in the study between December 2003 and August 2004. Six of the women in this group had a superimposed preeclampsia. The mean homocysteine level in the first group was 11,04 mol/l, while in the control group it was 6,24 micromol/l (p < 0.05). The women with a severe preeclampsia had a significantly higher serum homocysteine levels than those with mild form (F = 0.025). Seven of the patients (50%) gave birth before 34th weeks of gestation. The study finds a link between the serum homocysteine as an endothelial dysfunction marker and the development of preeclampsia and a relation between the severity of preeclampsia and the degree of the elevation of the serum homocysteine levels.

  10. Effects of physical activity and training programs on plasma homocysteine levels: a systematic review.

    PubMed

    e Silva, Alexandre de Souza; da Mota, Maria Paula Gonçalves

    2014-08-01

    Homocysteine is an amino acid produced in the liver that, when present in high concentrations, is thought to contribute to plaque formation and, consequently, increased risk of cardiovascular disease. However, daily physical activity and training programs may contribute to controlling atherosclerosis. Given that physical exercise induces changes in protein and amino acid metabolism, it is important to understand whether homocysteine levels are also affected by exercise and to determine possible underlying mechanisms. Moreover, regarding the possible characteristics of different training programs (intensity, duration, repetition, volume), it becomes prudent to determine which types of exercise reduce homocysteine levels. To these ends, a systematic review was conducted to examine the effects of daily physical activity and different training programs on homocysteine levels. EndNote(®) was used to locate articles on the PubMed database from 2002 to 2013 with the keyword combinations "physical activity and homocysteine", "training and homocysteine", and/or "exercise and homocysteine". After 34 studies were identified, correlative and comparative studies of homocysteine levels revealed lower levels in patients engaged in greater quantities of daily physical activity. Regarding the acute effects of exercise, all studies reported increased homocysteine levels. Concerning intervention studies with training programs, aerobic training programs used different methods and analyses that complicate making any conclusion, though resistance training programs induced decreased homocysteine levels. In conclusion, this review suggests that greater daily physical activity is associated with lower homocysteine levels and that exercise programs could positively affect homocysteine control.

  11. Serum homocysteine level in vegetarians in District Tharparker, Sindh

    PubMed Central

    Kapoor, Aneel; Zuberi, Nudrat Anwar; Rathore, M. Imran; Baig, Mukhtiar

    2015-01-01

    Objectives: The aim of present study was to investigate serum homocysteine levels in apparently healthy vegetarians and ominvores in Mithi, district Tharparker, Sindh, Pakistan. Methods: This study was conducted in the Department of Biochemistry, Basic Medical Sciences Institute (BMSI), Jinnah Postgraduate Medical Center (JPMC), Karachi and blood samples were collected from Mithi, district Tharparker, Sindh, Pakistan, in 2012. One hundred vegetarian and one hundred omnivores (age ranging from 20-40 years) were enrolled for this study. Serum homocysteine levels were measured by the chemiluminescence enzyme immunoassay method. Results: Serum homocysteine (Hcy) level was considerably higher (p<0.001) in vegetarian group compared to omnivores. We further grouped and analyzed our study subjects according to their gender and according to Hcy level (greater than or lower than 15µmol/L). A considerable number of vegetarian subjects 30% were having Hcy >15µmol/L compared to omnivores 6%, (p<0.001). Gender-wise comparison showed that 27.02% male and 38.46% females had >15µmol/L serum Hcy level in vegetarian group and 6.9% male and 3.5% females had >15µmol/L serum Hcy level in omnivores group, but the difference was not significant in any group. Conclusion: Vegetarians are more prone to develop hyperhomocysteinemia, so they are at high risk to develop cardiovascular disease. PMID:25878628

  12. Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps

    PubMed Central

    Joshi, Manjunath B; Baipadithaya, Guruprasad; Balakrishnan, Aswath; Hegde, Mangala; Vohra, Manik; Ahamed, Rayees; Nagri, Shivashankara K; Ramachandra, Lingadakai; Satyamoorthy, Kapaettu

    2016-01-01

    Constitutively active neutrophil extracellular traps (NETs) and elevated plasma homocysteine are independent risk factors for Type 2 Diabetes (T2D) associated vascular diseases. Here, we show robust NETosis due to elevated plasma homocysteine levels in T2D subjects and increased components of NETs such as neutrophil elastase and cell free DNA. Cooperative NETs formation was observed in neutrophils exposed to homocysteine, IL-6 and high glucose suggesting acute temporal changes tightly regulate constitutive NETosis. Homocysteine induced NETs by NADPH oxidase dependent and independent mechanisms. Constitutively higher levels of calcium and mitochondrial superoxides under hyperglycemic conditions were further elevated in response to homocysteine leading to accelerated NETosis. Homocysteine showed robust interaction between neutrophils and platelets by inducing platelet aggregation and NETosis in an interdependent manner. Our data demonstrates that homocysteine can alter innate immune function by promoting NETs formation and disturbs homeostasis between platelets and neutrophils which may lead to T2D associated vascular diseases. PMID:27811985

  13. High-level expression and preparation of recombinant human fibrinogen as biopharmaceuticals.

    PubMed

    Hirashima, Masaki; Imamura, Takayuki; Yano, Kentaro; Kawamura, Ryoichi; Meta, Akihiro; Tokieda, Yoshiyuki; Nakashima, Toshihiro

    2016-02-01

    Fibrinogen is a large and complex glycoprotein containing two sets of each of three different chains (α, β and γ). There have been no reports of high-level expression of fibrinogen at commercial levels using mammalian cultured cells such as CHO cells because of the difficulty in highly expressing a protein with such a complex structure. We achieved high-level (1.3 g/l or higher) expression of recombinant human fibrinogen using CHO DG44 cells by optimizing the expression system and culture conditions. We also succeeded in establishing a high-recovery preparation method for recombinant fibrinogen that rarely yields degraded products. To characterize the properties of the recombinant human fibrinogen, we performed SDS-PAGE; western blotting of the α, β and γ chains using specific antibodies and scanning electron microscopy observations of fibrin fibres. We also evaluated the functional equivalence between recombinant fibrinogen and plasma fibrinogen with respect to the release of fibrinopeptides initiated by thrombin and its cross-linking properties. The basic properties of recombinant fibrinogen showed no apparent differences from those of plasma fibrinogen. Here, we report the development of methods for the culture and preparation of recombinant human fibrinogen of satisfactory quality that can be scaled up to the commercial level.

  14. Association between plasma fibrinogen levels and mortality in acute-on-chronic hepatitis B liver failure.

    PubMed

    Shao, Zhexin; Zhao, Ying; Feng, Limin; Feng, Guofang; Zhang, Juanwen; Zhang, Jie

    2015-01-01

    Acute-on-chronic liver failure (AoCLF) is the most common type of liver failure and is associated with high mortality. Fibrinogen is critical in maintaining primary and secondary hemostasis. Therefore, we prospectively analyzed the association between fibrinogen and outcomes in AoCLF patients. Plasma fibrinogen was measured in 169 AoCLF, 173 chronic hepatitis B (CHB), and 171 healthy patients using a coagulation method. The predictive ability of fibrinogen for 3-month mortality in AoCLF patients was assessed using receiver operating characteristic (ROC) curve and multivariable logistic regression analyses. Plasma fibrinogen was significantly lower in nonsurvivor AoCLF patients compared with survivor AoCLF, CHB, and control patients. The sensitivity, specificity, and area under the ROC curve of 1/fibrinogen predicting mortality in AoCLF patients were 66.7%, 72.5%, and 0.746 (95% confidence interval (CI): 0.672-0.820, P < 0.001), and the fibrinogen cutoff value was 0.90 g/L. On multivariate logistic regression analysis, low fibrinogen was an independent factor predicting mortality (odds ratio: 0.304; 95% CI: 0.094-0.983; P = 0.047). Nonsurvivor AoCLF patients had significantly decreased fibrinogen levels, suggesting that low plasma fibrinogen may be a useful predictor of poor prognosis in AoCLF patients.

  15. Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.

    PubMed

    Kim, Sungeun; Nho, Kwangsik; Ramanan, Vijay K; Lai, Dongbing; Foroud, Tatiana M; Lane, Katie; Murrell, Jill R; Gao, Sujuan; Hall, Kathleen S; Unverzagt, Frederick W; Baiyewu, Olusegun; Ogunniyi, Adesola; Gureje, Oye; Kling, Mitchel A; Doraiswamy, P Murali; Kaddurah-Daouk, Rima; Hendrie, Hugh C; Saykin, Andrew J

    2016-01-01

    Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

  16. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy.

    PubMed

    Levy, Jerrold H; Welsby, Ian; Goodnough, Lawrence T

    2014-05-01

    Fibrinogen plays a critical role in achieving and maintaining hemostasis and is fundamental to effective clot formation. There is increasing awareness of the important role of fibrinogen as a key target for the treatment and prevention of acquired bleeding. Fibrinogen is the first coagulation factor to fall to critically low levels (<1.0 g/L) during major hemorrhage (normal plasma fibrinogen levels range from 2.0 to 4.5 g/L), and current guidelines recommend maintaining the plasma fibrinogen level above 1.5 g/L. Fibrinogen supplementation can be achieved using plasma or cryoprecipitate; however, there are a number of safety concerns associated with these allogeneic blood products and there is a lack of high-quality evidence to support their use. Additionally, there is sometimes a long delay associated with the preparation of frozen products for infusion. Fibrinogen concentrate provides a promising alternative to allogeneic blood products and has a number of advantages: it allows a standardized dose of fibrinogen to be rapidly administered in a small volume, has a very good safety profile, and is virally inactivated as standard. Administration of fibrinogen concentrate, often guided by point-of-care viscoelastic testing to allow individualized dosing, has been successfully used as hemostatic therapy in a range of clinical settings, including cardiovascular surgery, postpartum hemorrhage, and trauma. Results show that fibrinogen concentrate is associated with a reduction or even total avoidance of allogeneic blood product transfusion. Fibrinogen concentrate represents an important option for the treatment of coagulopathic bleeding; further studies are needed to determine precise dosing strategies and thresholds for fibrinogen supplementation.

  17. Homocysteine Serum Levels in Diabetic Patients with Non Proliferative, Proliferative and without Retinopathy

    PubMed Central

    Gagliano, Caterina; Giordano, Maria; Vacante, Marco; Caraci, Filippo; Drago, Filippo; Avitabile, Teresio; Motta, Massimo

    2014-01-01

    Homocysteine has been associated with extracellular matrix changes. The diabetic retinopathy is a neurovascular complication of diabetes mellitus and it is the leading cause of vision loss among working adults worldwide. In this study, we evaluate the role of homocysteine in diabetic retinopathy analyzing the plasma levels of homocysteine in 63 diabetic type 2 patients with nonproliferative retinopathy (NPDR), 62 patients with proliferative diabetic retinopathy (PDR), 50 healthy subjects used as control group, and 75 randomly selected patients. PMID:24877066

  18. Homocysteine serum levels in diabetic patients with non proliferative, proliferative and without retinopathy.

    PubMed

    Malaguarnera, Giulia; Gagliano, Caterina; Giordano, Maria; Salomone, Salvatore; Vacante, Marco; Bucolo, Claudio; Caraci, Filippo; Reibaldi, Michele; Drago, Filippo; Avitabile, Teresio; Motta, Massimo

    2014-01-01

    Homocysteine has been associated with extracellular matrix changes. The diabetic retinopathy is a neurovascular complication of diabetes mellitus and it is the leading cause of vision loss among working adults worldwide. In this study, we evaluate the role of homocysteine in diabetic retinopathy analyzing the plasma levels of homocysteine in 63 diabetic type 2 patients with nonproliferative retinopathy (NPDR), 62 patients with proliferative diabetic retinopathy (PDR), 50 healthy subjects used as control group, and 75 randomly selected patients.

  19. Increased fibrinogen levels at diagnosis are associated with adverse outcome in patients with acute myeloid leukemia.

    PubMed

    Berger, Martin D; Heini, Alexander D; Seipel, Katja; Mueller, Beatrice; Angelillo-Scherrer, Anne; Pabst, Thomas

    2016-06-15

    Increased plasma fibrinogen levels are associated with shortened overall survival (OS) in some solid tumor types. In contrast, the prognostic significance of varying fibrinogen levels in acute myeloid leukemia (AML) at diagnosis is unknown. In this study, we assessed the prognostic significance of fibrinogen levels in AML patients. In a comprehensive retrospective single-center study, we determined the survival rates of 375 consecutive AML patients undergoing at least one cycle of intensive chemotherapy induction treatment. Patients were dichotomized between low (<4.1 g/L) and high fibrinogen levels (≥4.1 g/L) at diagnosis of AML before initiation of treatment. Subsequently, quartile ranges were applied to analyze the association of varying fibrinogen levels on survival. We observed that the rates of complete remission, early death, and admission to intensive care unit were equal in the low versus high fibrinogen group. However, OS was significantly better in the low fibrinogen group (27.3 vs 13.5 months; p = 0.0009) as well as progression-free survival (12.3 vs 7.8 months; p = 0.0076). This survival difference remained significant in the multivariate analysis (p = 0.003). Assessing quartiles of fibrinogen values, we further confirmed this observation. Our data suggest that high fibrinogen levels at diagnosis of AML are associated with unfavorable OS and progression-free survival but not with increased mortality during induction treatment. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder.

    PubMed

    Puig-Alcaraz, Carmen; Fuentes-Albero, Milagros; Calderón, Jesús; Garrote, Dolores; Cauli, Omar

    2015-10-30

    The clinical significance of high levels of homocysteine in autism spectrum disorder (ASD) is unknown. An experimental study was conducted in order to evaluate the concentration of homocysteine in children with ASD and typically developing children and to analyse any relationships with the severity of core symptoms of ASD and other clinical features (drugs, co-morbidities, gender, age, diet). Core symptoms of autism were evaluated by DSM-IV criteria. Homocysteine, glutathione, methionine, 3-nitrotyrosine were measured in urine. The increase in homocysteine concentration was significantly and directly correlated with the severity of the deficit in communication skills, but was unrelated to deficit in socialisation or repetitive/restricted behaviour. Urinary homocysteine concentration may be a possible biomarker for communication deficits in ASD and a potential diagnostic tool useful to evaluate new treatment options since no treatment for core symptoms of ASD are available.

  1. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective?

    PubMed

    Kocer, Bilge; Guven, Hayat; Comoglu, Selim Selcuk

    2016-01-01

    Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia.

  2. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective?

    PubMed Central

    Guven, Hayat; Comoglu, Selim Selcuk

    2016-01-01

    Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia. PMID:27493964

  3. Plasma homocysteine levels in Taiwanese vegetarians are higher than those of omnivores.

    PubMed

    Hung, Chien-Jung; Huang, Po-Chao; Lu, Shao-Chun; Li, Yi-Hwei; Huang, Hsien-Bin; Lin, Bi-Fong; Chang, Sue-Joan; Chou, Hsu-Fang

    2002-02-01

    Mild hyperhomocysteinemia is an independent risk factor for cardiovascular disease and may result from a deficiency of folate, vitamin B-6 or vitamin B-12. Because vitamin B-12 deficiency is often associated with vegetarianism, this study was designed to examine the effect of Taiwanese vegetarian diets on B-vitamin status and plasma homocysteine levels. Female Buddhist lacto-vegetarians (n = 45; 31-45 y) and matched omnivores (n = 45) recruited in Hualien, Taiwan, were investigated. Taiwanese vegetarians consumed normal amount of folate, but only 21% of Taiwan Recommended Daily Nutrient Allowances (RDNA) values of vitamin B-12. Compared with the omnivores, the vegetarians had significantly higher levels of plasma folate (14.79 +/- 7.70 vs. 11.98 +/- 8.29 nmol/L), but lower levels of vitamin B-12 (207.7 +/- 127.1 vs. 403.5 +/- 138.9 pmol/L). Fasting plasma homocysteine levels were significantly higher in vegetarians than in omnivores (mean: 11.20 +/- 4.27 vs. 8.64 +/- 2.06 micromol/L; median: 10.5 vs. 8.5 micromol/L). Fasting plasma homocysteine was inversely correlated with plasma folate and vitamin B-12 in the vegetarian group. Multiple regression analysis revealed that plasma folate, vitamin B-12 and creatinine were independent determinants of homocysteine variation and contributed to 38.6% of homocysteine variation in the vegetarians. Compared with the omnivores, vegetarians also had significantly lower serum levels of valine, isoleucine, leucine, lysine, alanine and arginine, but higher levels of glycine. In the vegetarian group, fasting plasma homocysteine correlated negatively with serum threonine, lysine, histidine, arginine and cystine, and these amino acids contributed to 38.7% of homocysteine variation. In conclusion, the Buddhist nuns who consumed a lacto-vegetarian diet had mildly elevated fasting plasma homocysteine levels presumably due to lower levels of plasma vitamin B-12.

  4. Homocysteine levels after acute levodopa intake in patients with Parkinson's disease.

    PubMed

    Müller, Thomas; Kuhn, Wilfried

    2009-07-15

    Levodopa (L-dopa) administered with a dopadecarboxylase inhibitor (DDI) increases homocysteine plasma levels. This may support the onset of atherosclerosis-related disorders and neuropsychiatric complications in patients with Parkinson's disease (PD). This homocysteine elevation is considered as long-term effect of chronic L-dopa/DDI treatment. Little is known about the acute effects of L-dopa/DDI intake on homocysteine generation. The objective of this trial was to investigate the relations between L-dopa and homocysteine after acute L-dopa/DDI administration in PD patients with different L-dopa metabolism. Thirty PD patients were divided into groups with superior (I) and less (II) L-dopa absorption after standardized intake of 125 mg L-dopa/benserazide with determination of L-dopa, 3-O-methyl-dopa (3-OMD) and homocysteine in plasma at baseline, 30, 60, and 90 minutes. There was a homocysteine increase in Group I (F = 5; P = 0.005) and a moderate decrease in Group II (F = 4.27; P = 0.01). A rise of 3-OMD (F = 10.51; P < 0.0001) appeared in Group I, but not in Group II (F = 0.91; P = 0.44), accordingly L-dopa accumulation was better in Group I than in Group II. Thus, in conclusion, L-dopa metabolism is an important component for homocysteine elevation after one time L-dopa/DDI administration in PD patients.

  5. Blood folic acid, vitamin B12, and homocysteine levels in pregnant women with fetal growth restriction.

    PubMed

    Jiang, H L; Cao, L Q; Chen, H Y

    2016-12-19

    Deficiencies in nutrients such as folic acid and vitamin B12 may play a role in fetal growth restriction (FGR). However, whether folic acid, vitamin B12, or homocysteine is associated with FGR in Chinese populations remains unclear. This study investigated the relationship between these nutrient deficiencies and FGR in pregnant Chinese women. We selected 116 mother and infant pairs, and categorized the neonates into the FGR, appropriate for gestational age, and large for gestational age groups. Birth weight, body length, head circumference, body mass index (BMI), and Rohrer's body index of the newborns were measured. Serum folic acid, vitamin B12, and homocysteine levels were measured in mothers during the first three days of their hospital stay. Results showed that the FGR group exhibited reduced folic acid and vitamin B12 levels and elevated homocysteine levels than those in the other two groups. Folic acid and vitamin B12 levels were positively correlated with birth weight, head circumference, and BMI, whereas homocysteine level was negatively correlated with these variables. The FGR ratio in the folic acid and vitamin B12 deficiency group was higher than that in the sufficiency group (χ(2) = 4.717 and 4.437, P = 0.029 and 0.035, respectively). In addition, elevated homocysteine was associated with FGR (χ(2) = 5.366, P = 0.021). In conclusion, we found that folic acid and vitamin B12 deficiency was associated with elevated homocysteine levels, which may increase susceptibility to FGR.

  6. A study of changes in homocysteine levels during normal pregnancy and pre-eclampsia.

    PubMed

    Singh, Urmila; Gupta, H P; Singh, R K; Shukla, Manju; Singh, Ranjana; Mehrotra, Seema Sinha Nee; Prasad, Shweta

    2008-08-01

    To find out changes in homocysteine levels that occur during normal pregnancy and pregnancy with pre-eclamptic toxaemia and also to find out correlation between homocysteine concentration and preeclamptic toxaemia a study was carried out among 90 women of which 30 were control which included normotensive non-pregnant women and the study group I comprised 30 pregnant normotensive women and the study group II comprised 30 pregnant women with pre-eclamptic toxaemia. Serum homocysteine was measured in all subjects using fluorescence polarisation immuno-assay. Control group had highest mean homocysteine levels while the study group I had least mean homocysteine levels (p < 0.001). Levels were significantly higher in subjects with BP > 146/100 mm Hg as compared to subjects with BP >140/90 and <146/100 mm Hg (p=0.017). There was significant difference between study group I and II at same gestational age. Hyperhomocysteinaemia was observed in pre-eclamptic females, also it was found that homocysteine levels were directly correlated with severity of pre-eclampsia.

  7. Rapid evaluation of fibrinogen levels using the CG02N whole blood coagulation analyzer.

    PubMed

    Hayakawa, Mineji; Gando, Satoshi; Ono, Yuichi; Mizugaki, Asumi; Katabami, Kenichi; Maekawa, Kunihiko; Miyamoto, Daisuke; Wada, Takeshi; Yanagida, Yuichiro; Sawamura, Atsushi

    2015-04-01

    Rapid evaluation of fibrinogen (Fbg) levels is essential for maintaining homeostasis in patients with massive bleeding during severe trauma and major surgery. This study evaluated the accuracy of fibrinogen levels measured by the CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) using heparinized blood drawn for blood gas analysis (whole blood-Fbg). A total of 100 matched pairs of heparinized blood samples and citrated blood samples were simultaneously collected from patients in the intensive care unit. Whole blood-Fbg results were compared with those of citrated plasma (standard-Fbg). The whole blood coagulation analyzer measured fibrinogen levels within 2 minutes. Strong correlations between standard-Fbg and whole blood-Fbg were observed (ρ = 0.91, p < 0.001). Error grid analysis showed that 88% of the values were clinically acceptable, and 12% were in a range with possible effects on clinical decision-making; none were in a clinically dangerous range without appropriate treatment. Using a fibrinogen cutoff value of 1.5 g/L for standard-Fbg, the area under the receiver operating characteristic curve of whole blood-Fbg was 0.980 (95% confidence interval 0.951-1.000, p < 0.001). The whole blood coagulation analyzer can rapidly measure fibrinogen levels in heparinized blood and could be useful in critical care settings where excessive bleeding is a concern.

  8. Elevated plasma homocysteine level is possibly associated with skin sclerosis in a series of Japanese patients with systemic sclerosis.

    PubMed

    Motegi, Sei-Ichiro; Toki, Sayaka; Yamada, Kazuya; Uchiyama, Akihiko; Ishikawa, Osamu

    2014-11-01

    Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of cardiovascular diseases, including carotid, coronary and peripheral arterial disease (PAD). The association of plasma homocysteine levels with peripheral vascular involvements, such as Raynaud phenomenon (RP), digital ulcers (DU) in systemic sclerosis (SSc) patients has not been well studied. The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with SSc. Plasma homocysteine levels in 151 Japanese patients with SSc and 20 healthy controls were examined. No significant differences were observed in plasma homocysteine levels between SSc patients and healthy individuals. Demographic and clinical features of the SSc patients revealed that severe skin sclerosis, anti-topoisomerase I antibody positivity, complications of DU, acro-osteolysis (AO) and interstitial lung disease (ILD) were significantly more prevalent among the patients with elevated plasma homocysteine levels. The plasma homocysteine levels were positively correlated with modified Rodnan total skin score. The plasma homocysteine levels in the SSc patients with DU, AO and ILD were significantly higher than those in the SSc without DU, AO and ILD, respectively. Plasma homocysteine levels did not correlate with either the mean or max intima-media thickness (IMT) or plaque score, suggesting that plasma homocysteine levels might not be associated with carotid artery atherosclerosis in SSc patients. The measurement of plasma homocysteine levels in SSc patients might be useful for the risk stratifications of severe skin sclerosis, DU and AO.

  9. What is the influence of hormone therapy on homocysteine and crp levels in postmenopausal women?

    PubMed Central

    Lakryc, Eli Marcelo; Machado, Rogério Bonassi; Soares, José Maria; Fernandes, César Eduardo; Baracat, Edmund Chada

    2015-01-01

    OBJECTIVE: To evaluate the influence of estrogen therapy and estrogen-progestin therapy on homocysteine and C-reactive protein levels in postmenopausal women. METHODS: In total, 99 postmenopausal women were included in this double-blind, randomized clinical trial and divided into three groups: Group A used estrogen therapy alone (2.0 mg of 17β-estradiol), Group B received estrogen-progestin therapy (2.0 mg of 17 β-estradiol +1.0 mg of norethisterone acetate) and Group C received a placebo (control). The length of treatment was six months. Serum measurements of homocysteine and C-reactive protein were carried out prior to the onset of treatment and following six months of therapy. RESULTS: After six months of treatment, there was a 20.7% reduction in homocysteine levels and a 100.5% increase in C-reactive protein levels in the group of women who used estrogen therapy. With respect to the estrogen-progestin group, there was a 12.2% decrease in homocysteine levels and a 93.5% increase in C-reactive protein levels. CONCLUSION: Our data suggested that hormone therapy (unopposed estrogen or estrogen associated with progestin) may have a positive influence on decreasing cardiovascular risk due to a significant reduction in homocysteine levels. PMID:25789519

  10. Homocysteine levels in morbidly obese patients: its association with waist circumference and insulin resistance.

    PubMed

    Vayá, Amparo; Rivera, Leonor; Hernández-Mijares, Antonio; de la Fuente, Miguel; Solá, Eva; Romagnoli, Marco; Alis, R; Laiz, Begoña

    2012-01-01

    The association between morbid obesity and hyperhomocysteinemia (HH) remains controversial and the nature of this relationship needs to be clarified as several metabolic, lipidic, inflammatory and anthropometric alterations that accompany morbid obesity may be involved. In 66 morbidly obese patients, 47 women and 19 men aged 41 ± 12 years and 66 normo-weight subjects, 43 women and 23 men, aged 45 ± 11 years, we determined homocysteine (Hcy) levels along with lipidic, anthropometric, inflammatory and insulin resistance markers. In addition, we investigated the effect of Metabolic Syndrome (MS) and its components on Hcy levels. Obese patients had statistically higher Hcy levels than controls: 12.76 ± 5.30 μM vs. 10.67 ± 2.50 μM; p = 0.006. Moreover, morbidly obese subjects showed higher waist circumference, glucose, insulin, HOMA, leptin, triglycerides, fibrinogen, C reactive protein (CRP) (p < 0.001, respectively), and lower vitamin B12 (p = 0.002), folic acid and HDL-cholesterol (p < 0.001, respectively). In the multivariate regression analysis, waist circumference, glucose, leptin and folic acid levels were independent predictors for Hcy values (p < 0.050). When obese patients were classified as having MS or not, no differences in Hcy levels were found between the two groups (p = 0.752). Yet when we analysed separately each MS component, only abdominal obesity was associated with Hcy levels (p = 0.031). Moreover when considering glucose >110 mg/dL (NCEP-ATPIII criteria) instead of glucose intolerance >100 mg/dl (updated ATPIII criteria), it also was associated with HH (p = 0.042). These results were confirmed in the logistic regression analysis where abdominal obesity and glucose >115 mg/dL constitute independent predictors for HH (OR = 3.2; CI: 1.23-13.2; p = 0.032, OR: 4.6; CI: 1.7-22.2; p = 0.016, respectively). The results of our study indicate that increased Hcy levels are related mostly with abdominal obesity and with insulin resistance. Thus, HH may

  11. Plasma fibrinogen levels are correlated with postoperative distant metastasis and prognosis in esophageal squamous cell carcinoma.

    PubMed

    Zhang, Danhong; Zhou, Xia; Bao, Wuan; Chen, Ying; Cheng, Lei; Qiu, Guoqin; Sheng, Liming; Ji, Yongling; Du, Xianghui

    2015-11-10

    This study investigated the correlation of preoperative plasma fibrinogen level with distant metastasis and prognosis in esophageal squamous cell carcinoma (ESCC). A total of 255 patients with ESCC who underwent surgery in Zhejiang cancer hospital (Hangzhou, China), between October 2006 and December 2009, were evaluated in this retrospective study. Population controls were selected from a pool of cancer-free subjects in the same region. Each patient and cancer-free people provided 3-mL pretreatment blood. Plasma fibrinogen level was measured by the Clauss method. The effects of hyperfibrinogenemia on locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), relapse-free survival (RFS), and overall survival (OS) were assessed using Kaplan-Meier analysis. Independent prognostic factors were identified in the multivariate Cox analysis. The proportion of hyperfibrinogenemia was higher in ESCC patients than those in controls (40.4% vs 13.6%). Subjects with hyperfibrinogenemia had a significantly higher risk of ESCC than those with normal plasma fibrinogen level (adjust OR = 4.61; 95% CI = 3.02-7.01, P < 0.001) after adjusted for age, sex and smoking status. The Kaplan-Meier curves showed that patients with hyperfibrinogenemia had worse DMFS, RFS and OS (P < 0.001). Tumor length, lymph node metastasis and plasma fibrinogen level were independent prognostic factors of ESCC (P < 0.05). Increased plasma fibrinogen level was significantly associated with elevated risk of ESCC. Preoperative plasma fibrinogen level was a predictor of distant metastasis and independently associated with prognosis of patients with ESCC.

  12. The Role of Serum Fibrinogen Level in the Diagnosis of Acute Appendicitis

    PubMed Central

    Nyuwi, Kuotho T; Khumukcham, Sridartha; Rangaswamy, Raju; Ezung, Yibenthung S; Chittvolu, Sowdin Reddy; Sharma, A Barindra; Singh, H Manihar

    2017-01-01

    Introduction Acute appendicitis is the most common indication for emergent surgery and affects a wide range of patients at any age group. However, inspite of the presence of various imaging modalities, biochemical markers, and scoring systems the negative appendectomy rate remain high. Serum fibrinogen, an acute inflammatory mediator is usually raised in any acute inflammatory condition and the same is expected to rise in acute appendicitis, which may be used as a new inflammatory marker in the diagnosis and more importantly in decision making of management of acute appendicitis. Aim To determine the relationship between the rise in the level of serum fibrinogen and acute appendicitis and its role in reducing the negative appendectomy rate. Materials and Methods A total of 82 patients with clinical signs and symptoms of acute appendicitis who underwent emergency appendectomy were included in the study, the serum fibrinogen level were measured just before the operation and the sensitivity and the specificity was calculated. The final diagnosis was based on the histopathological examination. Results In our study, the Mean±SD of serum fibrinogen in mg/dl in those patient proved to be having acute appendicitis by histopathology was 436.6±40.6 while those with normal appendix was 391.91±66.54. The area under the curve was 0.697 i.e., it has an accuracy of around 70% and this is statistically significant (p=0.018). On further sub-analysis when the cut off level of fibrinogen level was reduced to 397, it resulted in a sensitivity of 82% and specificity of 60% and if the level was further reduced to 375 it increased the sensitivity to 88% with a specificity of 55%. Conclusion In the diagnosis of acute appendicitis, use of fibrinogen blood level may be a new diagnostic acute-phase reactant with possible role in reducing negative appendectomy rate. PMID:28274001

  13. Plasma homocysteine levels in cycling, pregnant, and spayed bitches.

    PubMed

    Trisolini, C; Minoia, G; Manca, R; Rizzo, A; Robbe, D; Valentini, L; Sciorsci, R L

    2008-10-01

    The aim of this study was to evaluate the physiological range of homocysteine (Hcy) exhibited by bitches during the follicular (pro-oestrus), luteal (dioestrus) and anoestrus phases of cycling animals, and in pregnant and spayed bitches. The lowest concentrations of Hcy were observed during dioestrus (3.2+/-1.27micromol/L) and in pregnant bitches (3.9+/-1.72micromol/L), and the highest concentrations during anoestrus (7.8+/-0.6micromol/L) and in spayed bitches (12.1+/-5.16micromol/L).

  14. Effects of zinc deficiency and zinc supplementation on homocysteine levels and related enzyme expression in rats.

    PubMed

    Jing, Mingyan; Rech, Leslie; Wu, Yinghong; Goltz, Douglas; Taylor, Carla G; House, James D

    2015-04-01

    Methionine synthase (MS) and betaine-homocysteine methyltransferase (BHMT) are both zinc (Zn)-dependent methyltransferases and involved in the methylation of homocysteine. The objective of this study was to investigate the effects of dietary Zn supply on homocysteine levels and expression of the two enzymes in growing rats. Male weanling Sprague-Dawley rats were assigned randomly to four dietary groups (n=8/group) for 3 weeks: Zn deficient (ZD; <1mg Zn/kg); Zn control (ZC; 30mg Zn/kg); Zn supplemented (ZS; 300mg Zn/kg); pair fed (PF; 30mg Zn/kg) to the ZD group. Serum and femur Zn concentrations were 83% and 58% lower in ZD, and 49% and 62% higher in ZS compared to ZC (P<0.001), respectively. The ZD rats had lower feed intake (37%), body weight gains (45%), liver (43%) and kidney (31%) weights than those of ZC (P<0.001), but these parameters in ZD were not significantly different from the PF controls. Serum homocysteine concentrations were 65% higher in ZD compared to PF (P<0.05), and there was no significant difference in serum folate levels between ZD and PF groups. The mRNA expression of liver and kidney MS was 57% and 38% lower in ZD than PF (P<0.001), respectively. Hepatic and renal BHMT mRNA levels were not altered in ZD compared to controls. The aforementioned measurements were not significantly different between ZS and ZC groups, except Zn levels. These results demonstrated that homocysteine homeostasis appeared to be disturbed by Zn deficiency but not Zn supplementation, and elevated serum homocysteine might be due to reduced expression of MS during Zn deficiency.

  15. Effects of oral N-acetylcysteine on plasma homocysteine and whole blood glutathione levels in healthy, non-pregnant women.

    PubMed

    Roes, Eva Maria; Raijmakers, Maarten T M; Peters, Wilbert H M; Steegers, Eric A P

    2002-05-01

    Oral N-acetylcysteine supplementation in nine young healthy females induced a quick and highly significant decrease in plasma homocysteine levels and an increase in whole blood concentration of the antioxidant glutathione. N-acetylcysteine impresses as an efficient drug in lowering homocysteine concentration and might be beneficial for individuals with hyperhomocysteinemia who are at increased risk of cardiovascular disease.

  16. Increased serum level of homocysteine correlates with retinal nerve fiber layer thinning in diabetic retinopathy

    PubMed Central

    Srivastav, Khushboo; Mahdi, Abbas A.; Shukla, Rajendra K.; Meyer, Carsten H.; Akduman, Levent; Khanna, Vinay K.

    2016-01-01

    Purpose To study the correlation between serum levels of vitamin B12, folic acid, and homocysteine and the severity of diabetic retinopathy and the correlation with retinal nerve fiber layer (RNFL) thinning on spectral domain optical coherence tomography (SD-OCT). Methods In a tertiary care center–based prospective cross-sectional study, 60 consecutive cases and 20 healthy controls in the age group of 40–65 years were included. The eyes of the cases were divided into three groups according to Early Treatment Diabetic Retinopathy Study (ETDRS) classification: diabetes mellitus without retinopathy (n = 20), non-proliferative diabetic retinopathy with macular edema (n = 20), and proliferative diabetic retinopathy with macular edema (n = 20). The serum levels of vitamin B12 and folic acid were measured using a standard protocol. The serum homocysteine assay was performed using an enzyme-linked immunosorbent assay (ELISA) kit. Average RNFL thickness was measured using SD-OCT. Statistical analysis was used to assess the correlations between the study variables. Results Increased severity of diabetic retinopathy was found to correlate with an increase in the serum levels of homocysteine (F = 53.79; p<0.001). The mean serum levels of vitamin B12 and folic acid were found to be within the normal reference range. A positive correlation was found between retinal nerve fiber layer thinning and serum levels of homocysteine (p<0.001). Conclusions This study, for the first time, demonstrated a correlation between increased homocysteine with a decrease in RNFL thickness and increased severity of diabetic retinopathy. PMID:27994434

  17. Signal transduction pathways in erythrocyte nitric oxide metabolism under high fibrinogen levels

    NASA Astrophysics Data System (ADS)

    Saldanha, Carlota; Freitas, T.; Lopez de Almeida, J. P.; Silva-Herdade, A.

    2014-05-01

    Previous studies show that the fibrinogen molecule modulates the metabolism of nitric oxide (NO) in erythrocyte. The in vitro induced hiperfibrinogenemia interferes in the metabolism of the NO in the erythrocyte in dependence of the phosphorylation degree of the band 3. The soluble form of fibrinogen binds into CD47 protein present in the erythrocyte membrane. The soluble thrombomodulin is an inflammatory marker that binds to the erythrocyte CD47 in a site with a sequence peptide known as 4N1K. A study done in vitro shows that when hiperfibrinogenemia was induced in the presence of the peptide 4N1K agonist of CD47 it were observed variations in the efflux of NO from erythrocyte and an increase in the concentrations of GSNO, peroxinitrite, nitrite and nitrate of the erythrocytes. The aim of this work was to study the influence of the peptide 4N1K, on the metabolism of NO in the erythrocyte under high fibrinogen concentration and in the presence of inhibitors of the status of phosphorylation of protein band 3. In this in vitro study, whole blood samples were harvested from healthy subjects and NO, peroxynitrite, nitrite, nitrate and S-nitro-glutathione (GSNO) were determined in presence of 4N1K, calpeptine, Syk inhibitor and under high fibrinogen concentrations. The results obtained in erythrocytes under high fibrinogen levels when 4N1K is present with the Syk inhibitor or with calpeptine, showed in relation to the control samples increased significant concentrations of efflux of NO and of peroxynitrite, nitrite, nitrate and GSNO. In conclusion it was verified that in the in vitro model of hiperfibrinogenemia the peptide 4N1K, agonist of CD47, induces mobilization of NO in the erythrocyte in dependence of the status of phosphorylation of protein band 3.

  18. Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis

    PubMed Central

    Ni, Guanzhong; Qin, Jiaming; Fang, Ziyan; Chen, Yishu; Chen, Ziyi; Zhou, Jueqian; Zhou, Liemin

    2014-01-01

    Objective To determine whether valproate (VPA) monotherapy influences homocysteine metabolism in patients with epilepsy. Design Systematic review and meta-analysis. Data sources We searched all articles in English through PubMed, Web of Science and EMBASE published up to August 2013 concerning the homocysteine levels in VPA monotherapeutic patients with epilepsy. Participants VPA-treated patients with epilepsy (n=266) and matched healthy controls (n=489). Outcome measures Heterogeneity between studies was assessed using I2 statistics. Pooled standardised mean difference (SMD) and 95% CIs were calculated using a random effect model. Results A total of eight eligible studies were enrolled in our meta-analysis. We compared the plasma levels of homocysteine in VPA-treated patients with epilepsy and healthy controls. There was significant heterogeneity in the estimates according to the I2 test (I2=65.6%, p=0.005). Plasma homocysteine levels in VPA-treated patients with epilepsy were significantly higher than in healthy controls under a random effect model. (SMD, 0.62; 95% CI 0.32 to 0.92). Further subgroup analyses suggested that no significant differences were present when grouped by ethnicity and age, but the risk of heterogeneity in the West Asian group (I2=47.4%, p=0.107) was diminished when compared with that of the overall group (I2=65.6%, p=0.005). Conclusions Our meta-analysis indicates that VPA monotherapy is associated with the increase in plasma homocysteine levels in patients with epilepsy. Whether this association is influenced by ethnicity needs further research. PMID:25031190

  19. Plasma homocysteine levels are independently associated with alterations of large artery stiffness in men but not in women

    PubMed Central

    Sheng, Li; Wu, Cai; Bai, Yong-Yi; Xiao, Wen-Kai; Feng, Dan; Ye, Ping

    2015-01-01

    Objectives To investigate the associations of the plasma homocysteine levels with the alterations in arterial stiffness in a community-based cohort. The gender differences in these associations were examined. Methods We evaluated the relationship between plasma homocysteine levels to three measures of vascular function [carotid-femoral pulse wave velocity (CF-PWV), carotid-ankle PWV (CA-PWV) and heart rate corrected augmentation index (AI)] in 1680 participants (mean age: 61.5 years; 709 men, 971 women) from communities of Beijing, China. Results In univariate analysis, plasma homocysteine levels was positively related to the CF-PWV (r = 0.211, P < 0.0001) and CA-PWV (r = 0.148, P < 0.0001), whereas inversely associated with AI (r = −0.052, P = 0.016). In multiple linear regression models adjusting for covariants, plasma homocysteine remained positively related to the CF-PWV (standardized β = 0.065, P = 0.007) in total cases. When the groups of men and women were examined separately, plasma homocysteine remained positively associated with the CF-PWV (standardized β = 0.082, P = 0.023) in men, whereas the relations between homocysteine and any of the arterial stiffness indices were not further present in women. Conclusions In Chinese population, plasma homocysteine levels are independently associated with alterations of large artery stiffness in men but not in women. PMID:26089849

  20. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo.

    PubMed

    Yasar, Ali; Gunduz, Kamer; Onur, Ece; Calkan, Mehmet

    2012-01-01

    The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo.

  1. Excess levels of cysteine and homocysteine induce tibial dyschondroplasia in broiler chicks.

    PubMed

    Orth, M W; Bai, Y; Zeytun, I H; Cook, M E

    1992-03-01

    The effect of excessive levels of cysteine and homocysteine on tibial dyschondroplasia (TD) in broiler chicks was studied. In the first experiment, graded levels of L-cysteine as well as one level of L-homocysteine were supplemented to a corn-soybean-based diet adequate in sulfur amino acids. Levels equal to or above 0.5% supplemental cysteine increased the incidence of TD, and levels equal to or above 0.75% supplemental cysteine increased the severity of TD above that found in chicks fed the basal diet. Also, L-homocysteine at 0.5% induced TD. In the second experiment, graded levels of DL-homocystine were added to the basal diet to determine the threshold value of homocystine needed to induce TD, and a level of ammonium sulfate isosulfurous to 0.45% homocystine was added to a basal diet. The results showed that 0.45% DL-homocystine was the lowest level that increased the severity of TD above that found in chicks fed the basal diet and that sulfate did not induce TD. In the third experiment, a 2 x 2 factorial design was used to investigate the interaction between DL-homocystine and copper. Copper supplementation lessened the severity of TD caused by DL-homocystine. Copper supplementation also tended to improve growth, especially in birds fed DL-homocystine.

  2. PCOS women show significantly higher homocysteine level, independent to glucose and E2 level

    PubMed Central

    Eskandari, Zahra; Sadrkhanlou, Rajab-Ali; Nejati, Vahid; Tizro, Gholamreza

    2016-01-01

    Background: It is reasonable to think that some biochemical characteristics of follicular fluid (FF) surrounding the oocyte may play a critical role in determining the quality of oocyte and the subsequent potential needed to achieve fertilization and embryo development. Objective: This study was carried out to evaluate the levels of FF homocysteine (Hcy) in IVF candidate polycystic ovary syndrome (PCOS) women and any relationships with FF glucose and estradiol (E2) levels. Materials and Methods: In this case control study which was performed in Dr. Tizro Day Care and IVF Center 70 infertile patients were enrolled in two groups: comprising 35 PCOS and 35 non PCOS women. Long protocol was performed for all patients. FF Hcy, glucose and E2 levels were analyzed at the time of oocyte retrieval. Results: It was observed that FF Hcy level was significantly higher in PCOS patients compared with non PCOSs (p<0.01). Observations demonstrated that in PCOS group, the Hcy level increased independent to E2, glucose levels, BMI and age, while the PCOS group showed significantly higher BMI compared with non-PCOS group (p=0.03). However, no significant differences were revealed between groups for FF glucose and E2 levels. Conclusion: Present data showed that although FF glucose and E2 levels were constant in PCOS and non PCOS patients, but the FF Hcy levels in PCOS were significantly increased (p=0.01). PMID:27679823

  3. Vitamin B12, folate, homocysteine and urinary methylmalonic acid levels in infants.

    PubMed

    Karademir, F; Suleymanoglu, S; Ersen, A; Aydinoz, S; Gultepe, M; Meral, C; Ozkaya, H; Gocmen, I

    2007-01-01

    Serum vitamin B12 and folate, and their functional markers, plasma homocysteine and urinary methylmalonate (uMMA) were measured in 204 healthy, term infants at birth, and at 2 and 6 months. Compared with infants receiving formula food, those fed mother's milk had lower vitamin B12 and folate at 2 and 6 months. In infants receiving mother's milk, vitamin B12 levels were similar at birth (238 pg/ml) and 2 months (243 pg/ml), whereas with formula milk the level was significantly higher at 2 months (558 pg/ml) than at birth (257 pg/ml). Vitamin B12 was negatively correlated with homocysteine at birth and 6 months. The level of uMMA (mmol/mol creatinine) was higher at 2 (mother's milk, 25.5; formula, 23.97) and 6 months (19.77; 15) than at birth (11.97; 10.88), and was not correlated with vitamin B12 levels. Homocysteine may be a reliable marker of vitamin B12 status in neonates and infants; however, uMMA is not suitable as a marker of vitamin B12 status.

  4. Plasma homocysteine levels and hematological toxicity in NSCLC patients after the first cycle of pemetrexed under folate supplementation.

    PubMed

    Tanaka, Hisashi; Horiike, Atsushi; Sakatani, Toshio; Saito, Ryota; Yanagitani, Noriko; Kudo, Keita; Ohyanagi, Fumiyoshi; Horai, Takeshi; Nishio, Makoto

    2015-06-01

    Although baseline plasma homocysteine levels are related to pemetrexed toxicities in patients treated without folate supplementation, the relationship between these parameters in patients treated with folate supplementation is not well understood. The pretreatment plasma homocysteine levels were measured in non-small-cell lung cancer patients treated with pemetrexed alone under folate supplementation. Pemetrexed (500 mg/m) was administered every 3 weeks. As folate supplementation, folic acid (0.5 mg) was orally administered daily and vitamin B12 (1 mg) was injected intramuscularly every 9 weeks starting at least 1 week before treatment. The rate of toxicities during the first cycle of pemetrexed treatment with folate supplementations was evaluated and the relationship between the plasma homocysteine levels and toxicities was examined. Between June 2009 and November 2010, 58 patients were enrolled in this study. The median pretreatment plasma homocysteine level was 7.7 μmol/ml (3.5-34.6 μmol/ml). The pretreatment plasma homocysteine levels were above 11.5 μmol/ml in nine patients (15.5%). The pretreatment plasma homocysteine level correlated significantly with the nadir of the absolute counts of leukocytes, neutrophils, and thrombocytes (r = -0.374, P = 0.004; r = -0.286, P = 0.028; r = -0.324, P = 0.012, respectively). In addition, the rates of decrease in leukocytes, neutrophils, and thrombocytes correlated significantly with the pretreatment plasma homocysteine level (r = +0.378, P = 0.003; r = +0.335, P = 0.009; r = +0.363, P = 0.005, respectively). The plasma homocysteine level is associated with hematological toxicities in patients receiving pemetrexed with folate supplementation.

  5. HIGH D-DIMER LEVELS PREDICT A POOR OUTCOME IN PATIENTS WITH SEVERE TRAUMA, EVEN WITH HIGH FIBRINOGEN LEVELS ON ARRIVAL: A MULTICENTER RETROSPECTIVE STUDY.

    PubMed

    Hayakawa, Mineji; Maekawa, Kunihiko; Kushimoto, Shigeki; Kato, Hiroshi; Sasaki, Junichi; Ogura, Hiroshi; Matauoka, Tetsuya; Uejima, Toshifumi; Morimura, Naoto; Ishikura, Hiroyasu; Hagiwara, Akiyoshi; Takeda, Munekazu; Kaneko, Naoyuki; Saitoh, Daizoh; Kudo, Daisuke; Kanemura, Takashi; Shibusawa, Takayuki; Furugori, Shintaro; Nakamura, Yoshihiko; Shiraishi, Atsushi; Murata, Kiyoshi; Mayama, Gou; Yaguchi, Arino; Kim, Shiei; Takasu, Osamu; Nishiyama, Kazutaka

    2016-03-01

    Elevated D-dimer level in trauma patients is associated with tissue damage severity and is an indicator of hyperfibrinolysis during the early phase of trauma. To investigate the interacting effects of fibrinogen and D-dimer levels on arrival at the emergency department for massive transfusion and mortality in severe trauma patients in a multicenter retrospective study. This study included 519 adult trauma patients with an injury severity score ≥16. Patients with ≥10 units of red cell concentrate transfusion and/or death during the first 24 h were classified as having a poor outcome. Receiver operating characteristic curve analysis for predicting poor outcome showed the optimal cut-off fibrinogen and D-dimer values to be 190 mg/dL and 38 mg/L, respectively. On the basis of these values, patients were divided into four groups: low D-dimer (<38 mg/L)/high fibrinogen (>190 mg/dL), low D-dimer (<38 mg/L)/low fibrinogen (≤190 mg/dL), high D-dimer (≥38 mg/L)/high fibrinogen (>190 mg/dL), and high D-dimer (≥38 mg/L)/low fibrinogen (≤190 mg/dL). The survival rate was lower in the high D-dimer/low fibrinogen group than in the other groups. Moreover, the survival rate was lower in the high D-dimer/high fibrinogen group than in the low D-dimer/high fibrinogen and low D-dimer/low fibrinogen groups. High D-dimer level on arrival is a strong predictor of early death or requirement for massive transfusion in severe trauma patients, even with high fibrinogen levels.

  6. Vascular endothelial dysfunction associated with elevated serum homocysteine levels in rat adjuvant arthritis: effect of vitamin E administration.

    PubMed

    Can, Cenk; Cinar, Mehtap G; Koşay, Sezen; Evinç, Akgün

    2002-06-14

    We aimed to study the alterations in serum homocysteine levels and endothelium-dependent and -independent vascular relaxant responses in adjuvant-induced arthritis of the rat and to determine the effects of vitamin E administration on these changes. Arthritis was induced by a single intradermal injection of Freund's complete adjuvant into the paw. 26 days after the induction of arthritis, serum homocysteine levels and relaxant responses to acetylcholine and sodiumnitroprusside in thoracic aortas were evaluated. The relaxant responses to acetylcholine were decreased in aortas from arthritic rats, whereas the responses to sodiumnitroprusside were not significantly different when compared to the aortas from control rats. A significant increase was observed in serum homocysteine levels of the arthritic rats in comparison to those of controls. Vitamin E administration (100 mg/kg/day, i.m. for 26 days) to arthritic rats resulted in a significant increase in endothelium-dependent aortic responses to acetylcholine and a significant decrease in serum homocysteine levels with respect to the non-treated arthritic rats. However, in healthy rats, vitamin E treatment significantly decreased the acetylcholine-induced relaxant responses. We conclude that adjuvant-induced arthritis in the rat is associated with increased serum homocysteine levels and this is accompanied by a reduction in endothelium-dependent vascular responses in the thoracic aortas. Vitamin E treatment leads to normalization of the increased serum homocysteine levels and improves the endothelium-dependent relaxant responses in this experimental model.

  7. Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population

    PubMed Central

    Yakub, Mohsin; Moti, Naushad; Parveen, Siddiqa; Chaudhry, Bushra; Azam, Iqbal; Iqbal, Mohammad Perwaiz

    2012-01-01

    Background Hyperhomocysteinemia (>15 µmol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-β-synthase (CBS; T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population. Methodology/Principal Findings In a cross-sectional survey, 872 healthy adults (355 males and 517 females; age 18–60 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine; folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length- polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [β(SE β), 2.01(0.63) and 16.19(1.8) µmol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [β(SE β), −0.56(0.58) and −0.83(0.99) µmol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was −1.88(0.81) µmol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p value <0.001). Odds of having hyperhomocysteinemia with MTHFR 677TT genotype was 10-fold compared to MTHFR 677CC genotype [OR (95%CI); 10.17(3.6–28.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.34–0.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in

  8. Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients.

    PubMed

    Valkovic, Peter; Benetin, Ján; Blazícek, Pavol; Valkovicová, L'udmila; Gmitterová, Karin; Kukumberg, Peter

    2005-06-01

    Hyperhomocysteinemia is not only a major risk factor for atherothrombotic disease, but is also strongly associated with an increased risk of dementia and cognitive impairment, both of which are common in the course of Parkinson's disease (PD). Previous work has found that levodopa increases plasma homocysteine concentrations. Animal studies have indicated that the catechol-O-methyltransferase (COMT) inhibitors can prevent levodopa-induced elevation of homocysteine concentrations by reducing the O-methylation of levodopa. The objective of our study was to assess the impact of entacapone, a COMT inhibitor, on plasma levels of homocysteine, serum folate, and vitamin B12 in levodopa-treated PD patients. Nineteen PD patients receiving only levodopa and 21 PD patients on a combination of levodopa and entacapone participated in the cross-sectional study. The control group consisted of 17 subjects on dopamine agonists. The mean plasma homocysteine concentration in the subjects on only levodopa was higher than that in the subjects on a combination of levodopa and entacapone (P=0.001) or in the control group (P=0.0001). Concentrations of serum vitamin B12 and serum folate were on average normal in all groups, but levodopa-treated subjects (with or without entacapone therapy) were more prone to have hypovitaminosis B12 (45%) than controls on dopamine agonists (6%). We suggest that the COMT inhibition may play a promising role in successfully controlling levodopa-induced hyperhomocysteinemia and in reducing the risk of pathologies probably linked to it. These preliminary findings and postulated hypotheses must now be confirmed in prospective studies.

  9. Levels of Key Enzymes of Methionine-Homocysteine Metabolism in Preeclampsia

    PubMed Central

    Pérez-Sepúlveda, Alejandra; España-Perrot, Pedro P.; Fernández B, Ximena; Ahumada, Verónica; Bustos, Vicente; Arraztoa, José Antonio; Dobierzewska, Aneta; Figueroa-Diesel, Horacio; Rice, Gregory E.; Illanes, Sebastián E.

    2013-01-01

    Objective. To evaluate the role of key enzymes in the methionine-homocysteine metabolism (MHM) in the physiopathology of preeclampsia (PE). Methods. Plasma and placenta from pregnant women (32 controls and 16 PE patients) were analyzed after informed consent. Protein was quantified by western blot. RNA was obtained with RNA purification kit and was quantified by reverse transcritase followed by real-time PCR (RT-qPCR). Identification of the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and A2756G methionine synthase (MTR) SNP was performed using PCR followed by a high-resolution melting (HRM) analysis. S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH) were measured in plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). The SNP association analysis was carried out using Fisher's exact test. Statistical analysis was performed using a Mann-Whitney test. Results. RNA expression of MTHFR and MTR was significantly higher in patients with PE as compared with controls. Protein, SAM, and SAH levels showed no significant difference between preeclamptic patients and controls. No statistical differences between controls and PE patients were observed with the different SNPs studied. Conclusion. The RNA expression of MTHFR and MTR is elevated in placentas of PE patients, highlighting a potential compensation mechanism of the methionine-homocysteine metabolism in the physiopathology of this disease. PMID:24024209

  10. Preoperative Plasma Fibrinogen Level as a Significant Prognostic Factor in Patients With Localized Renal Cell Carcinoma After Surgical Treatment.

    PubMed

    Lee, Hakmin; Lee, Sang Eun; Byun, Seok-Soo; Kim, Hyeon Hoe; Kwak, Cheol; Hong, Sung Kyu

    2016-01-01

    We sought to investigate the association of preoperative fibrinogen levels with clinicopathologic outcomes after surgical treatment of nonmetastatic renal cell carcinoma. We reviewed the records of 1511 patients who had their fibrinogen levels measured preceding surgery. The associations between preoperative fibrinogen level and risk of adverse clinicopathologic outcomes were tested using the multivariate logistic regression and multiple Cox-proportional hazards model, respectively. Based on plasma fibrinogen levels, we stratified the patients into 2 groups with a cut-off value of 328  mg/dL. Kaplan-Meier analysis showed significantly inferior survival outcomes in progression-free (P < 0.001), cancer-specific (P < 0.001), and overall survival (P < 0.001). In multivariate analyses, a high fibrinogen level (≥328  mg/dL) was significantly related to a higher Fuhrman grade (hazard ratio [HR] 1.374, P = 0.006) and a larger tumor size (≥7  cm) (HR 2.364, P < 0.001). Multivariate Cox analysis also revealed that a high preoperative fibrinogen level is a significant predictor for poor disease progression (HR 1.857, P < 0.001), cancer-specific survival (HR 3.608, P = 0.003), and overall survival (HR 1.647, P = 0.027). Increased plasma fibrinogen levels were significantly associated with poor pathological features and worse survival outcomes in patients with nonmetastatic renal cell carcinoma after surgical treatment. Further evaluations such as prospective randomized trials are needed to understand the underlying mechanism for these associations.

  11. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects.

    PubMed

    Hsia, Chien-Hsun; Shen, Ming-Ching; Lin, Jen-Shiou; Wen, Yao-Ke; Hwang, Kai-Lin; Cham, Thau-Ming; Yang, Nae-Cherng

    2009-03-01

    Nattokinase, a serine proteinase from Bacillus subtilis, is considered to be one of the most active functional ingredients found in natto. In this study, we hypothesized that nattokinase could reduce certain factors of blood clotting and lipids that are associated with an increase risk for cardiovascular disease (CVD). Thus, an open-label, self-controlled clinical trial was conducted on subjects of the following groups: healthy volunteers (Healthy Group), patients with cardiovascular risk factors (Cardiovascular Group), and patients undergoing dialysis (Dialysis Group). All subjects ingested 2 capsules of nattokinase (2000 fibrinolysis units per capsule) daily orally for 2 months. The laboratory measurements were performed on the screening visit and, subsequently, regularly after the initiation of the study. The intent-to-treat analysis was performed on all 45 enrolled subjects. By use of mixed model analysis, a significant time effect, but not group effect, was observed in the change from baseline of fibrinogen (P = .003), factor VII (P < .001), and factor VIII (P < .001), suggesting that the plasma levels of the 3 coagulation factors continuously declined during intake; also, the extents of decrease were similar between groups. After 2 months of administration, fibrinogen, factor VII, and factor VIII decreased 9%, 14%, and 17%, respectively, for the Healthy Group; 7%, 13%, and 19%, respectively, for the Cardiovascular Group; and 10%, 7%, and 19%, respectively, for the Dialysis Group, whereas blood lipids were unaffected by nattokinase. No significant changes of uric acid or notable adverse events were observed in any of the subjects. In summary, this study showed that oral administration of nattokinase could be considered as a CVD nutraceutical by decreasing plasma levels of fibrinogen, factor VII, and factor VIII.

  12. Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk of arsenic-associated carotid atherosclerosis

    SciTech Connect

    Wu, M.-M.; Chiou, H.-Y. . E-mail: hychiou@tmu.edu.tw; Hsueh, Y.-M.; Hong, C.-T.; Su, C.-L.; Chang, S.-F.; Huang, W.-L.; Wang, H.-T.; Wang, Y.-H.; Hsieh, Y.-C.; Chen, C.-J.

    2006-10-01

    Arsenic-contaminated well water has been shown to increase the risk of atherosclerosis. Because of involving S-adenosylmethionine, homocysteine may modify the risk by interfering with the biomethylation of ingested arsenic. In this study, we assessed the effect of plasma homocysteine level and urinary monomethylarsonic acid (MMA{sup V}) on the risk of atherosclerosis associated with arsenic. In total, 163 patients with carotid atherosclerosis and 163 controls were studied. Lifetime cumulative arsenic exposure from well water for study subjects was measured as index of arsenic exposure. Homocysteine level was determined by high-performance liquid chromatography (HPLC). Proportion of MMA{sup V} (MMA%) was calculated by dividing with total arsenic species in urine, including arsenite, arsenate, MMA{sup V}, and dimethylarsinic acid (DMA{sup V}). Results of multiple linear regression analysis show a positive correlation of plasma homocysteine levels to the cumulative arsenic exposure after controlling for atherosclerosis status and nutritional factors (P < 0.05). This correlation, however, did not change substantially the effect of arsenic exposure on the risk of atherosclerosis as analyzed in a subsequent logistic regression model. Logistic regression analyses also show that elevated plasma homocysteine levels did not confer an independent risk for developing atherosclerosis in the study population. However, the risk of having atherosclerosis was increased to 5.4-fold (95% CI, 2.0-15.0) for the study subjects with high MMA% ({>=}16.5%) and high homocysteine levels ({>=}12.7 {mu}mol/l) as compared to those with low MMA% (<9.9%) and low homocysteine levels (<12.7 {mu}mol/l). Elevated homocysteinemia may exacerbate the formation of atherosclerosis related to arsenic exposure in individuals with high levels of MMA% in urine.

  13. Evaluation of an Association of Blood Homocysteine Levels With Gastric Cancer Risk From 27 Case-Control Studies.

    PubMed

    Xu, Wei; Cheng, Yuelei; Zhu, Huirong

    2016-05-01

    High blood homocysteine levels may risk gastric cancer. However, observational studies have been plagued by chance, bias, confounding, or reverse causality. In this study, we assessed the relationship between blood homocysteine levels and gastric cancer by using a Mendelian randomization method, which is independent of nongenetic confounding.We took 2 steps to perform Mendelian randomization analysis. First, we evaluated the methylenetetrahydrofolate reductase (MTHFR) C677T association with gastric cancer by a meta-analysis of case-control studies including 7566 patients with gastric cancer and 10 640 control subjects from 27 Case-Control studies. Second, MTHFR C677T polymorphism, which affects the blood homocysteine levels, was used as an instrumental variable to calculate the risk and estimate the association of gastric cancer with this single nucleotide polymorphism (SNP). We obtained an estimate to the association of blood total homocysteine levels with this SNP from a meta-analysis of Genome-Wide Association Studies (GWAS), which comprises a total of 44 147 individuals.In our Mendelian randomization analysis, we demonstrated a significant effect of the blood homocysteine levels on gastric cancer risk, representing an OR of 2.56 (95% CI = 2.41-2.72; P = 5.0×10) for gastric cancer per 1-SD increase in the natural log-transformed blood total homocysteine levels.We proved that there is a causal relationship between blood total homocysteine and risk of gastric cancer, and this study will add insight into the treatment and pathology research of gastric cancer.

  14. The pretreatment platelet and plasma fibrinogen level correlate with tumor progression and metastasis in patients with pancreatic cancer.

    PubMed

    Wang, Haiyan; Gao, Jinbiao; Bai, Ming; Liu, Rui; Li, Hongli; Deng, Ting; Zhou, Likun; Han, Rubing; Ge, Shaohua; Huang, Dingzhi; Ba, Yi

    2014-01-01

    Cancer patients frequently present with activated coagulation pathways and thrombocytosis, which are potentially associated with tumor progression and prognosis. However, the prognostic value of abnormal plasma fibrinogen and platelet levels for the treatment of pancreatic cancer is unclear. The purpose of our study was to evaluate the prognostic value of plasma fibrinogen and platelet levels in pancreatic cancer, and to devise a prognostic model to identify the patients with greatest risk for a poor overall survival. One hundred and twenty-five patients diagnosed with pancreatic ductal adenocarcinoma in our hospital between May 2000 and June 2005 were included in this study. The plasma fibrinogen and platelet levels were examined before treatment and analyzed along with patient clinicopathological parameters and overall survival. The foundation of prognostic model was based on the risk factors according to the Cox proportional hazard model. The incidence of hyperfibrinogenemia and thrombocytosis was 24.8% (31/125) and 15.2% (19/125), respectively. The mean fibrinogen concentration differed significantly between the early (I/II) and late (III/IV) stage patients (3.19 ± 0.70 vs. 3.65 ± 0.90 g/l, p = 0.008). Patients with a higher concentration of plasma fibrinogen and platelets had a worse prognosis (p < 0.05). There also existed a significant correlation between higher fibrinogen/platelet levels and distant organ metastasis (p < 0.05, respectively). Bivariate correlation analysis showed that plasma fibrinogen levels correlated significantly with platelet levels (p = 0.000). Multivariate analysis revealed that pretreatment plasma fibrinogen levels (p = 0.027), tumor stage (p = 0.026) and distant metastasis (p = 0.027) were independent prognostic factors. The median survival time for the low-, intermediate-, and high-risk groups was 9.6 months (95% CI 6.2-13.0), 3.8 months (95% CI 2.3-5.3), and 2.3 months (95% CI 0

  15. Evaluation and correlation of stress scores with blood pressure, endogenous cortisol levels, and homocysteine levels in patients with central serous chorioretinopathy and comparison with age-matched controls

    PubMed Central

    Agarwal, Abhishek; Garg, Monika; Dixit, Nikhil; Godara, Rohini

    2016-01-01

    Context: Stress had been associated with the development of central serous chorioretinopathy (CSC). The study was designed to evaluate the effect of stress on other risk factors of CSC such as serum cortisol levels, serum homocysteine levels, and blood pressure (BP) in CSC patients. Aims: To compare stress scores, serum cortisol and serum homocysteine levels, and BP of CSC patients with that of control population and to correlate stress scores of CSC patients with BP, serum cortisol levels, and serum homocysteine levels. Materials and Methods: Stress scores, serum morning and evening cortisol levels, serum homocysteine levels, systolic and diastolic BP of 54 CSC patients were measured and compared with that of 54 age- and sex-related controls using Student's t-test. Stress scores of CSC patients were correlated with systolic and diastolic BP, serum morning and evening cortisol levels and serum homocysteine levels and Pearson correlation coefficient (r) were calculated. Results: Stress scores, serum homocysteine levels, serum morning and evening cortisol levels, and systolic and diastolic BP were all elevated in CSC patients as compared with age- and sex-related controls (P < 0.05). Stress scores of CSC patients were found to correlate strongly with serum homocysteine levels, serum morning and evening cortisol levels, and systolic and diastolic BP, with r values 0.82, 0.8, 0.8, 0.8, and 0.81, respectively (P < 0.0001). Conclusions: Stress scores were elevated in CSC patients and were strongly correlated with serum homocysteine and cortisol levels and BP. PMID:27958201

  16. Serum Asymmetric Dimethylarginine, Nitrate, Vitamin B12, and Homocysteine Levels in Individuals with Pulmonary Embolism

    PubMed Central

    Altuntaş, Murat; Atalay, Figen; Can, Murat; Altın, Remzi; Tor, Meltem

    2011-01-01

    We aimed to analyze the pre- and posttreatment serum asymmetric dimethylarginine (ADMA), nitrate (NO3), vitamin B12 and homocysteine levels in pulmonary embolism (PTE) patients and to determine the prognostic value of these variables in predicting chronic thromboembolic pulmonary hypertension (CTEPH). This study was conducted in 64 patients. The patients were classified into the two groups: patients with normal pulmonary artery pressure (PAP) (group I) and patients with high PAP with persistent lung perfusion defects or who died at the end of 3 months of therapy (group II). We found statistically significant differences between two groups with respect to the partial oxygen pressure, the oxygen saturation, and the PAP, but there was no difference between the two groups with respect to the pretreatment ADMA, NO3, or homocysteine levels. The vitamin B12 levels were higher in group II. The NO3 levels increased and the ADMA and vitamin B12 levels decreased with treatment in both groups. These results suggest that these parameters are not predictive of the development of CTEPH. PMID:21765614

  17. Serum asymmetric dimethylarginine, nitrate, vitamin B(12), and homocysteine levels in individuals with pulmonary embolism.

    PubMed

    Altuntaş, Murat; Atalay, Figen; Can, Murat; Altın, Remzi; Tor, Meltem

    2011-01-01

    We aimed to analyze the pre- and posttreatment serum asymmetric dimethylarginine (ADMA), nitrate (NO(3)), vitamin B(12) and homocysteine levels in pulmonary embolism (PTE) patients and to determine the prognostic value of these variables in predicting chronic thromboembolic pulmonary hypertension (CTEPH). This study was conducted in 64 patients. The patients were classified into the two groups: patients with normal pulmonary artery pressure (PAP) (group I) and patients with high PAP with persistent lung perfusion defects or who died at the end of 3 months of therapy (group II). We found statistically significant differences between two groups with respect to the partial oxygen pressure, the oxygen saturation, and the PAP, but there was no difference between the two groups with respect to the pretreatment ADMA, NO(3), or homocysteine levels. The vitamin B(12) levels were higher in group II. The NO(3) levels increased and the ADMA and vitamin B(12) levels decreased with treatment in both groups. These results suggest that these parameters are not predictive of the development of CTEPH.

  18. Association of plasma homocysteine, vitamin B12 and folate levels with cognitive function in Parkinson's disease: A meta-analysis.

    PubMed

    Xie, Yi; Feng, Hongliang; Peng, Sisi; Xiao, Jinsong; Zhang, Junjian

    2017-01-01

    Hyperhomocysteinemia has been associated with cognitive disorders such as mild cognitive impairment, Alzheimer's disease and vascular dementia. Previous studies showed that levodopa-treated Parkinson's disease (PD) patients were likely to have elevated homocysteine levels. In addition, epidemiological evidence found that cognitive impairment presented in the vast majority of PD patients. However, what role homocysteine played in cognitive function of PD patients remained debated. Therefore, we conducted this meta-analysis to investigate the possible correlations among cognitive function, homocysteine, folate and vitamin B12 levels in PD patients. A structured literature search was carried out on Pubmed, Springer, EMbase, Cochrane library, CNKI, VP and Wanfang database up to April 2016 using strict inclusion criteria. Data on demographic information, levodopa equivalent dosage, homocysteine, folate and vitamin B12 levels and Mini Mental Scale Examination scores were collected and pooled. The mean difference (MD) with 95% confidence intervals (CIs) was used as the effect size. Of 75 articles identified, 15 were eligible for inclusion. The results suggested that PD patients with cognitive dysfunction were likely to have higher homocysteine levels(MD=5.05, 95%CI [4.03, 6.07]), lower folate(MD=-0.21, 95%CI [-0.34, -0.08]) and vitamin B12 levels(MD=-47.58, 95%CI [-72.07, -23.09]). We again verified a close relationship between hyperhomocysteinemia and PD (MD=5.67, 95%CI [4.40, 6.94]). We concluded that hyperhomocysteinemia was related to cognitive impairment of PD patients, and further studies should focus on the intervention to lower homocysteine level, hopefully to provide useful advice for clinical practice.

  19. C677T and A1298C Polymorphisms of MTHFR Gene and Their Relation to Homocysteine Levels in Turner Syndrome

    PubMed Central

    Oliveira, Kelly C.; Verreschi, Ieda T.N.; Sugawara, Eduardo K.; Silva, Vanessa C.; Galera, Bianca B.; Galera, Marcial Francis; Bianco, Bianca

    2012-01-01

    Aims: To determine the frequency of C677T and A1298C polymorphisms of the MTHFR gene and correlate them with homocysteine serum levels in patients with Turner syndrome (TS) and controls. Methods: This case–control study included 78 women with TS and a control group of 372 healthy individuals without personal or family history of cardiovascular disease and cancer. C677T (rs1801133) and A1298C (rs1801131) polymorphisms were detected by polymerase chain reaction–restriction fragment-length polymorphism and the TaqMan system, respectively. Homocysteine serum levels were determined by high-performance liquid chromatography. The results were analyzed statistically, and p<0.05 was considered to represent a significant difference. Results: The homocysteine levels change was 13.9+3.3 nM in patients with TS and 8.8+3.2 nM in the control group. No significant difference between groups was found (p=0.348). Single-marker analysis revealed no association between MTHFR C677T polymorphism and TS when genotype (p=0.063) or allelic (p=0.277) distribution was considered. Regarding MTHFR A1298C polymorphism, a statistical difference was found between the TS group and the control group, for both genotype (p<0.0001) and allele (p<0.0001) distribution. Haplotype analysis of 2 MTHFR polymorphisms identified 2 haplotypes—CC and TC—associated with TS (p<0.001 and p=0.0165, respectively). However, homocysteine levels were not higher in patients with haplotype risk. Conclusion: The results suggest that the C677T and A1298C polymorphisms of the MTHFR gene are not related to homocysteine levels in Brazilian patients with TS, despite the differential distribution of the mutated allele C (A1298C) in these patients. Further studies are needed to investigate the possible genetic interaction with homocysteine levels in TS. PMID:22283972

  20. The effect of N-acetylcysteine supplementation on serum homocysteine levels and hepatic and renal oxidative stress in homocysteine thiolactone-treated rats.

    PubMed

    Kondakçı, Gamze; Aydın, A Fatih; Doğru-Abbasoğlu, Semra; Uysal, Müjdat

    2017-05-01

    The effect of N-acetylcysteine (NAC) (1 g/kg body weight/day) on serum homocysteine (Hcy) levels, insulin resistance (IR), and hepatic and renal prooxidant-antioxidant balance was evaluated in rats treated with homocysteine thiolactone (HcyT) (500 mg/kg body weight/day for 6 weeks). Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione, ferric reducing antioxidant power, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were determined in the liver and kidney. HcyT elevated serum Hcy levels and caused IR, but liver and kidney function tests remained unchanged. HcyT increased ROS and MDA without any change in hepatic antioxidants, but it elevated renal SOD and GSH-Px activities. NAC decreased serum Hcy, hepatic and renal ROS and MDA levels, and renal SOD and GSH-Px activities in rats with high Hcy levels. However, it did not ameliorate IR. Our results indicate that NAC supplementation may be effective in decreasing Hcy levels and Hcy-induced hepatic and renal oxidative stress.

  1. Effect of body weight on serum homocysteine level in patients with polycystic ovarian syndrome: A case control study

    PubMed Central

    I. Al- Gareeb, Ali; Abd Al- Amieer, Wafaa Salah; M. Alkuraishy, Hayder; J. Al- Mayahi, Thabat

    2016-01-01

    Background: Polycystic ovarian syndrome (PCOS) represent one of the common endocrine disorders which influence around 8% of reproductive women whom usually suffering from obesity and increase cardiovascular risk. Serum homocysteine levels are associated with bad impact on endothelial functions and considered as an independent risk factor for cardiovascular disease. Objective: The aim was to study the level of plasma homocysteine in obese and non-obese Iraqi patients with PCOS. Materials and Methods: This study was carried out on 207 women. Of theme, 101 women with PCOS and 106 PCOS- free women served as controls. Blood sample was taken from each participant on the 2nd day of menstruation morning after an overnight fasting. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone and androstenedione were measured. Moreover, total lipid profile and plasma homocysteine levels were measured in both groups. Results: Sixty percent of PCOS women were overweight or obese and 56% of them had a waist circumference >88cm. Moreover plasma homocysteine concentrations were found to be higher in patients with PCOS (11.5±5.41μmol/L) as compared with control (8.10±1.89 μmol/L) (p<0.002). Furthermore the homocysteine concentrations were 13.19±5.97 μmol/L and 9.38±2.99 μmol/L in both obese and normal-weight PCOS women respectively which was significantly higher than obese (p<0.002) and normal-weight (p<0.004) control women. Conclusion: Increase in body weight is not an independent risk factor to increase plasma homocysteine levels in PCOS women. PMID:27200421

  2. The estimation of fibrinogen levels in animal plasmas by a simple refractometric method. A comparison with a biuret method.

    PubMed

    Sutton, R H

    1977-05-01

    A comparison was made between a biuret (reference) method and a simple refractometric (test) method for measuring fibrinogen levels in 84 animal plasmas. Although the correlation between the two methods was high (4=0.90 P less than 0-001) there was considerable random variation in the refractometric results in relation to the biuret results. This was thought to be due in part to the fact that refractometric results could only be expressed in multiples of 2.4 g/litre. In spite of this limitation, the refractometric method, on the grounds of speen and simplicity, is considered to have worthwhile application for fibrinogen determinations in practice laboratory.

  3. Elevated D-dimer and fibrinogen levels in serum of preoperative bone fracture patients.

    PubMed

    Liu, Chen; Song, Ying; Zhao, Jingzhong; Xu, Qinzhu; Liu, Ning; Zhao, Lei; Lu, Songsong; Wang, Hui

    2016-01-01

    The changes of coagulation parameters in preoperative fracture patients reflect the coagulation status before surgery. We did retrospective assessment of preoperative fracture patients (n = 113) admitted to the hospital between September 2013 and September 2014. The control group were selected from healthy adults (n = 113) with matched age and gender. Platelet, PT INR, APTT, fibrinogen (FIB) and D-dimer values were collected and analyzed. PT INR level was 1.043 ± 0.119, APTT was 31.91 ± 7.56 s, FIB was 320.6 ± 71.8 mg/dl and D-dimer was 1283 ± 1582 ng/ml for the fracture patients. For the control group, PT INR level was 0.9976 ± 0.0602, APTT was 33.22 ± 2.55 s, FIB was 277.3 ± 44.7 mg/dl and D-dimer was 97.53 ± 63.90 ng/ml. Meanwhile, D-dimer levels of different sites of fractures were also measured: Femora 2448 ± 1961 ng/ml; Humerus 792.4 ± 691.2 ng/ml; Ulna/Radius 619.4 ± 843.7 ng/ml; Vertebra 647.7 ± 787.1 ng/ml; Tibia/Fibula 496.3 ± 268.8 ng/ml; Clavicle 260.9 ± 170.9 ng/ml; Ankle 415.4 ± 286.6 ng/ml. To conclude, D-dimer and fibrinogen levels get higher in preoperative fracture patients than controls. Besides, D-dimer levels are significantly different among different locations of fractures, and our data revealed that D-dimer levels of Femora fracture were higher than other sites.

  4. No relation between folate and homocysteine levels and depression in early pregnant women.

    PubMed

    Watanabe, Hiroko; Suganuma, Nobuhiko; Hayashi, Ayako; Hirowatari, Yumiko; Hirowatari, Tsuneharu; Ohsawa, Masami

    2010-12-01

    The objective in this study was to evaluate the association between folate and homocysteine (Hcy) levels and depressive symptoms in early pregnancy. A cross-sectional study was conducted with 86 pregnant women in the first trimester. A Japanese version of the Center for Epidemiologic Studies Depression (CES-D) scale was used to screen for depression. Non-fasting blood samples were collected from the women to measure folate and Hcy levels. Fifty-three (61.6%) women scored at or above a clinical cut-off of 16, and were classified with depression. In logistic regression analyses, no significant associations were observed between the incidence of depression in the first trimester and elevated Hcy and deficiencies of serum folate, folate intake, vitamin B6 intake and vitamin B12 intake. Folate and Hcy concentrations, and folate consumption, may not be protective against depression in early pregnancy.

  5. Critical levels of brain atrophy associated with homocysteine and cognitive decline.

    PubMed

    de Jager, Celeste A

    2014-09-01

    Few B-vitamin trials to lower homocysteine (Hcy) have reported evidence of beneficial effects on cognition in older adults with cognitive impairment or Alzheimer's disease. This article reviews the role of Hcy in cognitive decline. It also considers some reasons why meta-analyses have failed to find effects of B-vitamin treatment. Findings from the successful VITACOG trial are examined from a new perspective of critical levels of Hcy and brain atrophy that may impact on the efficacy of B-vitamin treatment. It appears that there is a critical level of brain shrinkage, possibly mediated by elevated Hcy, which when reached, results in cognitive decline, especially in episodic memory performance. Supplements, food sources, and effects of folic acid fortification are discussed in relation to B12 deficiency.

  6. Mutations in methylenetetrahydrofolate reductase and in cysthationine beta synthase: is there a link to homocysteine levels in peripheral arterial disease?

    PubMed

    Santos, Maria E R C; das C L E Silva, Francisco; Gomes, Karina B; Fernandes, Ana Paula M; Freitas, Fernanda R; Faria, Mayara C; Mota, Ana Paula L; Carvalho, Maria G

    2011-06-01

    Peripheral arterial disease (PAD) is an atherosclerotic disturbance characterized by a progressive obstruction of lower limb arteries. Many risk factors associated with PAD development have being reported in the literature. The present study aimed to investigate whether mutations in the methylenetetrahydrofolate reductase (MTHFR) or in the cystathionine beta synthase (CBS) genes are associated with higher levels of homocysteine and the risk of PAD in patients from Brazil. This study analyzed 39 patients with PAD and 32 without PAD in whom risk factors and C677T mutations in the MTHFR gene and both 844ins68 and T833C mutations in the CBS gene were investigated. Although higher levels of homocysteine could be observed in patients with PAD compared to controls, no association between the increase of homocysteine and the frequency of C677T, 844ins68, and T833C mutations could be observed. The results suggest that these mutations do not appear to be related to either homocysteine levels or the development of the disease. However, hyperhomocysteinemia and smoking are important factors in PAD development.

  7. Reintroduction of a Homocysteine Level-Associated Allele into East Asians by Neanderthal Introgression.

    PubMed

    Hu, Ya; Ding, Qiliang; He, Yungang; Xu, Shuhua; Jin, Li

    2015-12-01

    In this study, we present an analysis of Neanderthal introgression at the dipeptidase 1 gene, DPEP1. A Neanderthal origin for the putative introgressive haplotypes was demonstrated using an established three-step approach. This introgression was under positive natural selection, reached a frequency of >50%, and introduced a homocysteine level- and pigmentation-associated allele (rs460879-T) into East Asians. However, the same allele was also found in non-East Asians, but not from Neanderthal introgression. It is likely that rs460879-T was lost in East Asians and was reintroduced subsequently through Neanderthal introgression. Our findings suggest that Neanderthal introgression could reintroduce an important previously existing allele into populations where the allele had been lost. This study sheds new light on understanding the contribution of Neanderthal introgression to the adaptation of non-Africans.

  8. Circulating tumor cell detection during chemotherapy in patients with breast cancer is not associated with plasma homocysteine levels.

    PubMed

    Yoshihara, Renata Nunes; Teixeira, Bianca Marinelli; Adami, Fernando; Kuniyoshi, Renata K; Alves, Beatriz C A; Gehrke, Flávia S; Vilas-Bôas, Viviane A; Azzalis, Ligia A; Junqueira, Virginia B C; Pereira, Edimar Cristiano; Fonseca, Fernando L A

    2013-10-01

    Breast cancer remains the second most frequent type of cancer in the world and the first among women, and systemic chemotherapy is an adjuvant therapeutic modality that improves survival in a great part of patients. Women with breast cancer, however, frequently show a higher risk of thromboembolism, an event associated to hyperhomocysteinemia and the presence of circulating tumor cells (CTC). Our aim is to correlate the presence of CTCs, detected by the analysis of CK19 and c-erbB2 gene expressions, and the homocysteine plasma levels in the peripheral blood in patients with breast cancer undergoing chemotherapy. Epithelial marker expression (CK19 and c-erbB2) and homocysteine levels were analyzed in a mononuclear fraction of the peripheral blood and plasma, respectively, obtained from 35 patients diagnosed with breast cancer at diagnosis and throughout chemotherapy treatment. No significant relation between the CK19 and c-erbB2 expressions and hyperhomocysteinemia was observed at any moment of the evaluation throughout the chemotherapy treatment (3 and 6 months after the onset). Among clinical data, only menopausal status showed a statistically significant correlation with homocysteine concentration. Although differences in the expressions of the analyzed epithelial markers were detected at 3 and 6 months of chemotherapy treatment, no relation between plasma homocysteine variations and the CK19 and c-erbB2 gene expressions was found in patients under chemotherapy treatment at any moment of the evaluation, suggesting that chemotherapy affects the expressions of the studied genes independently.

  9. Elevated Plasma Homocysteine Level Increased the Risk of Early Renal Impairment in Acute Ischemic Stroke Patients.

    PubMed

    Chen, Jingjuan; Li, Guode; Xu, Zuohang; Zhang, Chengguo; Wang, Yukai; Xie, Haiqun; Shao, Yan; Peng, Lingmei; Lu, Jiancong; Yuan, Dahua

    2017-03-08

    Renal insufficiency is associated with the prognosis of acute ischemic stroke (AIS) and homocysteine (Hcy) levels. This study investigated the association between plasma Hcy levels and renal insufficiency in patients with AIS. A total of 987 patients with AIS who had been treated at the First People's Hospital of Foshan between 2011 and 2014 were retrospectively studied. Based on their cystatin C (Cys C) levels, the patients were divided into the normal renal function group (Cys C ≤ 1.25 mg/L) or the renal impairment group (Cys C > 1.25 mg/L). Multivariate regression analysis was applied to reveal the association between hyperhomocysteinemia (HHcy) and renal impairment. The renal impairment group showed more advanced age of onset, higher percentage of prior stroke and hypertension, higher baseline National Institute of Health Stroke Scale score, lower high-density lipoprotein cholesterol levels, and higher Hcy levels compared with the normal renal function group. A multivariate analysis revealed a relationship between early renal impairment and Hcy levels: an increase of Hcy by 1 μmol/L was associated with an increase of 12-18% of the risk of renal impairment among patients with AIS and HHcy. Patients with AIS and HHcy had a 2.42-3.51 fold increase of the risk of renal impairment compared with patients with normal Hcy level (P < 0.001). In conclusion, patients with stroke and HHcy could be more prone to renal impairment.

  10. Zinc and homocysteine levels in polycystic ovarian syndrome patients with insulin resistance.

    PubMed

    Guler, Ismail; Himmetoglu, Ozdemir; Turp, Ahmet; Erdem, Ahmet; Erdem, Mehmet; Onan, M Anıl; Taskiran, Cagatay; Taslipinar, Mine Yavuz; Guner, Haldun

    2014-06-01

    In this study, our objective was to evaluating the value of serum zinc levels as an etiologic and prognostic marker in patients with polycystic ovarian syndrome. We conducted a prospective study, including 53 women with polycystic ovarian syndrome and 33 healthy controls. We compared serum zinc levels, as well as clinical and metabolic features, of the cases. We also compared serum zinc levels between patients with polycystic ovarian syndrome with insulin resistance. Mean zinc levels were found to be significantly lower in patients with polycystic ovarian syndrome than healthy controls. Multiple logistic regression analysis of significant metabolic variables between polycystic ovarian syndrome and control groups (serum zinc level, body mass index, the ratio of triglyceride/high-density lipoprotein cholesterol, and homocysteine) revealed that zinc level was the most significant variable to predict polycystic ovarian syndrome. Mean serum zinc levels tended to be lower in patients with polycystic ovarian syndrome with impaired glucose tolerance than patients with normal glucose tolerance, but the difference was not statistically significant. In conclusion, zinc deficiency may play a role in the pathogenesis of polycystic ovarian syndrome and may be related with its long-term metabolic complications.

  11. Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia.

    PubMed

    Nishi, Akira; Numata, Shusuke; Tajima, Atsushi; Kinoshita, Makoto; Kikuchi, Kumiko; Shimodera, Shinji; Tomotake, Masahito; Ohi, Kazutaka; Hashimoto, Ryota; Imoto, Issei; Takeda, Masatoshi; Ohmori, Tetsuro

    2014-09-01

    Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia.

  12. Electrocardiogram Derived QRS Duration >120 ms is Associated With Elevated Plasma Homocysteine Levels in a Rural Australian Cross-Sectional Population.

    PubMed

    Leng, Yvonne Lee Yin; Zhou, Yuling; Ke, Honghong; Jelinek, Herbert; McCabe, Joel; Assareh, Hassan; McLachlan, Craig S

    2015-07-01

    Homocysteine levels in the low to moderate range for cardiovascular risk have been previously associated with left ventricular cardiac hypertrophy (LVH). Electrocardiogram (ECG) derived QRS duration has also been used as an epidemiological screening marker for cardiac hypertrophy risk. QRS duration cut offs have not been previously modeled to assess homocysteine levels in community populations. Our aims are to determine if QRS duration is associated with an elevated homocysteine level in a cross-sectional Australian aging rural population.A retrospective study design utilizing a rural health diabetic screening clinic database containing observational data from the period January 9, 2002 till September 25, 2012. One hundred seventy-eight individuals (>21 years of age) from the database were included in the study. Inclusion criteria included being nondiabetic and having both a QRS duration measure and a matching homocysteine level within the same subject. All participants were from the Albury-Wodonga area, with a mean age of >64 years for both sexes.Mean population homocysteine plasma levels were 10.4 μmol/L (SD = 3.6). The mean QRS duration was 101.8 ms (SD = 17.4). Groups were stratified on the basis of QRS duration (≤120 ms [n = 157] and >120 ms [n = 21]). QRS duration subgroup (≤120 ms vs >120 ms) mean differences across homocysteine levels were 10.1 μmol/L (SD = 3.3) and 12.2 μmol/L (SD = 4.7), respectively (P = 0.016). Other ECG parameters (PQ interval, QTc interval, and QT dispersion) measurements were not significantly associated with differences in plasma homocysteine (P = not significant).We conclude that in community populations homocysteine may be moderately elevated when QRS durations are >120 ms. Small additional increases in homocysteine levels may suggest a risk factor for ECG diagnosis of LVH.

  13. Plasmatic higher levels of homocysteine in Non-alcoholic fatty liver disease (NAFLD)

    PubMed Central

    2013-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The increased serum levels of homocysteine (Hcy) may be associated with hepatic fat accumulation. Genetic mutations in the folate route may only mildly impair Hcy metabolism. The aim of this study was to investigate the relation between liver steatosis with plasma homocysteine level and MTHFR C677T and A1298C polymorphisms in Brazilian patients with NAFLD. Methods Thirty-five patients diagnosed with NAFLD by liver biopsy and forty-five healthy controls neither age nor sex matched were genotyped for C677T and A1298C MTHFR polymorphisms using PCR-RFLP and PCR-ASA, respectively, and Hcy was determined by HPLC. All patients were negative for markers of Wilson’s, hemochromatosis and autoimmune diseases. Their daily alcohol intake was less than 100 g/week. A set of metabolic and serum lipid markers were also measured at the time of liver biopsies. Results The plasma Hcy level was higher in NAFLD patients compared to the control group (p = 0.0341). No statistical difference for genotypes 677C/T (p = 0.110) and 1298A/C (p = 0.343) in patients with NAFLD and control subjects was observed. The genotypes distribution was in Hardy-Weinberg equilibrium (677C/T p = 0.694 and 1298 A/C p = 0.188). The group of patients and controls showed a statistically significant difference (p < 0.001) for BMI and HOMA_IR, similarly to HDL cholesterol levels (p < 0,006), AST, ALT, γGT, AP and triglycerides levels (p < 0.001). A negative correlation was observed between levels of vitamin B12 and Hcy concentration (p = 0.005). Conclusion Our results indicate that plasma Hcy was higher in NAFLD than controls. The MTHFR C677T and A1298C polymorphisms did not differ significantly between groups, despite the 677TT homozygous frequency was higher in patients (17

  14. Social connectedness is associated with fibrinogen level in a human social network.

    PubMed

    Kim, David A; Benjamin, Emelia J; Fowler, James H; Christakis, Nicholas A

    2016-08-31

    Socially isolated individuals face elevated rates of illness and death. Conventional measures of social connectedness reflect an individual's perceived network and can be subject to bias and variation in reporting. In this study of a large human social network, we find that greater indegree, a sociocentric measure of friendship and familial ties identified by a subject's social connections rather than by the subject, predicts significantly lower concentrations of fibrinogen (a biomarker of inflammation and cardiac risk), after adjusting for demographics, education, medical history and known predictors of cardiac risk. The association between fibrinogen and social isolation, as measured by low indegree, is comparable to the effect of smoking, and greater than that of low education, a conventional measure of socioeconomic disadvantage. By contrast, outdegree, which reflects an individual's perceived connectedness, displays a significantly weaker association with fibrinogen concentrations.

  15. Fatty acid status and its relationship to cognitive decline and homocysteine levels in the elderly.

    PubMed

    Baierle, Marília; Vencato, Patrícia H; Oldenburg, Luiza; Bordignon, Suelen; Zibetti, Murilo; Trentini, Clarissa M; Duarte, Marta M M F; Veit, Juliana C; Somacal, Sabrina; Emanuelli, Tatiana; Grune, Tilman; Breusing, Nicolle; Garcia, Solange C

    2014-09-12

    Polyunsaturated fatty acids (PUFAs), especially the n-3 series, are known for their protective effects. Considering that cardiovascular diseases are risk factors for dementia, which is common at aging, the aim of this study was to evaluate whether fatty acid status in the elderly was associated with cognitive function and cardiovascular risk. Forty-five elderly persons (age ≥ 60 years) were included and divided into two groups based on their Mini-Mental Status Examination score adjusted for educational level: the case group (n = 12) and the control group (n = 33). Serum fatty acid composition, homocysteine (Hcy), hs-CRP, lipid profile and different cognitive domains were evaluated. The case group, characterized by reduced cognitive performance, showed higher levels of 14:0, 16:0, 16:1n-7 fatty acids and lower levels of 22:0, 24:1n-9, 22:6n-3 (DHA) and total PUFAs compared to the control group (p < 0.05). The n-6/n-3 ratio was elevated in both study groups, whereas alterations in Hcy, hs-CRP and lipid profile were observed in the case group. Cognitive function was positively associated with the 24:1n-9, DHA and total n-3 PUFAs, while 14:0, 16:0 and 16:1n-7 fatty acids, the n-6/n-3 ratio and Hcy were inversely associated. In addition, n-3 PUFAs, particularly DHA, were inversely associated with cardiovascular risk, assessed by Hcy levels in the elderly.

  16. Evaluation of homocysteine levels in individuals having nonsyndromic cleft lip with or without palate

    PubMed Central

    Abdulla, Riaz; Tellis, Rouchelle Charmaine; Athikari, Roshan; Kudkuli, Jagadish

    2016-01-01

    Context: Nonsyndromic cleft lip with or without palate (NSCL ± P) is a genetic predisposition involving defects in shape and makeup of the lip and palate. Elevation of homocysteine (Hcy) levels is seen in medical complications such as developmental anomalies causing neural tube defects, congenital vascular diseases, neurodegenerative and psychiatric conditions. Evaluation of serum Hcy levels forms an important feature to look further into molecular aspects. Aims: The aim of this study was to evaluate the Hcy levels in NSCL ± P cases by comparing with control cases having no orofacial deformities. Settings and Design: This study was performed with a biochemical assay in a research laboratory. Materials and Methods: A cross-sectional prevalence study was done to compare the concentrations of Hcy between 25 NSCL ± P patients and 15 healthy controls. Blood samples were collected from both the patients and controls and assessed for serum Hcy level using competent chemiluminescent immunoassay technique. Statistical Analysis Used: Student's t-test was used for statistical analysis. Results: The average Hcy concentration was 9.5 μmol/L in control group. There was an increase in Hcy concentration among the NSCL ± P cases with an average value of 18.4 μmol/L. The results were found to be statistically significant using Student's t-test. Conclusions: The results of this study indicate that Hcy concentration has a significant elevation in NSCL ± P patients when compared with that of control cases. PMID:27721602

  17. Homocysteine levels in patients with primary and secondary Raynaud's phenomenon. Its association with microangiopathy severity.

    PubMed

    Vayá, Amparo; Sánchez, Fernando; Todolí, Jose; Calvo, Javier; Alis, Rafael; Collado, Susana; Ricart, Jose M

    2014-01-01

    The association between hyperhomocysteinemia (HHcy) and Raynaud's phenomenon (RP) remains a matter of debate. In 18 primary RP, 23 secondary RP and 41 controls, we investigated homocysteine (Hcy) levels along with biochemical and inflammatory parameters. The Hcy levels in both primary and secondary RP were elevated when compared with controls (p < 0.05 and p < 0.01, respectively). As age was higher in secondary RP as compared with controls (p < 0.01), both primary and secondary RP were age-matched with a corresponding control group, and with Hcy maintaining its statistical significance (p < 0.05). No differences in creatinine, B12 vitamin or folic acid were observed between groups (p > 0.05), or in the prevalence of cardiovascular risk factors (p > 0.05). When patients were classified according to presence or absence of digital ulcers, as a sign of microangiopathy severity, the former showed higher Hcy levels than the latter (p = 0.035). Our results indicate that both primary and secondary RP patients show a mild increase in Hcy levels, which is not related to age, vitamin deficiencies or impaired renal function, but is related to microangiopathy severity. Therefore the association of HHcy and RP suggest that Hcy may contribute to endothelial dysregulation, which characterizes this disease. Specific studies should be designed to elucidate the pathogenesis of HHcy in these patients.

  18. Physical functioning related to C-reactive protein and fibrinogen levels in mid-life women

    PubMed Central

    Tomey, Kristin; Sowers, MaryFran; Zheng, Huiyong; Jackson, Elizabeth A.

    2009-01-01

    We investigated whether subclinical inflammatory markers high-sensitivity C-reactive protein (CRP) and fibrinogen are related to measures of physical functioning in midlife women. Our sample included 543 participants in the Michigan site of Study of Women’s Health Across the Nation (SWAN). Predictors included CRP from serum and fibrinogen from plasma. Performance-based outcomes included measures of gait, hand grip strength, flexibility, stair climb, 40-foot walk, and chair rise. Perception of physical functioning was assessed with the Medical Outcomes Study Short-Form 36 questionnaire. Regression analyses adjusted for relevant covariates. Cross-sectional associations were identified between higher CRP and more time spent in double support (with both feet on the floor while walking), shorter forward reach, slower 2-lb lift, and slower stair climb. Higher CRP and fibrinogen were associated with worse perceived functioning in cross-sectional analyses. Predictive associations across time were found between higher CRP and increased time spent in double support, diminishing forward reach distance and grip strength and worse perceived physical functioning. Predictive associations across time were also found between higher fibrinogen and greater time spent in double support, slower stair climb and worse perceived physical functioning. Our results suggest that inflammatory processes are associated with poor physical functioning in midlife women. PMID:19819323

  19. Four-Group Classification Based on Fibrinogen Level and Fibrin Polymerization Associated With Postoperative Bleeding in Cardiac Surgery.

    PubMed

    Kawashima, Shingo; Suzuki, Yuji; Sato, Tsunehisa; Kikura, Mutsuhito; Katoh, Takasumi; Sato, Shigehito

    2016-10-01

    Fibrinogen and fibrin formation have a key role in perioperative hemostasis. The aim of this study is to examine the association of postoperative hemostasis with a combined evaluation of the fibrinogen level and fibrin polymerization in cardiac surgery. We retrospectively classified 215 consecutive cardiac surgery patients into 4 groups (Fuji-san classification) that were divided by fibrinogen level <150 mg/dL (ie, hypofibrinogenemia) and fibrinogen thromboelastometry value at 10 minutes with rotational thromboelastometry <6 mm (ie, low fibrin polymerization) at the warming of cardiopulmonary bypass. Four groups resulted; group I, the acceptable range (n = 85); group II, only hypofibrinogenemia (<150 mg/dL, ≥6 mm, n = 63); group III, hypofibrinogenemia and low fibrin polymerization (<150 mg/dL, <6 mm, n = 60); and group IV, only low fibrin polymerization (≥150 mg/dL, <6 mm, n = 7). The risk of chest tube drainage volume greater than 500 mL within the first 24 hours after surgery (with group I as the reference) was increased in group II (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.5-7.4; P < .01) and group III (OR, 8.5; 95% CI, 3.5-21.7; P < .01), and the risk greater than 1000 mL (with group I as the reference) was increased in group III (OR, 4.0; 95% CI, 1.1-17.3; P = .03) and group IV (OR, 23.1; 95% CI, 3.2-201.0; P < .01). Intraoperative blood transfusions were decreased by 24.5%, after stratifying the starting amount of fresh frozen plasma by the 4-group classification in the recent consecutive 65 (30.2%) patients (P < .01). The 4-group classification is associated with postoperative bleeding and may improve the quality of perioperative blood transfusion in cardiac surgery.

  20. Association between High Serum Homocysteine Levels and Biochemical Characteristics in Women with Polycystic Ovarian Syndrome: A Systematic Review and Meta-Analysis

    PubMed Central

    Peng, Zheng; Liu, Xuexiang; Sun, Yifan; Dai, Shengming

    2016-01-01

    Background Elevated homocysteine levels have been observed in previous studies of PCOS; however, the nature of the associations between high homocysteine levels and the biochemical characteristics of polycystic ovarian syndrome (PCOS)—such as obesity, insulin resistance (IR), and androgen levels—is still uncertain. Methods A systematic search was conducted electronically up to December 28, 2015 using specific eligibility criteria. Standardized mean difference (SMD) and the corresponding 95% confidence intervals (95% CIs) were used as a measure of effect size. Results A total of 34 studies (with 1,718 cases and 1,399 controls) of homocysteine levels in PCOS were pooled in this meta-analysis. Significantly lower homocysteine levels were found in controls than in PCOS patients (SMD = 0.895, 95% CI = 0.643–1.146, P<0.001; I2 = 90.4% and P<0.001 for heterogeneity), regardless of the degree of obesity, IR, or androgen levels. Homocysteine levels in non-IR PCOS patients were significantly lower than those of PCOS patients with IR (SMD = 0.69, 95% CI = 0.37–1.01, P<0.01; I2 = 0% and P = 0.50 for heterogeneity). However, metformin treatment did not appear to cause any significant change in the homocysteine levels of PCOS patients (SMD = –0.17, 95% CI = –1.10–0.75, P = 0.71; I2 = 92% and P<0.01 for heterogeneity). Conclusions High homocysteine levels in women with PCOS are not related to degree of obesity, IR, or androgen levels. Metformin treatment cannot decrease the homocysteine levels in PCOS patients. PMID:27281026

  1. [Homocysteine metabolism].

    PubMed

    Hashimoto, Takao; Shinohara, Yoshihiko; Hasegawa, Hiroshi

    2007-10-01

    Homocysteine, a sulfur amino acid, is an intermediate metabolite of methionine. In 1969, McCully reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in children with elevated plasma homocysteine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocysteine (hyperhomocysteinemia) can cause atherosclerotic vascular disease. Hyperhomocysteinemia is now well established as an independent risk factor for atherosclerotic vascular disease. Mild hyperhomocysteinemia is quite prevalent in the general population. It can be caused by genetic defects in the enzymes involved in homocysteine metabolism or nutritional deficiencies in vitamin cofactors, certain medications or renal disease. An increase of 5 micromol per liter in the plasma homocysteine concentration raises the risk of coronary artery disease by as much as an increase of 20 mg per deciliter in the cholesterol concentration. In this article, we review the biochemical, experimental and clinical studies on hyperhomocysteinemia, with emphasis on the metabolism and pharmacokinetics of homocysteine.

  2. Elevated plasma homocysteine levels in patients with multiple sclerosis are associated with male gender.

    PubMed

    Zoccolella, Stefano; Tortorella, Carla; Iaffaldano, Pietro; Direnzo, Vita; D'Onghia, Mariangela; Paolicelli, Damiano; Livrea, Paolo; Trojano, Maria

    2012-10-01

    Elevated homocysteine (Hcy) levels exert several neurotoxic actions and vascular dysfunctions that may be involved in pathogenesis and progression of multiple sclerosis (MS). The effective role of Hcy in MS however remains to be determined. The aim of this work was to compare plasma Hcy levels in MS patients and neurological disease controls (NDC) and to evaluate their relationships with clinical and demographic variables. In this cross-sectional study, we examined plasma Hcy levels in 217 patients with MS [53 clinically isolated syndromes (CIS) suggestive of MS, 134 relapsing remitting (RR), 23 secondary progressive (SP) and seven primary progressive (PP) MS], recruited among patients attending a tertiary clinical center in southern Italy and in 219 age/sex-matched controls. Median Hcy levels were slightly higher in MS patients compared to NDC (9.1 μmol/l; range, 3.4-35.9 vs. 8.6, range 3.5-27.4; p = 0.02). Median Hcy concentrations were increased in males more than in females in the MS population (10.4 vs. 8.4; p < 0.0001), whereas no differences across genders were found in NDC (9.1 vs. 8.5). Hcy levels were higher in male MS patients compared to the male NDC patients (p = 0.001). Patients with CIS had lower Hcy (7.5 μmol/l; p = 0.004) compared to patients with RR (9.5 μmol/l), SP (10.1 μmol/l) and PP (9.9 μmol/l). Median Hcy concentration was higher in patients with disease duration longer than 22 months (9.7 vs. 8.6 μmol/l; p = 0.02). Plasma Hcy levels are increased in patients with definite MS. Higher Hcy levels are associated with male sex, suggesting a role of Hcy in neurodegenerative processes of MS, which are prominent in male patients.

  3. Effect of Folic Acid, Betaine, Vitamin B6, and Vitamin B12 on Homocysteine and Dimethylglycine Levels in Middle-Aged Men Drinking White Wine

    PubMed Central

    Rajdl, Daniel; Racek, Jaroslav; Trefil, Ladislav; Stehlik, Pavel; Dobra, Jana; Babuska, Vaclav

    2016-01-01

    Moderate regular consumption of alcoholic beverages is believed to protect against atherosclerosis but can also increase homocysteine or dimethylglycine, which are putative risk factors for atherosclerosis. We aimed (1) to investigate the effect of alcohol consumption on vitamins and several metabolites involved in one-carbon metabolism; and (2) to find the most effective way of decreasing homocysteine during moderate alcohol consumption. Methods: Male volunteers (n = 117) were randomly divided into five groups: the wine-only group (control, 375 mL of white wine daily for one month) and four groups combining wine consumption with one of the supplemented substances (folic acid, betaine, and vitamins B12 or B6). Significant lowering of homocysteine concentration after the drinking period was found in subjects with concurrent folate and betaine supplementation. Vitamin B12 and vitamin B6 supplementation did not lead to a statistically significant change in homocysteine. According to a multiple linear regression model, the homocysteine change in the wine-only group was mainly determined by the interaction between the higher baseline homocysteine concentration and the change in dimethylglycine levels. Folate and betaine can attenuate possible adverse effects of moderate alcohol consumption. Dimethylglycine should be interpreted together with data on alcohol consumption and homocysteine concentration. PMID:26771632

  4. Fibrinogen Test

    MedlinePlus

    ... have also been associated with coronary heart disease , myocardial infarction , and peripheral arterial disease. In some cases, fibrinogen ... seen with: Acute infections Cancer Coronary heart disease , myocardial infarction Stroke Inflammatory disorders (like rheumatoid arthritis and glomerulonephritis , ...

  5. Plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with cognitive dysfunctions.

    PubMed

    Zoccolella, Stefano; Lamberti, Paolo; Iliceto, Giovanni; Diroma, Cosimo; Armenise, Elio; Defazio, Giovanni; Lamberti, Simona V; Fraddosio, Angela; de Mari, Michele; Livrea, Paolo

    2005-01-01

    Elevated plasma homocysteine (Hcy) concentrations are associated with Alzheimer's disease and vascular dementia. Several recent reports have indicated that L-dopa treatment is an acquired cause of hyperhomo-cysteinemia. Despite the fact that a large proportion of Parkinson's disease (PD) patients develop cognitive dysfunctions or dementia, particularly in the late stages of the illness and after long-term L-dopa treatment, the relationship between Hcy and dementia in PD has not been fully investigated. The aim of this study was to evaluate plasma Hcy levels in a group of L-dopa-treated PD patients with cognitive impairment and to elucidate a possible role of Hcy in the development of cognitive dysfunctions in PD. We compared Hcy, vitamin B12 and folate levels in 35 parkinsonian patients treated with L-dopa (14 with cognitive dysfunctions, 21 without cognitive impairment). Analysis of the data revealed that mean Hcy levels were significantly higher in the group with cognitive dysfunctions (21.2+/-7.4 vs. 15.8+/-4.4 micromol/L; p=0.0001), while there was no difference in age, sex, B12 and folate levels. In addition, logistic regression analysis showed that the risk of cognitive dysfunction progressively increased according to Hcy levels after correction for age, sex and B-vitamin status (odds ratio, 19.1; 95% CI, 1.5-241.4; p=0.02). Our results raise the possibility of a relationship between Hcy levels and cognitive dysfunctions in this group of L-dopa-treated PD patients. However, prospective studies on large cohorts of patients should be performed to clarify such an association.

  6. Distribution and Determinants of Plasma Homocysteine Levels in Rural Chinese Twins across the Lifespan

    PubMed Central

    Ji, Yuelong; Kong, Xiangyi; Wang, Guoying; Hong, Xiumei; Xu, Xin; Chen, Zhu; Bartell, Tami; Xu, Xiping; Tang, Genfu; Hou, Fanfan; Huo, Yong; Wang, Xiaobin; Wang, Binyan

    2014-01-01

    Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10–66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome. PMID:25529062

  7. Effects of folic acid supplementation on serum homocysteine and lipoprotein (a) levels during pregnancy

    PubMed Central

    Hekmati Azar Mehrabani, Zohreh; Ghorbanihaghjo, Amir; Sayyah Melli, Manizheh; Hamzeh-Mivehroud, Maryam; Fathi Maroufi, Nazila; Bargahi, Nasrin; Bannazadeh Amirkhiz, Maryam; Rashtchizadeh, Nadereh

    2015-01-01

    Introduction:There are many ideas concerning the etiology and pathogenesis of preeclampsia including endothelial dysfunction, inflammation and angiogenesis. Elevated levels of total homocysteine (Hcy) and lipoprotein (a) [Lp(a)] are risk factors for endothelial dysfunction. This study aimed to evaluate the effect of high dose folic acid (FA) on serum Hcy and Lp(a) concentrations with respect to methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677C→T during pregnancy. Methods: In a prospective uncontrolled intervention, 90 pregnant women received 5 mg FA supplementation before pregnancy till 36th week of pregnancy. The MTHFR polymorphisms 677C→T, serum lactate dehydrogenase activity, urine protein and creatinine concentrations were measured before starting folic acid administration. Serum levels of Hcy and Lp(a) were determined before and after completion of folic acid supplementation period. Results: Supplementation of the patients with FA for 36 week decreased the median (minimum– maximum) levels of serum Hcy from 11.40 μmol/L (4.40-28.70) to 9.70 (1.60-20.80) μmol/L (p=0.001). There was no significant change in serum Lp(a) after FA supplementation (p=0.17). The overall prevalence of genotypes in pregnant women that were under study for MTHFR C677T polymorphism was 53.3% CC, 26.7% CT and 20.0% TT. There was no correlation between decreasing level of serum Hcy in the patients receiving FA and MTHFR polymorphisms. Conclusion:Although FA supplementation decreased serum levels of Hcy in different MTHFR genotypes, serum Lp(a) was not changed by FA supplements. Our data suggests that FA supplementation effects on serum Hcy is MTHFR genotype independent in pregnant women. PMID:26929921

  8. Oxidative stress elevated DNA damage and homocysteine level in normal pregnant women in a segment of Pakistani population.

    PubMed

    Bukhari, Shazia A; Rajoka, Muhammad Ibrahim; Ibrahim, Z; Jalal, Fatima; Rana, Shahid Mahboob; Nagra, Saeed A

    2011-04-01

    Maternal oxidative stress during pregnancy may impair fetal growth and help in the development of diseases in adulthood. The aim of current study was to assess total oxidation status (TOS), related parameters and their relationship to DNA damage (%) and homocysteine level in normal pregnant women in low-income participants. In a cross-sectional study healthy women were grouped as normal, while age matched nulliparous and singleton pregnancies were included for first, second and third trimester groups. TOS (P<0.01), melanodialdehyde (MDA) (P<0.001), aspartate aminotransferase (AST) (P<0.01), triiodothyronine (T3) (P<0.01), thyroxine (T4) (P<0.01), and homocysteine (P<0.001), in pregnant women were significantly higher as compared to normal healthy women. While serum total proteins (P<0.01), albumin (P<0.01) and total antioxidant status (TAS) (P<0.001) decreased significantly as compared to normal healthy women. Women in third trimester showed a significantly high level of body temperature (P<0.01), triglyceride (P<0.01), LDL-cholesterol (P<0.05), AST (P<0.01), T3 (P<0.01), homocysteine (P<0.001), TOS (P<0.01) and MDA (P<0.001) but a lower concentration of serum proteins, albumin and TAS at the end of the pregnancy. Pearson correlation indicated a positive relationship of homocysteine with triglycerides (P<0.027), TOS (P<0.01), MDA (P<0.035) and had a negative relationship with total protein (P<0.026). DNA damage was strongly related with T3 (P<0.008), TOS (P<0.02), MDA (P<0.037) and MBI (P<0.048) profiles of pregnant women. These changes were considered normal for pregnant women having optimum blood pressure and normal child birth. Hormonal influences and hemodilution may contribute towards the observed changes in this study.

  9. [Treatment with levodopa can affect latent vitamin B 12 and folic acid deficiency. Patients with Parkinson disease runt the risk of elevated homocysteine levels].

    PubMed

    Lökk, Johan

    2003-08-28

    There is a well-known interaction between vitamin B12, folate, and homocysteine. More unknown is the fact that this interaction might be affected by long-term treatment with levo-dopa in patients with Parkinson's disease. An increase in homocysteine levels and tissue deficiency of vitamin B12 and folate may occur. The responsible doctor should be liberal in checking vitamin B12 and folate status and supplement with appropriate vitamins when needed.

  10. Genetic and Environmental Determinants of Plasma Total Homocysteine Levels: Impact of Population-wide Folate Fortification

    PubMed Central

    Nagele, Peter; Meissner, Konrad; Francis, Amber; Födinger, Manuela; Saccone, Nancy L.

    2011-01-01

    Objectives Folate metabolism is an important target for drug therapy. Drug-induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several non-genetic (e.g., folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nation-wide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy. Methods Two cohorts were compared in this study, one from the U.S. (with folate fortification, n=281), and one from Austria (without folate fortification, n=139). Several environmental factors as well as previously identified gene variants important for tHcy levels (MTHFR C677T, MTHFR A1298C, MTRR A66G) were examined for their ability to predict plasma tHcy in a multiple linear regression model. Results Non-genetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R2 ~ 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate fortified cohort (R2= 0.021) compared to the non-folate fortified cohort (R2= 0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male gender, smoking and folate levels were important predictors for non-folate fortified patients; age for folate fortified. Conclusions Population-wide folate fortification had a significant effect on the variability of plasma tHcy and reduced the influence of genetic factors, most importantly the MTHFR 677TT genotype, and may be an important confounder for a personalized drug therapy. PMID:21597397

  11. C677T methylenetetrahydrofolate reductase and plasma homocysteine levels among Thai vegans and omnivores.

    PubMed

    Kajanachumpol, Saowanee; Atamasirikul, Kalayanee; Tantibhedhyangkul, Phieuvit

    2013-01-01

    Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia.

  12. Adenosine plasma level correlates with homocysteine and uric acid concentrations in patients with coronary artery disease.

    PubMed

    Fromonot, J; Deharo, P; Bruzzese, L; Cuisset, T; Quilici, J; Bonatti, S; Fenouillet, E; Mottola, G; Ruf, J; Guieu, R

    2016-03-01

    The role of hyperhomocysteinemia in coronary artery disease (CAD) patients remains unclear. The present study evaluated the relationship between homocysteine (HCys), adenosine plasma concentration (APC), plasma uric acid, and CAD severity evaluated using the SYNTAX score. We also evaluated in vitro the influence of adenosine on HCys production by hepatoma cultured cells (HuH7). Seventy-eight patients (mean age ± SD: 66.3 ± 11.3; mean SYNTAX score: 19.9 ± 12.3) and 30 healthy subjects (mean age: 61 ± 13) were included. We incubated HuH7 cells with increasing concentrations of adenosine and addressed the effect on HCys level in cell culture supernatant. Patients vs. controls had higher APC (0.82 ± 0.5 μmol/L vs 0.53 ± 0.14 μmol/L; p < 0.01), HCys (15 ± 7.6 μmol/L vs 6.8 ± 3 μmol/L, p < 0.0001), and uric acid (242.6 ± 97 vs 202 ± 59, p < 0.05) levels. APC was correlated with HCys and uric acid concentrations in patients (Pearson's R = 0.65 and 0.52; p < 0.0001, respectively). The SYNTAX score was correlated with HCys concentration. Adenosine induced a time- and dose-dependent increase in HCys in cell culture. Our data suggest that high APC is associated with HCys and uric acid concentrations in CAD patients. Whether the increased APC participates in atherosclerosis or, conversely, is part of a protective regulation process needs further investigations.

  13. [Relation of socioeconomic levels and life style to fibrinogen and von Willebrand factor in healthy Venezuelans and those with ischemic cardiopathy].

    PubMed

    Rodríguez-Larralde, Alvaro; Mijares, Mercedes E; Nagy, Elena; Espinosa, Raul; Ryder, Elena; Diez-Ewald, María P; Torres, Enrique; Coll-Sangrona, Enriqueta; Rodríguez-Roa, Elsy; Carvajal, Zoila; Lundberg, Ulf; Campos, Gilberto; Gill, Amparo; Arocha-Piñango, Carmen L

    2005-06-01

    Previous studies in Europe, U.S.A and Japan have revealed an inverse relationship between socioeconomic levels and fibrinogen concentration. Similar results have been reported in a smaller number of studies for concentrations of von Willebrand factor. In this opportunity we present results on the relationship between smoking, drinking, physical activity, age and socioeconomic level on fibrinogen and von Willebrand factor concentrations in a Venezuelan sample. The control population consisted of 978 men and 968 women. Patients with coronary heart disease were 172 males and 78 females. The presence of one or more of the following conditions: smoking or less than 5 years of having quit, non drinkers or drinking in excess, and a reduced physical activity, was considered a health related risk factor for high levels of these two haemostatic variables. Our results indicate that in Controls, the socioeconomic level had a significant effect on fibrinogen and von Willebrand factor levels, only in women: those of lower socioeconomic levels had the highest concentrations. This difference was maintained when age was taken into account. Health related behaviors had no significant effect on either variable. In patients, age had no effect on either variable. The health behavior risk factor had a significant effect only on fibrinogen of male patients, and socioeconomic level had a significant effect only on the fibrinogen of female patients. More studies in Venezuela are recommended, in order to increase our knowledge on the relationship between socioeconomic levels, haemostatic markers and the occurrence of coronary heart disease.

  14. Influence of heparin on fibrinogen and D-dimer plasma levels in acute myocardial infarction treated with streptokinase.

    PubMed

    Salvioni, A; Marenzi, G C; Agostoni, P; Grazi, S; Guazzi, M D

    1994-05-01

    The purpose of this study was to investigate whether, to what extent, and through which mechanisms intravenous heparin, administered before and after streptokinase, affects the plasma levels of D-dimer and fibrinogen in myocardial infarction. Data concerning mortality and incidence of coronary recanalization in patients receiving heparin and thrombolytic therapy after acute myocardial infarction are controversial; furthermore, the mechanisms through which heparin acts in combination with thrombolytic therapy are unclear. Thirty-eight patients with acute myocardial infarction treated with streptokinase were considered. Nineteen of them received, immediately before the beginning of thrombolytic treatment, a bolus of heparin (100 U.kg-1 intravenously) and, 2 h later, intravenous heparin in doses raising the partial thromboplastin time to 2-2.5 times the normal value (Group 1); the remaining 19 did not receive anticoagulant treatment (Group 2). Multiple determinations of plasma D-dimer and fibrinogen levels were obtained in all patients before, and in the seven days following thrombolytic treatment. Six hours after streptokinase, fibrinogen decreased from 304 +/- 34 to 61 +/- 34 mg.dl-1 in Group 1 and from 312 +/- 29 to 38 +/- 21 mg.dl-1 in Group 2 (P < 0.02 versus Group 1). The same difference between groups persisted at the 12th and at the 18th hour. D-dimer values, from 0.5 +/- 0.1 microgram.dl-1 in Group 1 and 0.4 +/- 0.1 microgram.dl-1 in Group 2, increased at the 1st hour to 37.2 +/- 36.5 micrograms.dl-1 and 52.2 +/- 39.8 micrograms.dl-1, respectively. A peak value was reached in both groups at the 6th hour, which was followed by a slow decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Elevated fibrinogen plasma level is not an independent predictor of poor prognosis in a large cohort of Western patients undergoing surgery for colorectal cancer

    PubMed Central

    Pedrazzani, Corrado; Mantovani, Guido; Salvagno, Gian Luca; Baldiotti, Elisabeth; Ruzzenente, Andrea; Iacono, Calogero; Lippi, Giuseppe; Guglielmi, Alfredo

    2016-01-01

    AIM To evaluate the clinical significance of the preoperative fibrinogen plasma level as a prognostic marker after surgery for colorectal cancer. METHODS This retrospective study analysed 652 patients undergoing surgery for stage I-IV colorectal cancer between January 2005 and December 2012, at the Division of General Surgery A, University of Verona Hospital Trust, in whom preoperative fibrinogen plasma values were assessed at baseline. Fibrinogen is involved in tumourigenesis as well as tumour progression in several malignancies. Correlations between preoperative plasma fibrinogen values and clinicopathological characteristics were investigated. Univariate and multivariate survival analyses were performed to identify factors associated with overall and tumour-related survival. RESULTS Among the 652 patients, the fibrinogen value was higher than the threshold of 400 mg/dL in 345 patients (53%). The preoperative mean ± SD of fibrinogen was 426.2 ± 23.2 mg/dL (median: 409 mg/dL; range: 143-1045 mg/dL). Preoperative fibrinogen values correlated with age (P = 0.003), completeness of tumour resection, potentially curative vs palliative (P < 0.001), presence of systemic metastasis (P < 0.001), depth of tumour invasion pT (P < 0.001), nodes involvement pN (P = 0.001) and CEA serum level (P < 0.001). The mean fibrinogen value (± SD) was 395.6 ± 120.4 mg/dL in G1 tumours, 424.1 ± 121.4 mg/dL in G2 tumours and 453.4 ± 131.6 mg/dL in G3 tumours (P = 0.045). The overall survival and tumour-related survival were significantly higher in patients with fibrinogen values ≤ 400 mg/dL (P < 0.001). However, hyperfibrinogenemia did not retain statistical significance regarding either overall (P = 0.313) or tumour-related survival (P = 0.355) after controlling for other risk factors in a multivariate analysis. CONCLUSION Preoperative fibrinogen levels correlate with cancer severity but do not help in predicting patient prognosis after colorectal cancer surgery. PMID:28018106

  16. High levels of plasma malondialdehyde, protein carbonyl, and fibrinogen have prognostic potential to predict poor outcomes in patients with diabetic foot wounds: a preliminary communication.

    PubMed

    Rattan, Roma; Nayak, Debashish

    2008-12-01

    Diabetic foot ulcer (DFU) is the leading cause of lower extremity amputation and is generally known to have poor prognosis. Oxidative stress is considered important in the pathogenesis of chronic wounds. Fibrinogen is a recognized marker in peripheral vascular disease; increasing levels predict an increased mortality and risk of amputation. The aim of this study was to evaluate if plasma malondialdehyde (MDA), protein carbonyl (PC) and fibrinogen levels can be used as prognostic markers in patients with DFU. The study design was prospective, nonrandomized, and controlled. A total of 41 DFU grade 1 and 20 DFU grade 2 patients were studied in this case-control study. Diabetic controls without foot ulcers and healthy controls were also studied. Plasma MDA, PC, and fibrinogen levels were significantly higher in patients with DFU compared with those without ulcers (P < .05) and nondiabetic controls (P < .001). These parameters increased in association with DFU grade (P < .01). Increased levels of plasma fibrinogen, MDA, and PC correlated with worsened outcomes. An augmented oxidative stress and plasma fibrinogen level >300.4 mg% (95% confidence interval, 100% sensitivity, 99.2% specificity) was correlated with a high risk of amputation in DFU.

  17. Intermediate-Risk Chronic Stable Angina: Neutrophil-Lymphocyte Ratio and Fibrinogen Levels Improved Predicting Angiographically-Detected Coronary Artery Disease

    PubMed Central

    Haybar, Habib; Ahmadzadeh, Ahmad; Assareh, Ahmadreza; Afshari, Nader; Bozorgmanesh, Mohammadreza; Vakili, Mahdis

    2016-01-01

    Background Coronary heart disease (CHD) is the leading cause of death worldwide. Research indicates that coronary atherosclerosis is the most frequent cause of CHD. Evidence is scarce concerning the clinical efficacy of fibrinogen or neutrophil-lymphocyte ratio (NLR) measurement in risk-stratifying patients with chronic stable angina. Objectives To examine the independent and incremental prognostic value of fibrinogen and neutrophil-lymphocyte ratio (NLR) for angiographically-detected coronary artery disease (CAD). Patients and Methods In this cross-sectional study, angiography was performed for 183 Iranian patients with chronic stable angina with exercise ECG-determined intermediate risk. Generalized estimated equations were used to obtain the odd ratio (OR) of CAD for a 1-unit increase in log-NLR and a 1-SD increase in plasma fibrinogen. Models were adjusted for established CAD risk factors. Integrated discriminatory improvement index (IDI) and net reclassification improvement index (NRI) were used as measures of predictive ability for CAD, combined with traditional risk factors by NLR and fibrinogen. Results The mean age of the participants was 57.5, with 51.9% being male. Only 12% of participants had angiographically-determined patent coronary arteries. The number of participants with one, two, and three-vessel stenosis were 76, 31, 31, respectively, while 45 did not have stenosed vessels. NLR and fibrinogen levels were significantly higher in patients with stenosis in two (2.4 and 512 mg.dL-1) or three (2.6 and 517 mg.dL-1) coronary arteries, as compared to the group of patients with no significant involvement (2 and 430 mg.dL-1) (all P < 0.01). Patients with a higher NLR and a higher fibrinogen levels were more likely to have higher grades of CAD. OR log-NLR = 1.36 (95% CI: 1.05 - 1.94) and OR Z-Fibrinogen = 1.61 (95% CI: 1.18 - 2.22). When NLR and fibrinogen were added to the traditional risk factors separately, the NRIs were 0.170 (0.023 - 0.324) and 0

  18. Plasma homocysteine level is a risk factor for osteoporotic fractures in elderly patients

    PubMed Central

    Zhu, Yuefeng; Shen, Jie; Cheng, Qun; Fan, Yongqian; Lin, Weilong

    2016-01-01

    Objective To study the relationship of plasma homocysteine (Hcy), bone turnover biomarkers (BTB), and bone mineral density (BMD) with osteoporotic fracture (OPF) in elderly people. Methods Eighty-two patients (aged 65 years or older) admitted to our orthopedics department between October 2014 and May 2015 were randomly divided into three groups: 1) OPF group: 39 cases with the mean age 81.82±5.49 years, which included 24 females and 15 males; 2) high-energy fracture (HEF) group: 22 cases with the mean age 78.88±5.75 years, which included 16 females and six males; 3) non-bone-fracture group: 21 cases with mean age 79.75±5.47 years without bone fracture, which included 14 females and seven males. Plasma Hcy, BTB, and BMD were measured. Analysis of variance and multiple regression analysis were used in the statistical analysis. Results There was no significant difference in either age or sex among the three groups. There were significant differences in plasma Hcy and hip BMD between the OPF and HEF groups; there was also significant difference in plasma Hcy, 25-(OH) Vit D, and hip BMD between the OPF and non-fracture groups. There was no difference in lumbar spine BMD between the OPF group and the other two groups. There was no significant difference in plasma Hcy, 25-(OH) Vit D, hip or lumbar spine BMD between the HEF and non-fracture group. There was no significant difference in procollagen type I N-propeptide of type I collagen, serum C-terminal cross-linking telopeptide of type I collagen, and parathyroid hormone among the three groups. Plasma Hcy was linearly correlated with age and serum C-terminal cross-linking telopeptide of type I collagen, but not correlated with either hip or lumbar spine BMD or any other BTBs. Conclusion In this study, we found that the plasma Hcy level in elderly patients with OPF is higher than that of nonosteoporotic patients. It is not correlated with BMD, but positively correlated with bone resorption markers. An increased Hcy

  19. Carotid hemodynamics is associated with monocyte count determined by serum homocysteine level in patients with essential hypertension.

    PubMed

    Jotoku, Masanori; Okura, Takafumi; Miyoshi, Ken-Ichi; Irita, Jun; Nagao, Tomoaki; Kukida, Masayoshi; Tanino, Akiko; Kudo, Kayo; Enomoto, Daijiro; Pei, Zouwei; Higaki, Jitsuo

    2015-01-01

    To examine the association between pulsatility index (PI) in the common carotid artery (CCA) as a marker of vascular resistance and cardiovascular risk factors, including serum homocysteine and inflammation, 67 hypertensive patients were enrolled. PI correlated with homocysteine and interleukin-6, monocyte count, gender, age and BMI, with monocyte count and age being independent determinants for PI. In turn, monocyte count correlated with homocysteine, tumor necrosis factor-alpha, and HDL-cholesterol, BMI, and gender, with HDL-cholesterol and homocysteine being independent determinants for monocyte count. These results indicated monocyte count determined by homocysteine is associated with arterial stiffness in hypertensive patients.

  20. Plasma homocysteine, methionine and S-adenosylhomocysteine levels following high-dose methotrexate treatment in pediatric patients with acute lymphoblastic leukemia or Burkitt lymphoma: association with hepatotoxicity.

    PubMed

    Kubota, Masaru; Nakata, Rieko; Adachi, Souichi; Watanabe, Ken-Ichiro; Heike, Toshio; Takeshita, Yasufumi; Shima, Midori

    2014-07-01

    This study aimed to investigate: (i) changes of plasma homocysteine, methionine and S-adenosylhomocysteine levels following high-dose methotrexate (HD-MTX) treatment and (ii) the correlation of these sulfur-containing amino acids with MTX-induced hepatotoxicity. Fifteen pediatric patients with acute lymphoblastic leukemia and one patient with Burkitt lymphoma, with a total of 26 treatment courses of HD-MTX, were enrolled. Homocysteine levels increased at 24 h after HD-MTX treatment, and showed marginal decreases at 48 and 72 h. Methionine levels showed a biphasic pattern, i.e. an initial decrease at 24 h followed by increases at 48 and 72 h. S-adenosylhomocysteine exhibited a marginal decrease at 24 h. Changes of homocysteine exhibited significant correlation only with a maximum increase of alanine aminotransferase or total bilirubin from baseline. This study has demonstrated, for the first time, simultaneous changes of plasma homocysteine, methionine and S-adenosylhomocysteine following HD-MTX. The potential of homocysteine as a marker of hepatotoxicity is also presented.

  1. C677T polymorphism of the methylenetetrahydrofolate reductase gene does not affect folic acid, vitamin B12, and homocysteine serum levels in Turkish children with neural tube defects.

    PubMed

    Erdogan, M O; Yildiz, S H; Solak, M; Eser, O; Cosar, E; Eser, B; Koken, R; Buyukbas, S

    2010-06-22

    Association between neural tube defects (NTDs) and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was suspected, because the MTHFR gene codes for a key enzyme in folate metabolism. Its deficiency usually leads to significant reductions in plasma concentrations of folate, vitamin B(12) and methionine, whereas homocysteine levels are increased. We examined folate, vitamin B(12) and homocysteine serum concentrations and polymorphism of the C677T MTHFR gene in Turkish children with neural tube defects. Thirty-three children with NTDs, 26 mothers and 48 healthy individuals were studied. C677T MTHFR polymorphism was determined by melting curve analyses (LightCycler). The levels of folate, vitamin B(12) and homocysteine serum concentrations in NTDs were evaluated and compared, along with information concerning alleles of the MTHFR gene. C677T allele frequencies in NTD children and their mothers were similar to those found in controls. Serum folate and vitamin B(12) concentrations were significantly higher in NTD children than that of controls. Serum homocysteine concentrations were not significantly higher in NTD children and mothers. We concluded that C677T MTHFR gene polymorphism does not affect folic acid, vitamin B(12) and homocysteine metabolism in Turkish children with NTDs. C677T polymorphism of the MTHFR gene cannot be regarded as a major risk factor for NTDs in Turkish children.

  2. High levels of homocysteine downregulate apolipoprotein E expression via nuclear factor kappa B

    PubMed Central

    Trusca, Violeta G; Mihai, Adina D; Fuior, Elena V; Fenyo, Ioana M; Gafencu, Anca V

    2016-01-01

    AIM: To investigate the effect of high homocysteine (Hcy) levels on apolipoprotein E (apoE) expression and the signaling pathways involved in this gene regulation. METHODS: Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot were used to assess apoE expression in cells treated with various concentrations (50-500 μmol/L) of Hcy. Calcium phosphate-transient transfections were performed in HEK-293 and RAW 264.7 cells to evaluate the effect of Hcy on apoE regulatory elements [promoter and distal multienhancer 2 (ME2)]. To this aim, plasmids containing the proximal apoE promoter [(-500/+73)apoE construct] alone or in the presence of ME2 [ME2/(-500/+73)apoE construct] to drive the expression of the reporter luciferase gene were used. Co-transfection experiments were carried out to investigate the downstream effectors of Hcy-mediated regulation of apoE promoter by using specific inhibitors or a dominant negative form of IKβ. In other co-transfections, the luciferase reporter was under the control of synthetic promoters containing multiple specific binding sites for nuclear factor kappa B (NF-κB), activator protein-1 (AP-1) or nuclear factor of activated T cells (NFAT). Chromatin immunoprecipitation (ChIP) assay was accomplished to detect the binding of NF-κB p65 subunit to the apoE promoter in HEK-293 treated with 500 μmol/L Hcy. As control, cells were incubated with similar concentration of cysteine. NF-κB p65 proteins bound to DNA were immunoprecipitated with anti-p65 antibodies and DNA was identified by PCR using primers amplifying the region -100/+4 of the apoE gene. RESULTS: RT-PCR revealed that high levels of Hcy (250-750 μmol/L) induced a 2-3 fold decrease in apoE mRNA levels in HEK-293 cells, while apoE gene expression was not significantly affected by treatment with lower concentrations of Hcy (100 μmol/L). Immunoblotting data provided additional evidence for the negative role of Hcy in apoE expression. Hcy decreased apoE promoter

  3. Homocysteine and alcoholism.

    PubMed

    Bleich, S; Degner, D; Javaheripour, K; Kurth, C; Kornhuber, J

    2000-01-01

    Chronic alcohol consumption can induce alterations in the function and morphology of most if not all brain systems and structures. However, the exact mechanism of brain damage in alcoholics remains unknown. Partial recovery of brain function with abstinence suggests that a proportion of the deficits must be functional in origin (i.e. plastic changes of nerve cells) while neuronal loss from selected brain regions indicates permanent and irreversible damage. There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Recently, it has been shown that excitatory amino acid (EAA) neurotransmitters and homocysteine levels are elevated in patients who underwent withdrawal from alcohol. Furthermore, it has been found that homocysteine induces neuronal cell damage by stimulating NMDA receptors as well as by producing free radicals. Homocysteine neurotoxicity via overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both brain shrinkage and withdrawal seizures linked to alcoholism.

  4. Effect of Folic Acid therapy on Homocysteine Level in patients with Atherosclerosis or Buerger’s Disease and in Healthy individuals: A clinical trial

    PubMed Central

    Modaghegh, Mohammad Hadi Saeed; Ravari, Hassan; Haghighi, Mohammad Zare; Rajabnejad, Ata’ollah

    2016-01-01

    Background Hyperhomocysteinemia is considered a risk factor for atherosclerosis and some other vascular diseases such as Buerger’s disease. Objective The aim of this study was to measure the Homocysteine levels in 3 different groups of participants (Buerger’s disease, atherosclerosis patients, and healthy cases) and determine the therapeutic effect of folic acid therapy on homocysteine levels for these three groups Methods This nonrandomized clinical trial study was conducted in the vascular and endovascular surgery research center of Mashhad University of Medical Sciences in Mashhad, Iran. This interventional study consisted of 44 participants of which 22 patients had Buerger’s disease and a control group of 22 healthy individuals, all of which were enrolled in this study. All of the study’s participants had their serum homocysteine levels measured both before and after 12 weeks of folic acid (5mg/day) therapy. The data analysis used fo data analysis was a Chi square and t-test or their non-parametrical equivalents for data analysis by means of Statistical Package for the Social Sciences (SPSS) version 16 Results The homocysteine levels were found to be significantly higher in patients with Buerger’s disease as compared to other groups before treatment with folic acid (Buerger = 21.8 ± 8.5 Mm/L, atherosclerosis = 17.3 ± 6.9, healthy = 13.8 ± 3.1; p < 0.001). After treatment with folic acid at 5 mg/daily for 12 weeks, the new plasma homocysteine levels did not show any significant difference (p = 0.38) between the Buerger’s disease group (14.6 ± 4.5 Mm/L) and atherosclerosis group (13.9 ± 4.7), but it was found to besignificantly higher in both groups when compared to the healthy group (10.7 ± 3.9, p<0.05). The plasma homocysteine level was reduced significantly when compared to its initial level in all 3 groups. The comparison of differences among three groups was found not to be significant (p=0.41) Conclusions It seems that supplementary

  5. A Phospholipid-Protein Complex from Antarctic Krill Reduced Plasma Homocysteine Levels and Increased Plasma Trimethylamine-N-Oxide (TMAO) and Carnitine Levels in Male Wistar Rats

    PubMed Central

    Bjørndal, Bodil; Ramsvik, Marie S.; Lindquist, Carine; Nordrehaug, Jan E.; Bruheim, Inge; Svardal, Asbjørn; Nygård, Ottar; Berge, Rolf K.

    2015-01-01

    Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks. Rats fed PPC had reduced total homocysteine plasma level and increased levels of choline, dimethylglycine and cysteine, whereas the plasma level of methionine was unchanged compared to control. PPC feeding increased the plasma level of TMAO, carnitine, its precursors trimethyllysine and γ-butyrobetaine. There was a close correlation between plasma TMAO and carnitine, trimethyllysine, and γ-butyrobetaine, but not between TMAO and choline. The present data suggest that PPC has a homocysteine lowering effect and is associated with altered plasma concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. Moreover, the present study reveals a non-obligatory role of gut microbiota in the increased plasma TMAO level as it can be explained by the PPC’s content of TMAO. The increased level of carnitine and carnitine precursors is interpreted to reflect increased carnitine biosynthesis. PMID:26371012

  6. A Phospholipid-Protein Complex from Antarctic Krill Reduced Plasma Homocysteine Levels and Increased Plasma Trimethylamine-N-Oxide (TMAO) and Carnitine Levels in Male Wistar Rats.

    PubMed

    Bjørndal, Bodil; Ramsvik, Marie S; Lindquist, Carine; Nordrehaug, Jan E; Bruheim, Inge; Svardal, Asbjørn; Nygård, Ottar; Berge, Rolf K

    2015-09-08

    Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks. Rats fed PPC had reduced total homocysteine plasma level and increased levels of choline, dimethylglycine and cysteine, whereas the plasma level of methionine was unchanged compared to control. PPC feeding increased the plasma level of TMAO, carnitine, its precursors trimethyllysine and γ-butyrobetaine. There was a close correlation between plasma TMAO and carnitine, trimethyllysine, and γ-butyrobetaine, but not between TMAO and choline. The present data suggest that PPC has a homocysteine lowering effect and is associated with altered plasma concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. Moreover, the present study reveals a non-obligatory role of gut microbiota in the increased plasma TMAO level as it can be explained by the PPC's content of TMAO. The increased level of carnitine and carnitine precursors is interpreted to reflect increased carnitine biosynthesis.

  7. Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment.

    PubMed

    Jadavji, Nafisa M; Farr, Tracy D; Lips, Janet; Khalil, Ahmed A; Boehm-Sturm, Philipp; Foddis, Marco; Harms, Christoph; Füchtemeier, Martina; Dirnagl, Ulrich

    2015-04-15

    Dietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders. Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil-DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfursion in an animal model. Ung(+/+) and Ung(-/-) mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung(-/-) FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung(+/+) FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung(-/-) hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don't lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion or UNG deficiency is required.

  8. Homocysteine and its thiolactone may promote apoptotic events in blood platelets in vitro.

    PubMed

    Olas, Beata; Malinowska, Joanna; Rywaniak, Joanna

    2010-01-01

    The actions of homocysteine and its major metabolite, cyclic thioester, homocysteine thiolactone on endothelial cells, blood platelets, plasmatic fibrinogen and plasminogen--the important major components of haemostasis, regulating the flowing properties of blood--are complex and sometimes controversial. Homocysteine (Hcys) can promote apoptosis in endothelial cells, but the role of Hcys and its thiolactone in the apoptotic process in blood platelets is unknown. In order to study the appearance of apoptosis in platelets after treatment with the reduced form of Hcys or its thiolactone different markers were chosen: annexin V binding (phosphatidylserine exposure), platelet microparticle formation, mitochondrial membrane depolarization and αIIbβ3 expression in vitro. Apoptotic events and platelet activation were measured by a flow cytometer. In gel-filtered platelets treated with different concentrations of the reduced form of Hcys (25, 50 and 100 µM, 10 min) a significant increase of phosphatidylserine exposure (about 37% at the highest concentration, p < 0.001) and platelet microparticle formation were observed. Homocysteine caused also a dose-dependent depolarization of mitochondrial potential. The same apoptotic markers appeared in HTL-treated platelets (0.2 and 1 µM). Moreover, resveratrol (25 µM), a well known antioxidant, distinctly reduced the level of apoptotic markers. The obtained results indicate that Hcys and its thiolactone may promote in vitro apoptotic events in human gel-filtered platelets.

  9. Public health significance of elevated homocysteine.

    PubMed

    Selhub, Jacob

    2008-06-01

    Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation, which requires folic acid and vitamin B12 coenzymes; and transsulfuration, which requires pyridoxal-5'-phosphate, the vitamin B6 coenzyme. Data from a number of laboratories suggest that mild elevations of homocysteine in plasma are a risk factor for occlusive vascular disease. In the Framingham studies, we have shown that plasma homocysteine concentration is inversely related to the intake and plasma levels of folate and vitamin B6 as well as vitamin B12 plasma levels. Almost two-thirds of the prevalence of high homocysteine is attributable to low vitamin status or intake. Elevated homocysteine concentrations in plasma are a risk factor for prevalence of extracranial carotid-artery stenosis > or = 25% in both men and women. Prospectively elevated plasma homocysteine is associated with increased total and cardiovascular mortality, increased incidence of stroke, increased incidence of dementia and Alzheimer's disease, increased incidence of bone fracture, and higher prevalence of chronic heart failure. It was also shown that elevated plasma homocysteine is a risk factor for preeclampsia and maybe neural tube defects (NTD). This multitude of relationships between elevated plasma homocysteine and diseases that afflict the elderly, pregnant women, and the embryo points to the existence ofa common denominator which may be responsible for these diseases. Whether this denominator is homocysteine itself or homocysteine is merely a marker, remains to be determined.

  10. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss.

    PubMed

    Kumar, K S D; Govindaiah, V; Naushad, S E; Devi, R R; Jyothy, A

    2003-01-01

    Hyperhomocysteinaemia, a risk factor for recurrent pregnancy loss, is related either to a hereditary defect within the methionine-homocysteine pathway or it might be acquired as a result of deficiencies of vitamin B(12) and folate (B(9)). Because hyperhomocysteinaemia seems to be determined by both genetic and environmental factors, the current study was undertaken to find out the interactions between folate status and MTHFR mutation on the homocysteine concentration in 24 women experiencing unexplained three or more consecutive recurrent pregnancy losses. The median fasting total plasma homocysteine concentration in the study group was 10.23 micro mol/l compared to 8.95 micro mol/l; P = 0.096 in the controls. Elevated homocysteine levels > 18 micro mol/l, which was considered to be a risk factor for recurrent early pregnancy loss, was found in four women in the study group and none among the controls. Lower red cell folate levels (normal range >/= 160 ng/ml) were observed in nine (37.5%) women among the study group, compared to five (20.84%) women among controls. The mean +/- SD red cell folate levels in the study group was found to be 154.37 +/- 37.07, while in the controls it was 159.0 +/- 28.97. In the present study six women in the study group and two among controls were found to be carriers for the C677T MTHFR mutation. None were homozygous for the mutant (TT) allele. The highest values of homocysteine concentration were found in women experiencing recurrent pregnancy loss with both the CT genotype and folate deficiency. Identification of hyperhomocysteinaemia in women with recurrent pregnancy loss may help in therapeutic normalisation and might permit a normal birth.

  11. Relationship between plasma total homocysteine level and dietary caffeine and vitamin B6 intakes in pregnant women.

    PubMed

    Shiraishi, Mie; Haruna, Megumi; Matsuzaki, Masayo; Ota, Erika; Murayama, Ryoko; Sasaki, Satoshi; Yeo, SeonAe; Murashima, Sachiyo

    2014-06-01

    A high total homocysteine (tHcy) level during pregnancy is a risk factor for adverse perinatal outcomes, such as fetal growth restriction and preeclampsia. Caffeine is assumed to increase tHcy levels by acting as a vitamin B6 antagonist. The objective of this study was to examine a relationship between circulating tHcy levels and dietary caffeine and vitamin B6 intakes in pregnant Japanese women. A total of 321 healthy women with singleton pregnancies were recruited in metropolitan Tokyo, from June to December 2008, resulting in the final number included in the study as 254. Dietary caffeine intakes did not correlate with plasma tHcy levels. When we analyzed the data according to caffeinated beverages, caffeinated tea consumption was positively associated with plasma tHcy levels only among the women with a high intake of vitamin B6 , after controlling for confounding factors (P = 0.029). No correlation between coffee consumption and plasma tHcy levels was found. Pregnant Japanese women might need to cut down the consumption of caffeinated tea as well as take sufficient vitamin B6 in order to prevent the tHcy levels from increasing.

  12. Tracer diffusion inside fibrinogen layers

    NASA Astrophysics Data System (ADS)

    Cieśla, Michał; Gudowska-Nowak, Ewa; Sagués, Francesc; Sokolov, Igor M.

    2014-01-01

    We investigate the obstructed motion of tracer (test) particles in crowded environments by carrying simulations of two-dimensional Gaussian random walk in model fibrinogen monolayers of different orientational ordering. The fibrinogen molecules are significantly anisotropic and therefore they can form structures where orientational ordering, similar to the one observed in nematic liquid crystals, appears. The work focuses on the dependence between level of the orientational order (degree of environmental crowding) of fibrinogen molecules inside a layer and non-Fickian character of the diffusion process of spherical tracer particles moving within the domain. It is shown that in general particles motion is subdiffusive and strongly anisotropic, and its characteristic features significantly change with the orientational order parameter, concentration of fibrinogens, and radius of a diffusing probe.

  13. Electrochemiluminescent chemodosimeter based on iridium(III) complex for point-of-care detection of homocysteine levels.

    PubMed

    Kim, Hoon Jun; Lee, Kyung-Sik; Jeon, Yong-Jun; Shin, Ik-Soo; Hong, Jong-In

    2017-05-15

    Elevated levels of plasma homocysteine (Hcy) are an independent risk factor for cardiovascular disease. Although a routine, rapid, and simple determination of Hcy levels is highly desired, the existing methods are practically limited because of complicated sample preparation and bulky instrumentation. Herein, we report a chemodosimetric approach for one-step analysis of Hcy levels based on the electrochemiluminescence (ECL). A rationally designed cyclometalated iridium(III) complex possessing a phenylisoquinoline main ligand underwent a selective ring-formation reaction with Hcy to generate a binding adduct, which enabled producing highly luminescent excited states, and yielded strong ECL signals on the surface of electrode without any use of enzymes or antibodies. The level of Hcy was successfully monitored by the ECL increment with a linear correlation between 0 and 40µM in 99.9% aqueous media. The approach required neither sample preparation nor bulky instrument, suggesting the point-of-care testing of Hcy levels, and is potentially useful for routine, cost-effective, and precautionary diagnosis of various cardiovascular diseases.

  14. Plasma levels of homocysteine and cysteine increased in pediatric NAFLD and strongly correlated with severity of liver damage.

    PubMed

    Pastore, Anna; Alisi, Anna; di Giovamberardino, Gianna; Crudele, Annalisa; Ceccarelli, Sara; Panera, Nadia; Dionisi-Vici, Carlo; Nobili, Valerio

    2014-11-17

    Non-alcoholic fatty liver disease (NAFLD) is a spectrum of metabolic abnormalities ranging from simple triglyceride accumulation in the hepatocytes to hepatic steatosis with inflammation, ballooning and fibrosis. It has been demonstrated that the pathogenesis of NAFLD involves increased oxidative stress, with consumption of the major cellular antioxidant, glutathione (GSH). Liver has a fundamental role in sulfur compound metabolism, although the data reported on plasma thiols status in NAFLD are conflicting. We recruited 63 NAFLD patients, and we analyzed all plasma thiols, such as homocysteine (Hcy), cysteine (Cys), cysteinylglycine (CysGly) and GSH, by high-performance liquid chromatography (HPLC) with fluorescence detection. Hcy, Cys and CysGly plasma levels increased in NAFLD patients (p < 0.0001); whereas GSH levels were decreased in NAFLD patients when compared to controls (p < 0.0001). On the contrary, patients with steatohepatitis exhibited lower levels of Hcy and Cys than subjects without. Furthermore, a positive correlation was found between Hcy and Cys and the presence of fibrosis in children with NAFLD. Taken together, these data demonstrated a defective hepatic sulfur metabolism in children with NAFLD, and that high levels of Hcy and Cys probably correlates with a pattern of more severe histological liver damage, due to mechanisms that require further studies.

  15. Aerobic Physical Exercise Improved the Cognitive Function of Elderly Males but Did Not Modify Their Blood Homocysteine Levels

    PubMed Central

    Antunes, Hanna Karen M.; De Mello, Marco Túlio; de Aquino Lemos, Valdir; Santos-Galduróz, Ruth Ferreira; Camargo Galdieri, Luciano; Amodeo Bueno, Orlando Francisco; Tufik, Sergio; D'Almeida, Vânia

    2015-01-01

    Background Physical exercise influences homocysteine (Hcy) concentrations, cognitive function and the metabolic profile. The purpose of this study was to investigate the influence of regular physical exercise on Hcy levels, the metabolic profile and cognitive function in healthy elderly males before and after an endurance exercise program. Methods Forty-five healthy and sedentary volunteers were randomized into 2 groups: (1) a control group asked not to change their normal everyday activities and not to start any regular physical exercise program and (2) an experimental group trained at a heart rate intensity corresponding to ventilatory threshold 1 (VT-1) for 60 min/day 3 times weekly on alternate days for 6 months using a cycle ergometer. All volunteers underwent cognitive evaluations, blood sample analyses and ergospirometric assessments. Results A significant improvement in cognitive function was observed in the experimental group compared with the control group (p < 0.05). No significant changes in Hcy levels were observed in the experimental group (p > 0.05), but there was a significant increase in peak oxygen consumption and workload at VT-1 as well as a significant improvement in cholesterol, triglycerides, HDL, glucose, alkaline phosphatase, urea, T3, T4 and prostate-specific antigen compared with the control group (p < 0.05). Conclusion The data suggest that a physical exercise program does not reduce Hcy levels in healthy elderly males, although it improves the cardiovascular and metabolic profile as well as cognitive function. PMID:25759715

  16. Serum levels of homocysteine, folate and vitamin B12 in patients with vitiligo before and after treatment with narrow band ultraviolet B phototherapy and in a group of controls.

    PubMed

    Ataş, Hatice; Cemil, Bengü Çevirgen; Gönül, Müzeyyen; Baştürk, Eda; Çiçek, Emel

    2015-07-01

    The association between vitamin B12, folate, homocysteine and vitiligo were studied in several studies, but the results are contradictory. Narrow-band ultraviolet B (NBUVB) phototherapy is now considered as a gold standard for the treatment of diffuse vitiligo. The effects of NBUVB phototherapy on both vitamin B12, folate and homocysteine levels have not been studied in vitiligo patients yet. Serum levels of vitamin B12, folate and homocysteine were measured in vitiligo patients and control group and also both before and after NBUVB phototherapy in vitiligo patients. While levels of homocysteine in patients with vitiligo were significantly higher than controls (16.9±8.4 vs. 10. 9±3.4 μmol/L; p<0,001) vitamin B12 and folate levels were not different (p>0.05). NBUVB phototherapy led to a 33.7±21.9% (0-75%) response in patients with vitiligo after 80 seccions. Treatment with NBUVB improved vitiligo and decreased serum levels of vitamin B12 (375±151 vs. 346±119 pg/ml, p=0.024), while serum levels of folate and homocysteine did not change significantly after treatment (p=0.914, p=0.127). Further studies are needed to clarify the influence of NBUVB phototherapy on folate, vitamin B12 and homocysteine levels in patients with vitiligo. Furthermore, studies with the analysis of skin levels of homocysteine rather than circulating levels may be useful to elucidate the effects of phototherapy on homocysteine levels.

  17. Neurologic symptoms as the only manifestation of B12 deficiency in a young patient with normal hematocrit, MCV, peripheral blood smear and homocysteine levels

    PubMed Central

    Voukelatou, Panagiota; Vrettos, Ioannis; Kalliakmanis, Andreas

    2016-01-01

    B12 deficiency is associated with several neurological manifestations. It is well documented that neurologic symptoms due to B12 deficiency may sometimes present in the absence of anemia. However, in most cases there are several indicating factors like megaloblastic changes in complete blood count, hypersegmentated neutrophils or macroovalocytes in peripheral blood smear and abnormal homocysteine levels. In this report, we describe a case of a 32-year-old man with neurological symptomatology as the only manifestation of B12 deficiency with normal hematocrit, mean cell volume, peripheral blood smear and homocysteine levels. All the above emphasize the point that patients with neurologic symptoms must be screened for B12 deficiency even in the absence of any laboratory evidence. PMID:28031855

  18. Assessment of Folic Acid Supplementation in Pregnant Women by Estimation of Serum Levels of Tetrahydrofolic Acid, Dihydrofolate Reductase, and Homocysteine.

    PubMed

    Naithani, Manisha; Saxena, Vartika; Mirza, Anissa Atif; Kumari, Ranjeeta; Sharma, Kapil; Bharadwaj, Jyoti

    2016-01-01

    Background. Status of folic acid use in pregnant women of the hilly regions in North India was little known. This study was carried out to assess the folic acid use and estimate folate metabolites in pregnant women of this region. Materials and Methods. This cross-sectional study is comprised of 76 pregnant women, whose folic acid supplementation was assessed by a questionnaire and serum levels of homocysteine, tetrahydrofolic acid (THFA), and dihydrofolate reductase (DHFR) were estimated using Enzyme Linked Immunoassays. Results. The study data revealed awareness of folic acid use during pregnancy was present in 46.1% and 23.7% were taking folic acid supplements. The study depicted that there was no statistically significant difference between serum levels of THFA and DHFR in pregnant women with and without folic acid supplements (p = 0.790). Hyperhomocysteinemia was present in 15.78% of the participants. Conclusion. Less awareness about folic acid supplementation and low use of folic acid by pregnant women were observed in this region. Sufficient dietary ingestion may suffice for the escalated requirements in pregnancy, but since this cannot be ensured, hence folic acid supplementation should be made as an integral part of education and reproductive health programs for its better metabolic use, growth, and development of fetus.

  19. Assessment of Folic Acid Supplementation in Pregnant Women by Estimation of Serum Levels of Tetrahydrofolic Acid, Dihydrofolate Reductase, and Homocysteine

    PubMed Central

    Saxena, Vartika; Mirza, Anissa Atif; Kumari, Ranjeeta; Sharma, Kapil; Bharadwaj, Jyoti

    2016-01-01

    Background. Status of folic acid use in pregnant women of the hilly regions in North India was little known. This study was carried out to assess the folic acid use and estimate folate metabolites in pregnant women of this region. Materials and Methods. This cross-sectional study is comprised of 76 pregnant women, whose folic acid supplementation was assessed by a questionnaire and serum levels of homocysteine, tetrahydrofolic acid (THFA), and dihydrofolate reductase (DHFR) were estimated using Enzyme Linked Immunoassays. Results. The study data revealed awareness of folic acid use during pregnancy was present in 46.1% and 23.7% were taking folic acid supplements. The study depicted that there was no statistically significant difference between serum levels of THFA and DHFR in pregnant women with and without folic acid supplements (p = 0.790). Hyperhomocysteinemia was present in 15.78% of the participants. Conclusion. Less awareness about folic acid supplementation and low use of folic acid by pregnant women were observed in this region. Sufficient dietary ingestion may suffice for the escalated requirements in pregnancy, but since this cannot be ensured, hence folic acid supplementation should be made as an integral part of education and reproductive health programs for its better metabolic use, growth, and development of fetus. PMID:27064332

  20. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine.

    PubMed

    Papakostas, George I; Petersen, Timothy; Lebowitz, Barry D; Mischoulon, David; Ryan, Julie L; Nierenberg, Andrew A; Bottiglieri, Teodoro; Alpert, Jonathan E; Rosenbaum, Jerrold F; Fava, Maurizio

    2005-12-01

    The objective of the present study was to examine the relationship between serum folate, vitamin B12, and homocysteine levels and the timing of clinical improvement to fluoxetine in major depressive disorder (MDD) patients. A total of 110 outpatients with MDD who responded to an 8-wk trial of fluoxetine had serum folate, B12, and homocysteine measurements at baseline (prior to fluoxetine initiation). Onset of clinical improvement was defined as a 30% decrease in Hamilton Depression Scale scores that led to a 50% decrease by week 8. Patients with low folate levels (homocysteine level status did not predict time to clinical improvement ( p >0.05). In conclusion, low serum folate levels were found to be associated with a delayed onset of clinical improvement during treatment with fluoxetine in MDD by, on average, 1.5 wk.

  1. Plasma ω-3 fatty acid levels negatively and ω-6 fatty acid levels positively associated with other cardiovascular risk factors including homocysteine in severe obese subjects.

    PubMed

    Mehmetoglu, Idris; Yerlikaya, F Hümeyra; Kurban, Sevil; Polat, Hakkı

    2012-01-01

    Obesity and homocysteine (tHcy) are important risk factors for cardiovascular diseases (CVD). Plasma omega-3 fatty acids (ω-3 FAs) and omega-6 fatty acids (ω-6 FAs) are essential fatty acids with diverse biological effects in human health and disease. We have investigated the relation of plasma ω-3 FAs and ω-6 FAs levels with other cardiovascular risk factors including tHcy in severe obese subjects. This study was performed on 96 severe obese and 65 normal weight subjects. Plasma fatty acid composition was measured by GC/MS and serum tHcy level was measured by HPLC methods. There were no differences between groups in terms of concentrations of serum tHcy, plasma ω-3 FAs, ω-6 FAs and ω-3/ω-6 ratio, whereas serum vitamin B-12 (p<0.01) and folic acid (p<0.05) levels were lower than those of the normal weight subjects. Homocysteine positively correlated with ω-6 FAs and negatively correlated with ω-3 FAs in severe obese and normal weight subjects. Serum vitamin B-12 positively correlated with ω-3 FAs (p<0.01) and ω-3/ω-6 ratio (p<0.01) and negatively correlated with ω-6 FAs (p<0.05) in severe obese subjects. Serum folic acid positively correlated with ω-3 FAs (p<0.01) in severe obese subjects. Our results suggest an association between the plasma ω-3 FAs and ω-6 FAs and serum tHcy concentrations in severe obese and normal weight subjects. Low levels vitamin B-12 and folic acid may have been responsible for the elevated tHcy levels in severe obese subjects, increasing the risk for future development of cardiovascular diseases.

  2. Evolution of procalcitonin, C-reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis.

    PubMed

    Roques, Marjorie; Chretien, Marie Lorraine; Favennec, Camille; Lafon, Ingrid; Ferrant, Emmanuelle; Legouge, Caroline; Plocque, Alexia; Golfier, Camille; Duvillard, Laurence; Amoureux, Lucie; Bastie, Jean Noel; Maurin-Bernier, Lory; Dalle, Frederic; Caillot, Denis

    2016-06-01

    Unlike bacterial infections, the value of procalcitonin (PCT) in detecting fungal infections in leukaemia patients is not clear. To determine whether the monitoring of PCT coupled with C-reactive protein (CRP) and fibrinogen (Fib) could be helpful in the management of pulmonary aspergillosis (IPA) or mucormycosis (PM), we retrospectively analysed the evolution of PCT, CRP and Fib levels in 94 leukaemia patients with proven/probable IPA (n = 77) or PM (n = 17) from D-12 to D12 relative to IFI onset defined as D0. Overall, 2140 assays were performed. From D-12 to D0, 12%, 5% and 1.4% of patients had PCT >0.5, 1 and 1.5 μg l(-1) , respectively, while CRP was >50, 75 and 100 mg l(-1) in 84%, 70% and 57% and Fib was >4, 5 and 6 g l(-1) in 96%, 80% and 61% of cases respectively (P < 10(-7) ). The same trends were observed from D1 to D12. Overall, between D-12 and D12, only 6.4% of patients had PCT >1.5 μg l(-1) , while CRP >100 mg l(-1) and Fib >6 g l(-1) were observed in 80% and 75% of cases respectively (P < 10(-7) ). In leukaemia patients, IPA or PM was accompanied by a significant increase in CRP and Fib while PCT remained low.

  3. Homocysteine and prothrombin fragment 1+2 levels in patients with veno-occlusive disease after stem cell transplantation.

    PubMed

    Gerecitano, John; Mathias, Clarissa; Mick, Rosemarie; Duffy, Kathleen M; Luger, Selina; Stadtmauer, Edward A; Schuster, Stephen J; Tsai, Donald; Nasta, Sunita; Berlin, Jesse; Phillips, Deborah K; High, Katherine A; Porter, David L

    2003-04-01

    Veno-occlusive disease (VOD) of the liver remains a major complication after hematopoietic stem cell transplantation (SCT). VOD is thought to develop after hepatic endothelial cells are damaged by high-dose chemotherapy or radiation, causing microthrombosis in hepatic venules. However, the precise mechanisms leading to VOD are not well defined, and a diagnosis is often difficult to establish. It is also difficult to predict which patients are most likely to develop VOD. Elevated levels of homocysteine (HC) have been associated with thrombosis, and prothrombin fragment 1 + 2 (F1 + 2) is a measurable marker for coagulation. Therefore, we performed a prospective cohort study to determine if HC or F1 + 2 levels could be used to predict the development of VOD prior to SCT, or to help establish a diagnosis of VOD in association with other clinical parameters. Plasma levels of these factors were measured before conditioning and serially for 21 days after SCT in 42 consecutive patients undergoing SCT. Eleven of 26 allogeneic SCT recipients developed VOD, whereas no autologous SCT recipient (n = 16) developed VOD (p = 0.008). In patients who developed VOD, HC levels were consistently higher than those seen in non-VOD patients after day 7 of SCT. Patients with VOD also had higher levels of F1 + 2 after SCT, although this marker was less consistently elevated over time. A logistic regression model that evaluated all serial measures of HC and F1 + 2 showed a moderate sensitivity and specificity in diagnosing VOD in allogeneic SCT patients, but neither marker was useful to predict development of VOD when tested prior to SCT.

  4. Effects of Repeatedly Heated Palm Oil on Serum Lipid Profile, Lipid Peroxidation and Homocysteine Levels in a Post-Menopausal Rat Model

    PubMed Central

    Adam, Siti Khadijah; Soelaiman, Ima Nirwana; Umar, Nor Aini; Mokhtar, Norhayati; Mohamed, Norazlina; Jaarin, Kamsiah

    2008-01-01

    Oxidized unsaturated fatty acids may contribute to the pathogenesis of atherosclerosis. In the present study, we examined the effects of heated palm oil mixed with 2% cholesterol diet on serum lipid profile, homocysteine and thiobarbituric acid reactive substances (TBARS) levels in estrogen-deficient rats. Twenty-four female Sprague Dawley rats were ovariectomized and then were divided equally into four groups. The control group was given 2% cholesterol diet only throughout the study period. The three treatment groups received 2% cholesterol diet fortified with fresh, once-heated or five-times-heated palm oil, respectively. Serum TBARS, lipid profile and homocysteine levels were measured prior to ovariectomy and at the end of four months of the study. Five-times-heated palm oil caused a significant increase in TBARS and total cholesterol (TC) compared to control (F = 22.529, p < 0.05). There was a significant increase in serum homocysteine in the control as well as five-times heated palm oil group compared to fresh and once-heated palm oil groups (F = 4.432, p < 0.05). The findings suggest that repeatedly heated palm oil increase lipid peroxidation and TC. Ovariectomy increases the development of atherosclerosis as seen in this study. Feeding with fresh and once-heated palm oil does not cause any deleterious effect but repeatedly heated oil may be harmful because it causes oxidative damage thereby predisposing to atherosclerosis. PMID:19148313

  5. Diagnosis of congenital fibrinogen disorders.

    PubMed

    Lebreton, Aurélien; Casini, Alessandro

    2016-08-01

    Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of circulating fibrinogen and qualitative disorders characterized by a discrepancy between the activity and the antigenic levels of fibrinogen (dysfibrinogenemia and hypodysfibrinogenemia). The biological diagnosis is based on a standard haemostasis assessment. All the coagulation tests that depend on the formation of fibrin as the end point are affected; although in dysfibrinogenemia the specificity and sensitivity of routine test depend on reagent and techniques. A genetic exploration permits to confirm the diagnosis and may enhance the prediction of the patient's phenotype. Homozygous or composite heterozygous null mutations are most often responsible for afibrinogenemia while hypofibrinogenemic patients are mainly heterozygous carrier of an afibrinogenemic allele. Heterozygous missense mutations are prevalent in dysfibrinogenemia, with two hot spot localized in exon 2 of the FGA and in the exon 8 of the FGG. The correlation between phenotype and genotype has been identified in some fibrinogen variants, including six mutations clustered in exons 8 and 9 of the FGG leading to hypofibrinogenemia with hepatic inclusions of abnormal fibrinogen aggregates as well as a few mutations associated with an increase risk of thrombotic events. A familial screening and additional functional assays should be carried out when possible.

  6. Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians.

    PubMed

    Kumudini, Nadella; Uma, Addepally; Naushad, Shaik Mohammad; Mridula, Rukmini; Borgohain, Rupam; Kutala, Vijay Kumar

    2014-05-07

    This study from South India was performed to ascertain the impact of seven functional polymorphisms of one-carbon metabolic pathway on total plasma homocysteine levels and susceptibility to PD. A total of 151 cases of Parkinson's disease and 416 healthy controls were analyzed for fasting plasma homocysteine levels by reverse phase HPLC. PCR-RFLP approaches were used to analyze glutamate carboxypeptidase II (GCPII) 1561 C>T, reduced folate carrier 1 (RFC1) 80 G>A, cytosolic serine hydroxymethyl transferase (cSHMT) 1420 C>T, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, methionine synthase (MTR) 2756 A>G and methionine synthase reductase (MTRR) 66 A>G polymorphisms. PCR-AFLP was used for the analysis of thymidylate synthase (TYMS) 5'-UTR 28bp tandem repeat. PD cases exhibited elevated plasma homocysteine levels compared to controls (men: 28.8 ± 6.9 vs. 16.4 ± 8.8 μmol/L; women: 25.4 ± 5.3 vs. 11.2 ± 5.1μmol/L). Homocysteine levels showed positive correlation with male gender (r=0.39, p<0.0001) and MTRR 66 A>G (r=0.31, p<0.0001) whereas an inverse correlation was observed with cSHMT 1420 C>T polymorphism. MTRR 66 A>G polymorphism showed independent risk for PD (OR: 3.42, 95% CI: 2.35-4.98) whereas cSHMT 1420 C>T conferred protection against PD (OR: 0.11, 95% CI: 0.07-0.17). Multifactor dimensionality reduction analysis showed synergistic interactions between MTHFR 677 C>T and MTRR 66 A>G, whereas cSHMT 1420 C>T exhibited counteracting interactions in altering susceptibility to PD. To conclude, PD cases exhibited hyperhomocysteinemia and MTRR 66 A>G and cSHMT 1420 C>T gene variants were shown to modulate PD risk by altering the homocysteine levels.

  7. High homocysteine levels prevent via H2 S the CoCl2 -induced alteration of lymphocyte viability.

    PubMed

    Bruzzese, Laurie; Fenouillet, Emmanuel; Fromonot, Julien; Durand-Gorde, Josée-Martine; Condo, Jocelyne; Kipson, Nathalie; Mottola, Giovanna; Deharo, Pierre; Guieu, Régis; Ruf, Jean

    2016-08-01

    High homocysteine (HCy) levels are associated with lymphocyte-mediated inflammatory responses that are sometimes in turn related to hypoxia. Because adenosine is a potent lymphocyte suppressor produced in hypoxic conditions and shares metabolic pathways with HCy, we addressed the influence of high HCy levels on the hypoxia-induced, adenosine-mediated, alteration of lymphocyte viability. We treated mitogen-stimulated human lymphocytes isolated from healthy individuals and the human lymphoma T-cell line CEM with cobalt chloride (CoCl2 )to reproduce hypoxia. We found that CoCl2 -altered cell viability was dose-dependently reversed using HCy. In turn, the HCy effect was inhibited using DL-propargylglycine, a specific inhibitor of the hydrogen sulphide (H2 S)-synthesizing enzyme cystathionine-γ-lyase involved in HCy catabolism. We then addressed the intracellular metabolic pathway of adenosine and HCy, and the role of the adenosine A2A receptor (A2 A R). We observed that: (i) hypoxic conditions lowered the intracellular concentration of HCy by increasing adenosine production, which resulted in high A2 A R expression and 3', 5'-cyclic adenosine monophosphate production; (ii) increasing intracellular HCy concentration reversed the hypoxia-induced adenosinergic signalling despite high adenosine concentration by promoting both S-adenosylhomocysteine and H2 S production; (iii) DL-propargylglycine that inhibits H2 S production abolished the HCy effect. Together, these data suggest that high HCy levels prevent, via H2 S production and the resulting down-regulation of A2 A R expression, the hypoxia-induced adenosinergic alteration of lymphocyte viability. We point out the relevance of these mechanisms in the pathophysiology of cardiovascular diseases.

  8. Effect of resveratrol on hemostatic properties of human fibrinogen and plasma during model of hyperhomocysteinemia.

    PubMed

    Malinowska, Joanna; Olas, Beata

    2010-11-01

    Resveratrol (3,4', 5 - trihydroxystilben), a phenolic antioxidant synthesized in grapes and vegetables and presents in wine, has been supposed to be beneficial for the prevention of cardiovascular events. In this study the influence of resveratrol on the clot formation (using human plasma and purified fibrinogen) and the fibrin lysis during model of hyperhomocysteinemia was investigated. We induced this process using a reduced form of Hcys (at final dose of 0.1mM) and the most reactive form of Hcys - its cyclic thioester, homocysteine thiolactone (HTL, 0.5μM). The aim of our study in vitro was to investigate the modifications of human plasma total proteins after incubation with Hcys, HTL and resveratrol. We observed that HTL, like its precursor, Hcys stimulated polymerization of fibrinogen. Our present results also demonstrated that Hcys (0.1mM) and HLT at lower doses than Hcys (0.5μM) reduced the fibrin lysis in human plasma. Moreover, Hcys and HTL change the level of thiol and amino groups in plasma total proteins. Our results indicate that resveratrol reduced the toxicity action of Hcys and HTL on hemostatic properties of fibrinogen or plasma, suggesting its possible protector role in hyperhomocysteinemia - induced cardiovascular diseases.

  9. Comparative Assessment of Vitamin-B12, Folic Acid and Homocysteine Levels in Relation to p53 Expression in Megaloblastic Anemia

    PubMed Central

    Yadav, Manish K.; Manoli, Nandini M.

    2016-01-01

    Background Megaloblastic anemia (MBA), also known as macrocytic anemia, is a type of anemia characterized by decreased number of RBCs as well as the presence of unusually large, abnormal and poorly developed erythrocytes (megaloblasts), which fail to enter blood circulation due to their larger size. Lack of vitamin-B12 (VB12) and / or folate (Vitamin-B9, VB9) with elevated homocysteine is the key factor responsible for megaloblastic anemia. Prior studies have demonstrated the induction of apoptosis in these abnormal under-developed erythrocytes. However, it is not clear whether this apoptosis induction is due to elevated p53 level or due to any other mechanism. Furthermore, it is also not fully known whether decreased vitamin-B12 and / or folate are responsible for apoptosis induction mediated by p53 in pre-erythroblasts. Methods Levels of serum VB9, VB12 and homocysteine in 50 patients suffering from MBA were compared with 50 non-megaloblastic anemia control subjects, who were referred by the clinicians for bone marrow examination for medical conditions other than MBA. Next, we have measured the p53 expression in the paraffin embedded blocks prepared from bone marrow biopsy, using immunohistochemistry, and the expression levels correlated with VB9 and VB12 levels. Results Out of 50 MBA patients 40 (80%) and 44 (88%) subjects had very low VB12 and VB9 levels respectively. In contrast, only 2 (4%) and 12 (24%) non-megaloblastic anemia controls, out of 50 subjects, had low VB12 and VB9 respectively. Correlating with low vitamin B9 and B12, the homocysteine levels were high in 80% cases. But, only 20% non-megaloblastic controls exhibited high homocysteine in plasma. Immunohistochemical analysis for p53 expression showed a significantly high level of expression in MBA cases and no—or very low—expression in control subjects. Our correlation studies comparing the VB12 and VB9 levels with p53 expression concludes unusually high p53 levels in patients suffering from VB

  10. Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging.

    PubMed

    McCully, Kilmer S

    2015-12-15

    The importance of homocysteine in vascular function and arteriosclerosis was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by inherited enzymatic deficiencies of cystathionine synthase, methionine synthase, or methylene-tetrahydrofolate reductase. According to the homocysteine theory of arteriosclerosis, an elevated blood homocysteine level is an important risk factor for atherosclerosis in subjects without these rare enzymatic abnormalities. The homocysteine theory is supported by demonstration of arterial plaques in experimental animals with hyperhomocysteinemia, by discovery of a pathway for conversion of homocysteine thiolactone to sulfate in cell cultures from children with homocystinuria, and by demonstration of growth promotion by homocysteic acid in normal and hypophysectomized animals. Studies with cultured malignant cells revealed abnormal homocysteine thiolactone metabolism, resulting in homocysteinylation of proteins, nucleic acids, and glycosaminoglycans, explaining the abnormal oxidative metabolism, abnormalities of cellular membranes, and altered genetic expression observed in malignancy. Abnormal homocysteine metabolism in malignant cells is attributed to deficiency of thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide combine with cobalamin to form thioretinaco. Based on the molecular structure of thioretinaco, a theory of oxidative phosphorylation was proposed, involving oxidation to a disulfonium derivative by ozone, and binding of oxygen, nicotinamide adenine dinucleotide and phosphate as the active site of adenosine triphosphate synthesis in mitochondria. Obstruction of vasa vasorum by aggregates of microorganisms with homocysteinylated low-density lipoproteins is proposed to cause ischemia of arterial wall and a microabscess of the intima, the vulnerable atherosclerotic plaque.

  11. No Association between Elevated Total Homocysteine Levels and Functional Outcome in Elderly Patients with Acute Cerebral Infarction

    PubMed Central

    Wang, Wanjun; Gao, Chunlin; Yu, Changshen; Liu, Shoufeng; Hou, Dongzhe; Wang, Yajing; Wang, Chen; Mo, Lidong; Wu, Jialing

    2017-01-01

    Background: An elevated plasma total homocysteine (tHcy) level is an independent risk factor for vascular events. The aim of the present study was to investigate the association between tHcy levels in the acute phase of cerebral infarction and functional outcome among elderly patients. Methods: Between October 2009 and December 2012, we recruited 594 elderly patients (age > 75) with first-onset acute cerebral infarction who were consecutively admitted to the Department of Neurology of Tianjin Huanhu Hospital, China. Levels of tHcy and other biochemical values were measured within 24 h after admission. tHcy values were classified according to quartiles (<9.94; 9.94 to <12.7; 12.7 to <16.8; and ≥16.8 μmol/L). We examined the relationship between tHcy levels at admission and modified Rankin Scale scores (mRS) using univariate and multivariate analyses. Patients were followed up at 3 months and 1 year after stroke. Results: Within 3 months after stroke, 64 patients died, 37 had recurrent ischemic stroke, and 22 were lost to follow-up; thus, 471 patients were reviewed and analyzed. By the time of the 1-year follow-up, an additional 48 patients had died, 44 had recurrent ischemic stroke, and 40 had been lost to follow-up; the remaining 339 patients were thus reviewed and analyzed. Elevated tHcy levels were not associated with functional outcome among elderly patients with acute cerebral infarction (p > 0.05). Only the National Institutes of Health Stroke Scale score was associated with a poor outcome after adjusting for confounders at 3 months and 1 year (adjusted odds ratio, 1.38; 95% CI, 1.28–1.49; p < 0.01; adjusted odds ratio, 1.34; 95% CI, 1.25–1.44; p < 0.01, respectively). Conclusion: Among elderly patients with acute cerebral infarction, elevated tHcy at admission was not a predictive factor of outcome at 3 months and 1 year after stroke onset. PMID:28377713

  12. Molecular mechanisms of homocysteine toxicity.

    PubMed

    Boldyrev, A A

    2009-06-01

    Hyperhomocysteinemia is a risk factor for a number of cardiovascular and neurodegenerative processes as well as a complicating factor in normal pregnancy. Toxic effects of homocysteine and the product of its spontaneous oxidation, homocysteic acid, are based on their ability to activate NMDA receptors, increasing intracellular levels of ionized calcium and reactive oxygen species. Even a short-term exposure of cells to homocysteic acid at concentrations characteristic of hyperhomocysteinemia induces their apoptotic transformation. The discovery of NMDA receptors both in neuronal tissue and in several other tissues and organs (including immunocompetent cells) makes them a target for toxic action of homocysteine. The neuropeptide carnosine was found to protect the organism from homocysteine toxicity. Treatment of pregnant rats with carnosine under conditions of alimentary hyperhomocysteinemia increases viability and functional activity of their progeny.

  13. Elevated homocysteine levels in human immunodeficiency virus-infected patients under antiretroviral therapy: A meta-analysis

    PubMed Central

    Deminice, Rafael; Silva, Talita Capoani Vieira; de Oliveira, Vitor Hugo Fernando

    2015-01-01

    AIM: To evaluate the association between the levels of homocysteine (Hcy), folate, vitamin B12 in human immunodeficiency virus (HIV)-infected patients who were treated with antiretroviral therapy (ART) or not treated with ART. METHODS: The PubMed and Scielo databases were searched. Eligible studies regarding plasma Hcy level in HIV-infected patients were firstly identified. After careful analysis by two independent researches, the identified articles were included in the review according to two outcomes (1) Hcy, folate and vitamin B12 blood concentration in HIV-infected subjects vs health controls and; (2) Hcy blood concentration in HIV-infected subjects under ART vs not treated with ART. RevMan (version 5.2) was employed for data synthesis. RESULTS: A total of 12 studies were included in outcome 1 (1649 participants, 932 cases and 717 controls). Outcome 1 meta-analysis demonstrated higher plasma Hcy (2.05 µmol/L; 95%CI: 0.10 to 4.00, P < 0.01) and decreased plasma folate concentrations (-2.74 ng/mL; 95%CI: -5.18 to -0.29, P < 0.01) in HIV-infected patients compared to healthy controls. No changes in vitamin B12 plasma concentration were observed between groups. All studies included in the outcome 2 meta-analysis (1167 participants; 404 HIV-infected exposed to ART and 757 HIV-infected non-ART patients) demonstrated higher mean Hcy concentration in subjects HIV-infected under ART compared to non-ART HIV subjects (4.13 µmol/L; 95%CI: 1.34 to 6.92, P < 0.01). CONCLUSION: This meta-analysis demonstrated that the levels of Hcy and folate, but not vitamin B12, were associated with HIV infection. In addition, Hcy levels were higher in HIV-infected patients who were under ART compared to HIV-infected patients who were not exposed to ART. Our results suggest that hyperhomocysteinemia should be included among the several important metabolic disturbances that are associated with ART in patients with HIV infection. PMID:25964880

  14. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.

    PubMed

    Huffman, Jennifer E; de Vries, Paul S; Morrison, Alanna C; Sabater-Lleal, Maria; Kacprowski, Tim; Auer, Paul L; Brody, Jennifer A; Chasman, Daniel I; Chen, Ming-Huei; Guo, Xiuqing; Lin, Li-An; Marioni, Riccardo E; Müller-Nurasyid, Martina; Yanek, Lisa R; Pankratz, Nathan; Grove, Megan L; de Maat, Moniek P M; Cushman, Mary; Wiggins, Kerri L; Qi, Lihong; Sennblad, Bengt; Harris, Sarah E; Polasek, Ozren; Riess, Helene; Rivadeneira, Fernando; Rose, Lynda M; Goel, Anuj; Taylor, Kent D; Teumer, Alexander; Uitterlinden, André G; Vaidya, Dhananjay; Yao, Jie; Tang, Weihong; Levy, Daniel; Waldenberger, Melanie; Becker, Diane M; Folsom, Aaron R; Giulianini, Franco; Greinacher, Andreas; Hofman, Albert; Huang, Chiang-Ching; Kooperberg, Charles; Silveira, Angela; Starr, John M; Strauch, Konstantin; Strawbridge, Rona J; Wright, Alan F; McKnight, Barbara; Franco, Oscar H; Zakai, Neil; Mathias, Rasika A; Psaty, Bruce M; Ridker, Paul M; Tofler, Geoffrey H; Völker, Uwe; Watkins, Hugh; Fornage, Myriam; Hamsten, Anders; Deary, Ian J; Boerwinkle, Eric; Koenig, Wolfgang; Rotter, Jerome I; Hayward, Caroline; Dehghan, Abbas; Reiner, Alex P; O'Donnell, Christopher J; Smith, Nicholas L

    2015-09-10

    Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

  15. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

    PubMed Central

    Huffman, Jennifer E.; de Vries, Paul S.; Morrison, Alanna C.; Sabater-Lleal, Maria; Kacprowski, Tim; Auer, Paul L.; Brody, Jennifer A.; Chasman, Daniel I.; Chen, Ming-Huei; Guo, Xiuqing; Lin, Li-An; Marioni, Riccardo E.; Müller-Nurasyid, Martina; Yanek, Lisa R.; Pankratz, Nathan; Grove, Megan L.; de Maat, Moniek P. M.; Cushman, Mary; Wiggins, Kerri L.; Qi, Lihong; Sennblad, Bengt; Harris, Sarah E.; Polasek, Ozren; Riess, Helene; Rivadeneira, Fernando; Rose, Lynda M.; Goel, Anuj; Taylor, Kent D.; Teumer, Alexander; Uitterlinden, André G.; Vaidya, Dhananjay; Yao, Jie; Tang, Weihong; Levy, Daniel; Waldenberger, Melanie; Becker, Diane M.; Folsom, Aaron R.; Giulianini, Franco; Greinacher, Andreas; Hofman, Albert; Huang, Chiang-Ching; Kooperberg, Charles; Silveira, Angela; Starr, John M.; Strauch, Konstantin; Strawbridge, Rona J.; Wright, Alan F.; McKnight, Barbara; Franco, Oscar H.; Zakai, Neil; Mathias, Rasika A.; Psaty, Bruce M.; Ridker, Paul M.; Tofler, Geoffrey H.; Völker, Uwe; Watkins, Hugh; Fornage, Myriam; Hamsten, Anders; Deary, Ian J.; Boerwinkle, Eric; Koenig, Wolfgang; Rotter, Jerome I.; Hayward, Caroline; Dehghan, Abbas; Reiner, Alex P.; O’Donnell, Christopher J.

    2015-01-01

    Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76 000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways. PMID:26105150

  16. The effects of long-term resistance exercise on the relationship between neurocognitive performance and GH, IGF-1, and homocysteine levels in the elderly

    PubMed Central

    Tsai, Chia-Liang; Wang, Chun-Hao; Pan, Chien-Yu; Chen, Fu-Chen

    2015-01-01

    This study aimed to investigate the effects of a long-term resistance exercise intervention on executive functions in healthy elderly males, and to further understand the potential neurophysiological mechanisms mediating the changes. The study assessed forty-eight healthy elderly males randomly assigned to exercise (n = 24) or control (n = 24) groups. The assessment included neuropsychological and neuroelectric measures during a variant of the oddball task paradigm, as well as growth hormone (GH), insulin-like growth factor-1 (IGF-1), and homocysteine levels at baseline and after either a 12 month intervention of resistance exercise training or control period. The results showed that the control group had a significantly lower accuracy rate and smaller P3a and P3b amplitudes in the oddball condition after 12 months. The exercise group exhibited improved reaction times (RTs), sustained P3a and P3b amplitudes, increased levels of serum IGF-1, and decreased levels of serum homocysteine. The changes in IGF-1 levels were significantly correlated with the changes in RT and P3b amplitude of the oddball condition in the exercise group. In conclusion, significantly enhanced serum IGF-1 levels after 12 months of resistance exercise were inversely correlated with neurocognitive decline in the elderly. These findings suggest that regular resistance exercise might be a promising strategy to attenuate the trajectory of cognitive aging in healthy elderly individuals, possibly mediated by IGF-1. PMID:25713518

  17. Plasma homocysteine levels and genetic polymorphisms in folate metablism are associated with breast cancer risk in chinese women

    PubMed Central

    2014-01-01

    Background Folate plays a pivotal role in DNA synthesis, repair, methylation and homocysteine (Hcy) metabolism. Therefore, alterations in the folate-mediated one-carbon metabolism may lead to abnormal methylation proliferation, increases of tumor/neoplasia and vein thrombosis/cardiovascular risk. The serine hydroxymethyhransferase (SHMT), methionine synthase (MS), methionine synthase reductase (MTRR) and cystathionine beta synthase (CBS) regulate key reactions in the folate and Hcy metabolism. Therefore, we investigated whether the genetic variants of the SHMT, MS, MTRR and CBS gene can affect plasma Hcy levels and are associated with breast cancer risk. Methods Genotyping was performed by PCR-RFLP method. Plasma Hcy levels were measured by the fluorescence polarization immunoassay on samples of 96 cases and 85 controls. Results (a) The SHMT 1420 T, MS 2756G, MTRR 66G allele frequency distribution showed significant difference between case and controls (p < 0.01 ~ 0.05). (b) The concentration of plasma Hcy levels of SHMT 1420TT was significantly lower than that of the wild type, while the plasma Hcy levels of MS 2756GG, CBS 699TT/1080TT significantly higher than that of the wild type both in case and controls. The plasma Hcy levels of MTRR 66GG was significantly higher than that of wild type in cases. The plasma Hcy levels of the same genotype in cases were significantly higher than those of controls except SHMT 1420CC, MS 2756AA, MTRR 66GG; (c) Multivariate Logistic regression analysis showed that SHMT C1420T (OR = 0.527, 95% CI = 0.55 ~ 1.24), MS A2756G (OR = 2.32, 95% CI = 0.29 ~ 0.82), MTRR A66G (OR = 1.84, 95% CI = 0.25 ~ 1.66) polymorphism is significantly associated with breast cancer risk. And elevated plasma Hcy levels were significantly linked to increased risk of breast cancer (adjusted OR = 4.45, 95% CI = 1.89-6.24 for the highest tertile as compared with the lowest tertile). Conclusions The current

  18. Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment.

    PubMed

    Rozycka, Agata; Jagodzinski, Pawel P; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2013-12-01

    An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease.

  19. Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment

    PubMed Central

    Rozycka, Agata; Jagodzinski, Pawel P.; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2013-01-01

    An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease. PMID:24532985

  20. Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study.

    PubMed

    Ars, Charlotte L; Nijs, Ilse M; Marroun, Hanan E; Muetzel, Ryan; Schmidt, Marcus; Steenweg-de Graaff, Jolien; van der Lugt, Aad; Jaddoe, Vincent W; Hofman, Albert; Steegers, Eric A; Verhulst, Frank C; Tiemeier, Henning; White, Tonya

    2016-01-22

    Previous studies have suggested that prenatal maternal folate deficiency is associated with reduced prenatal brain growth and psychological problems in offspring. However, little is known about the longer-term impact. The aims of this study were to investigate whether prenatal maternal folate insufficiency, high total homocysteine levels and low vitamin B12 levels are associated with altered brain morphology, cognitive and/or psychological problems in school-aged children. This study was embedded in Generation R, a prospective population-based cohort study. The study sample consisted of 256 Dutch children aged between 6 and 8 years from whom structural brain scans were collected using MRI. The mothers of sixty-two children had insufficient (9·1 µmol/l) predicted poorer performance on the language (B -0·31; 95 % CI -0·56, -0·06; P=0·014) and visuo-spatial domains (B -0·36; 95 % CI -0·60, -0·11; P=0·004). No associations with psychological problems were found. Our findings suggest that folate insufficiency in early pregnancy has a long-lasting, global effect on brain development and is, together with homocysteine levels, associated with poorer cognitive performance.

  1. Adiponectin, C-reactive protein, fibrinogen and tissue plasminogen activator antigen levels among glucose-intolerant women with and without histories of gestational diabetes

    PubMed Central

    Kim, C.; Christophi, C. A.; Goldberg, R. B.; Perreault, L.; Dabelea, D.; Marcovina, S. M.; Pi-Sunyer, X.; Barrett-Connor, E.

    2015-01-01

    Aim To examine concentrations of biomarkers (adiponectin, C-reactive protein, fibrinogen and tissue plasminogen-activator antigen) associated with glucose homeostasis and diabetes risk by history of gestational diabetes. Methods We conducted a secondary analysis of the Diabetes Prevention Program, a randomized trial of lifestyle intervention or metformin for diabetes prevention. At baseline, participants were overweight and had impaired glucose tolerance. Biomarkers at baseline and 1 year after enrolment were compared between parous women with (n=350) and without a history of gestational diabetes (n=1466). Cox proportional hazard models evaluated whether history of gestational diabetes was associated with diabetes risk, after adjustment for baseline biomarker levels as well as for change in biomarker levels, demographic factors and anthropometrics. Results At baseline, women with histories of gestational diabetes had lower adiponectin (7.5 μg/ml vs. 8.7 μg/ml; p<0.0001) and greater log C-reactive protein (−0.90 mg/l vs. −0.78 mg/l, p=0.04) levels than women without histories of gestational diabetes, but these associations did not persist after adjustment for demographic factors. Fibrinogen and tissue plasminogen-activator antigen were similar between women with and without histories of gestational diabetes. Women with and without histories of gestational diabetes had a similar pattern of changes in biomarkers within randomization arm. Adjustment for age, race/ethnicity, baseline weight, change in weight, baseline biomarker level and change in biomarker level did not significantly alter the association between history of gestational diabetes and diabetes risk. Conclusions Among women with impaired glucose tolerance, biomarkers in women with and without histories of gestational diabetes are similar and respond similarly to lifestyle changes and metformin. Adjustment for biomarker levels did not explain the higher risk of diabetes observed in women with

  2. [Homocysteine and venous thromboembolism].

    PubMed

    Monnerat, C; Hayoz, D

    1997-09-06

    Congenital homocysteinuria is a rare inherited metabolic disorder with early onset atherosclerosis and arterial and venous trombosis. Moderate hyperhomocysteinemia is more frequently encountered and is recognized as an independent cardiovascular risk factor. Several case-control studies demonstrate an association between venous thromboembolism and moderate hyperhomocysteinemia. A patient with moderate hyperhomocysteinemia has a 2-3 relative risk of developing an episode of venous thromboembolism. The occurrence of mild hyperhomocysteinemia in heterozygotes for the mutation of Leiden factor V involves a 10-fold increase in the risk of venous thromboembolism. The biochemical mechanism by which homocysteine may promote thrombosis is not fully recognized. Homocysteine inhibits the expression of thrombomodulin, the thrombin cofactor responsible for protein C activation, and inhibits antithrombin-III binding. Treatment with folic acid reduces the plasma level of homocysteinemia, but no study has demonstrated its efficacy in reducing the incidence of venous thromboembolism or atherosclerosis. Hyperhomocysteinemia should be included in the screening of abnormalities of hemostasis and thrombosis in patients with idiopathic thromboembolism, and mild hyperhomocysteinemia may justify a trial of folic acid.

  3. Effects of long-term developmental patterns of adiposity on levels of C-reactive protein and fibrinogen among North-American men and women: the Spokane Heart Study.

    PubMed

    Hoekstra, Trynke; Barbosa-Leiker, Celestina; Wright, Bruce R; Twisk, Jos W R

    2014-01-01

    This study examined the heterogeneity in BMI development by identifying distinct developmental trajectories. These trajectories were further investigated by relating them to markers of low-grade inflammation later in life. Data from approximately 400 healthy volunteers participating in the Spokane Heart Study were collected in 2-year intervals, and four waves of data were available for the current analyses. Body weight was measured by BMI and low-grade inflammation by high-sensitivity C-reactive protein (CRP) and fibrinogen. Up to date statistical techniques, i.e., latent class growth models, were used to analyse heterogeneity in body weight, and linear regressions were run to analyse possible associations between trajectories of body weight and CRP/fibrinogen levels. Six trajectories were identified (three stable, two increasing, and one decreasing) which differed significantly on CRP/fibrinogen levels, highlighting the importance of weight trajectories. The differences were only partly explained by variations in lifestyle habits.

  4. "Long-term callisthenic exercise-related changes in blood lipids, homocysteine, nitric oxide levels and body composition in middle-aged healthy sedentary women".

    PubMed

    Guzel, Nevin Atalay; Pınar, Lamia; Colakoglu, Filiz; Karacan, Selma; Ozer, Cigdem

    2012-06-30

    "Regular physical exercise plays an important role in reducing obesity, preventing hyperglycemia, lowering blood lipids and reducing systemic blood pressure. But the question about the nature of the relationship between homocysteine, nitric oxide and physical activity remains unanswered. The aim of this study was to investigate the effects of callisthenic exercises on plasma lipids, homocysteine (Hcy), total nitric oxide (NOx) and body composition in middle-aged healthy sedentary women. Forty-two middle-aged women (ages: 28-49; mean: 41.40 ± 7.3 years) were asked to perform a callisthenic exercise 50 min per session, 3 times per week for 12 weeks in a sports hall. Before and after the exercise, plasma lipids (total cholesterol, high density lipoprotein, low density lipoprotein and triglyceride), Hcy and NO were determined. Body composition, including body mass index, fat percentage, fat free mass, resting systolic and diastolic blood pressures and heart rates were measured. After a 12-week callisthenic exercise program, plasma NOx and Hcy levels were found to be significantly increased (P < 0.05). Body composition parameters, lipid profile, resting systolic and diastolic blood pressures and heart rate significantly decreased (P < 0.05). Aerobic callisthenic exercises characterized by 50 min/day and 3 days/week resulted in positive changes in important health parameters like reducing obesity, lowering blood lipids and increasing plasma NOx. Cardiovascular improvements might be dependent on the increase of NOx values. But callisthenic exercise in such intensity did not lower the plasma Hcy level. Moreover, Hcy level increased significantly. The result shows that if the Hcy is in the normal levels in healthy subjects, long-term callisthenic exercise do not decrease the Hcy levels despite some beneficial effects on health. On the contrary, the Hcy levels are increased by long-term callisthenic exercises."

  5. Brain cell apoptosis and enhancement of nervous excitability in pregnant rats with high plasma levels of homocysteine.

    PubMed

    Wang, Jun; Ge, Jing; Yang, Liu; Zhang, Haiyan; Li, Xuli; Xue, Dan

    2012-10-05

    Hyperhomocysteinemia is an important risk factor for preeclampsia-eclampsia. This study established a pregnant rat model of hyperhomocysteinemia, in which blood plasma homocysteine concentrations were twice or three times greater than that of normal pregnant rats. TUNEL revealed an increase in the number of apoptotic cells in the frontal cortex of pregnant rats with hyperhomocysteinemia. In addition, immunohistochemical staining detected activated nuclear factor-κB-positve cells in the frontal cortex. Reverse transcription-PCR detected that mRNA expression of the anti-apoptotic gene bcl-2 diminished in the frontal cortex. In situ hybridization and western blotting revealed that N-methyl-D-aspartate receptor 1 mRNA and protein expression was upregulated in the frontal cortex and hippocampus. These results indicate that hyperhomocysteinemia can induce brain cell apoptosis, increase nerve excitability, and promote the occurrence of preeclampsia in pregnant rats.

  6. Homocysteine and Familial Longevity: The Leiden Longevity Study

    PubMed Central

    Wijsman, Carolien A.; van Heemst, Diana; Rozing, Maarten P.; Slagboom, P. Eline; Beekman, Marian; de Craen, Anton J. M.; Maier, Andrea B.; Westendorp, Rudi G. J.; Blom, Henk J.; Mooijaart, Simon P.

    2011-01-01

    Homocysteine concentrations are a read-out of methionine metabolism and have been related to changes in lifespan in animal models. In humans, high homocysteine concentrations are an important predictor of age related disease. We aimed to explore the association of homocysteine with familial longevity by testing whether homocysteine is lower in individuals that are genetically enriched for longevity. We measured concentrations of total homocysteine in 1907 subjects from the Leiden Longevity Study consisting of 1309 offspring of nonagenarian siblings, who are enriched with familial factors promoting longevity, and 598 partners thereof as population controls. We found that homocysteine was related to age, creatinine, folate, vitamin B levels and medical history of hypertension and stroke in both groups (all p<0.001). However, levels of homocysteine did not differ between offspring enriched for longevity and their partners, and no differences in the age-related rise in homocysteine levels were found between groups (p for interaction 0.63). The results suggest that homocysteine metabolism is not likely to predict familial longevity. PMID:21408159

  7. Superoxide-dependent cerebrovascular effects of homocysteine.

    PubMed

    Zhang, F; Slungaard, A; Vercellotti, G M; Iadecola, C

    1998-06-01

    Recent evidence indicates that elevated plasma levels of homocysteine are a risk factor for ischemic cerebrovascular diseases. However, little is known about cerebrovascular effects of homocysteine. Homocysteine could impair cerebrovascular function by metal-catalyzed production of activated oxygen species. We studied whether homocysteine, in the presence of Cu2+, alters reactivity of cerebral circulation and, if so, whether this effect depends on O-2 generation. In halothane-anesthetized rats the parietal cortex was exposed and superfused with Ringer solution. Cerebrocortical blood flow (CBF) was monitored by a laser-Doppler probe. With Ringer solution superfusion, CBF increased with hypercapnia (+134 +/- 7%; PCO2 = 50-60 mmHg) and topical application of 10 microM ACh (+35 +/- 3%), the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 500 microM; +66 +/- 6%), or 1 mM papaverine (+100 +/- 6%; n = 5). Superfusion with 40 microM Cu2+ alone did not perturb resting CBF or responses to hypercapnia, ACh, SNAP, or papaverine (P > 0.05, n = 5). However, superfusion of homocysteine-Cu2+ reduced resting CBF (-28 +/- 4%) and attenuated (P < 0.05) responses to hypercapnia (-31 +/- 9%), ACh (-73 +/- 6%), or SNAP (-48 +/- 4%), but not papaverine. The effect was observed only at 1 mM homocysteine. Cerebrovascular effects of homocysteine-Cu2+ were prevented by coadministration of superoxide dismutase (SOD; 1,000 U/ml; n = 5). SOD alone did not affect resting CBF or CBF reactivity (n = 5). The observation that homocysteine-Cu2+ attenuates the response to hypercapnia, ACh, and SNAP, but not the NO-independent vasodilator papaverine, suggests that homocysteine-Cu2+ selectively impairs NO-related cerebrovascular responses. The fact that SOD prevents such impairment indicates that the effect of homocysteine is O-2 dependent. The data support the conclusion that O-2, generated by the reaction of homocysteine with Cu2+, inhibits NO-related cerebrovascular responses by scavenging NO

  8. Homocysteine and Parkinson's disease: a dangerous liaison?

    PubMed

    Martignoni, E; Tassorelli, C; Nappi, G; Zangaglia, R; Pacchetti, C; Blandini, F

    2007-06-15

    Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.

  9. Specific assays of hemostasis proteins: fibrinogen.

    PubMed

    Palareti, G; Maccaferri, M

    1990-01-01

    Fibrinogen levels are considered a useful indicator in several pathological conditions and recent epidemiological studies have indicated a relationship between fibrinogen levels and increased risk of cardiovascular disease. An accurate measurement of this protein is therefore recommended and the Italian Committee for Standardization of Methods in Hematology and Laboratory has carried out a collaborative study to determine accuracy, precision and comparability of results obtained by six different methods, i.e., 1. Blombäck and Blombäck method, 2. clotting assay according to von Clauss, 3. radial immunodiffusion according to Mancini et al., 4. total amount of clottable fibrinogen by means of turbidimetric assay according to Ellis and Stransky, and 5. with ChromotimeSystem, 6. prothrombin time (PT)-derived fibrinogen assay on ACL coagulometer. The most accurate resulted the von Clauss method, but only if calibrated with an internal standard; in fact, when the manufacturer's tables are used, the method proved to be highly inaccurate. The best precision, both intra- and between-laboratory, was obtained by the PT-derived test on ACL. On the basis of this still incomplete evaluation of the CISMEL study data, we can conclude that: i. some methods used in clinical laboratories give accurate results only after adequate calibration; ii. a reference standard pool may be a valid tool for calibration and for a better between-laboratory comparability; iii. a predilution of the samples with high fibrinogen levels seems indicated; iv. automation markedly increases the precision of methods.

  10. Increased CSF Homocysteine in Pathological Gamblers Compared with Healthy Controls

    ERIC Educational Resources Information Center

    Nordin, Conny; Sjodin, Ingemar

    2009-01-01

    Neurocognitive disturbances suggesting a frontal lobe dysfunction have been observed in pathological gamblers and alcohol dependents. Given that a high homocysteine level has been suggested to be a mediating factor in alcohol-related cognitive decline, we have determined homocysteine and cobalamine in cerebrospinal fluid (CSF) obtained from 11…

  11. Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals

    PubMed Central

    Wu, Wei; Guo, Ye; Cui, Wei

    2015-01-01

    Background Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy), folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism on risk of cancer overall. Method Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs) and mean differences and presented with 95% confidence intervals (95% CIs) and 2-sided probability values. Results We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC) polymorphism was positively associated with overall risk of cancer. Conclusion Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer. PMID:25985325

  12. Recent insights into the molecular genetics of the homocysteine metabolism.

    PubMed

    Födinger, M; Wagner, O F; Hörl, W H; Sunder-Plassmann, G

    2001-02-01

    The homocysteine plasma level is determined by non-genetic and genetic factors. In recent years evidence has accumulated that the total homocysteine plasma level of patients under different forms of renal replacement therapy is influenced by a common mutation at nucleotide position 677 of the gene coding for 5,10-methylenetetrahydrofolate reductase (MTHFR 677C-->T). Furthermore, compound heterozygosity for the 677T allele and a novel A-->C polymorphism at nucleotide position 1298 of MTHFR is suggested to correlate with a decrease of folate plasma concentrations. Because polymorphisms of genes coding for proteins involved in the metabolism of homocysteine may contribute to elevated total homocysteine plasma concentrations, molecular genetic analyses of the homocysteine pathways experienced a drift towards screening for candidate genes with a putative relationship to total homocysteine plasma levels. One example is the cloning of the FOLR1 gene coding for the folate-binding protein (Folbp1), which has recently been inactivated in mice, thus representing an elegant model to investigate the consequence on the homocysteine metabolism. Furthermore, the recent characterization of the CUBN gene encoding the intrinsic factor-vitamin B12 receptor (cubilin) provides a basis to identify the causative mutations in patients suffering from a hereditary syndrome of hyperhomocysteinemia that presents with megaloblastic anemia and proteinuria. This review focuses on recent insights into the molecular genetics of MTHFR, FOLR1, and CUBN, and their relationships to the metabolism of the amino acid homocysteine.

  13. Leukocyte Telomere Length is Associated With Serum Vitamin B12 and Homocysteine Levels in Older Adults With the Presence of Systemic Inflammation.

    PubMed

    Shin, Chol; Baik, Inkyung

    2016-01-01

    Folate, vitamin B12, and homocysteine (HCY) are involved in the metabolism of nucleic acid precursors and it has been hypothesized that they also influence telomere length, a biomarker of aging. However, previous studies have reported inconsistent findings, and data for older adults are limited. Our study aimed to evaluate associations between leukocyte telomere length (LTL) and serum folate, vitamin B12, and HCY levels among adults aged 55 years and over. In a cross-sectional study in 798 men and women aged 55-79 years, serum folate, vitamin B12, and HCY levels were measured using chemiluminescent immunometric assays, and relative LTL was assessed using quantitative real-time polymerase chain reaction. To evaluate associations between LTL and serum folate, vitamin B12, and HCY levels, multiple linear regression models were used. In multiple models adjusted for age, sex, serum high sensitive C-reactive protein (hs-CRP) levels, and other potential confounding factors, we found no association between LTL and serum folate, vitamin B12, and HCY levels. However, we did find a significant inverse association between HCY levels and LTL in participants with serum hs-CRP levels of ≥ 2 mg/L (p < 0.05). Moreover, there was a trend toward an association between HCY and vitamin B12 levels in these individuals (p = 0.08). In those with serum hs-CRP levels of < 2 mg/L, HCY was inversely associated with vitamin B12 levels (p < 0.001) and had no association with LTL. Our findings suggest that increased serum HCY levels, when combined with the presence of systemic inflammation, may play a role in accelerating biological aging.

  14. Indications and Risks of Fibrinogen in Surgery and Trauma.

    PubMed

    Spahn, Donat R; Spahn, Gabriela H; Stein, Philipp

    2016-03-01

    Fibrinogen has a central role in coagulation. Following trauma and perioperatively, low fibrinogen levels have been found to be risk factors for exaggerated bleeding, transfusion needs, and adverse outcome. Conversely, treatment with exogenous fibrinogen in critically bleeding patients with low fibrinogen levels has been shown to decrease transfusion needs. Because following trauma and in many perioperative situations fibrinogen is the first coagulation "element" to become critically low, it appears reasonable to target fibrinogen in clinical coagulation algorithms aiming at early specific and goal-directed treatment. A low fibrinogen can be a low plasma concentration or a low functional fibrinogen as assessed by point-of-care techniques such as thromboelastography (TEG) or thromboelastometry (ROTEM). This review summarizes the evidence base for perioperative algorithm-based fibrinogen administration, including the exact thresholds for fibrinogen administration used in the different algorithms. Algorithm-based individualized goal-directed use of fibrinogen resulted in highly significant reduction in transfusion needs, adverse outcomes, in certain studies even mortality, and where investigated reduced costs, with high safety levels at the same time. Best evidence exists in cardiac surgery, followed by trauma, postpartum hemorrhage, and liver transplantation. The introduction of these concepts is highly demanding and requires a tremendous educational effort to familiarize all health care workers with the necessary knowledge and the skills of how to run TEG/ROTEM tests. Future research is needed to compare the efficacy, safety, and costs of different algorithms. This, however, should not prevent us from introducing these expedient point-of-care-based algorithms clinically today.

  15. Effect of Short-Term Maximal Exercise on Biochemical Markers of Muscle Damage, Total Antioxidant Status, and Homocysteine Levels in Football Players

    PubMed Central

    Hammouda, Omar; Chtourou, Hamdi; Chaouachi, Anis; Chahed, Henda; Ferchichi, Salyma; Kallel, Choumous; Chamari, Karim; Souissi, Nizar

    2012-01-01

    Purpose Prolonged physical exercise results in transient elevations of biochemical markers of muscular damage. This study examined the effect of short-term maximal exercise on these markers, homocysteine levels (Hcy), and total antioxidant status (TAS) in trained subjects. Methods Eighteen male football players participated in this study. Blood samples were collected 5-min before and 3-min after a 30-s Wingate test. Results The results indicated that plasma biochemical markers of muscle injury increased significantly after the Wingate test (P<0.05). Moreover, significant increase of white blood Cells and their main subpopulations (i.e. monocytes, neutrophiles, and lymphocytes) (P<0.001) has been observed. Likewise, uric acid, total bilirubin, and TAS increased significantly after exercise (P<0.05). However, Hcy levels were unaffected by the Wingate test (for 3-min post-exercise measurement). Conclusions Short-term maximal exercise (e.g. 30-s Wingate test) is of sufficient intensity and duration to increase markers of muscle damage, and TAS; but not Hcy levels. Increases in the selected enzymes probably come primarily from muscle damage, rather than liver damage. Moreover, increase of TAS confirms the Wingate test induced oxidative stress. PMID:23342222

  16. Comparison of the effects of pulmonary rehabilitation with chest physical therapy on the levels of fibrinogen and albumin in patients with lung cancer awaiting lung resection: a randomized clinical trial

    PubMed Central

    2014-01-01

    Background Systemic inflammation plays an important role in the initiation, promotion, and progression of lung carcinogenesis. In patients with non-small cell lung cancer (NSCLC), fibrinogen levels correlate with neoplasia. Here we compared the effects of pulmonary rehabilitation (PR) with chest physical therapy (CPT) on fibrinogen and albumin levels in patients with LC and previous inflammatory lung disease awaiting lung resection. Methods We conducted a randomized clinical trial with 24 patients who were randomly assigned to Pulmonary Rehabilitation (PR) and Chest Physical Therapy (CPT) groups. Each group underwent training 5 days weekly for 4 weeks. All patients were assessed before and after four weeks of training through clinical assessment, measurement of fibrinogen and albumin levels, spirometry, 6-minute Walk Test (6MWT), quality of life survey, and anxiety and depression scale. PR involved strength and endurance training, and CPT involved lung expansion techniques. Both groups attended educational classes. Results A mixed between-within subjects analysis of variance (ANOVA) revealed a significant interaction between time (before and after intervention) and group (PR vs. CPT) on fibrinogen levels (F(1, 22) = 0.57, p < 0.0001) and a significant main effect of time (F(1, 22) = 0.68, p = 0.004). Changes in albumin levels were not statistically significant relative to the interaction effect between time and group (F(1, 22) = 0.96, p = 0.37) nor the main effects of time (F(1, 22) = 1.00, p = 1.00) and group (F(1, 22 ) = 0.59, p = 0.45). A mixed between-within subjects ANOVA revealed significant interaction effects between time and group for the peak work rate of the unsupported upper limb exercise (F(1, 22) = 0.77, p = 0.02), endurance time (F(1, 22) = 0.60, p = 0.001), levels of anxiety (F(1, 22) = 0.60, p = 0.002) and depression (F(1, 22) = 0.74, p = 0.02), and the SF-36 physical

  17. Homocysteine and life-style in the elderly.

    PubMed

    Zamboni, M; Di Francesco, V; Zoico, E; Bissoli, L; Zivelonghi, A; Mandragona, R; Mazzali, G; Tosoni, P; Brocco, G; Faccini, G; Bosello, O

    2001-12-01

    Elevated homocysteine increases the risk of vascular diseases but little information is available about this issue in the elderly. The aim of this cross-sectional study was to evaluate the relationships between homocysteinemia and gender, anthropometric, and life-style characteristics in a community-dwelling elderly population (65 men and 120 women; 67-78 years). Basal plasma homocysteine levels were determined by High Performance Liquid Chromatography (HPLC). Clinical records, and nutritional and anthropometric variables were collected in all subjects. Body composition was evaluated in all subjects by Dual energy X-ray Absorptiometry (DXA). Thirty-three percent of women and 66% of men had hyper-homocysteinemia. In women, a positive correlation was present between homocysteinemia, age, diastolic blood pressure and plasmatic creatinine, and a negative correlation between homocysteine, fiber intake and folates. In males, there was a positive correlation between plasma homocysteine, age, and body mass index. Multiple regression analysis showed that fat-free mass, cigarette smoking, fiber intake, vitamin B6 and total kcal intake accounted for 18% of homocysteine variance in males (R2 = 0.18, p<0.05). Significantly higher homocysteine values were found in women with a history of cardiovascular disease than in those without (16.6 +/- 9.4 vs 13.8 +/- 4.4 micromol/L, p<0.05). Homocysteinemia was significantly higher in elderly men compared to women (16.7 +/- 4.7 vs 15.3 +/- 7.6; p<0.05). Gender differences in homocysteine disappeared after adjusting for fat-free mass. This study confirms the age-related increase in plasma homocysteine. Life-style characteristics seem to influence significantly homocysteine levels in the elderly. Our study shows that gender effects on homocysteine may be attributed to differences in body composition.

  18. Three-month variation of plasma pentraxin 3 compared with C-reactive protein, albumin and homocysteine levels in haemodialysis patients

    PubMed Central

    Sjöberg, Bodil; Snaedal, Sunna; Stenvinkel, Peter; Qureshi, Abdul Rashid; Heimbürger, Olof; Bárány, Peter

    2014-01-01

    Background Inflammatory markers vary considerably over time in haemodialysis (HD) patients, yet the variability is poorly defined. The aim of the study was to assess changes of plasma levels of pentraxin-3 (PTX-3), C-reactive protein (CRP), albumin and homocysteine (Hcy) over 3 months and the association between the changes in these biomarkers and mortality. Methods In 188 prevalent HD patients, inflammatory markers were measured at inclusion and after 3 months. Mortality was recorded during a median follow-up of 41 months. The changes of the biomarker levels were categorized according to change in tertile for the specific biomarker. The variation was calculated as the intra-class correlation (ICC). Mortality was analysed by Kaplan–Meier and Cox proportional hazards model. The predictive strength was calculated for single measurements and for the variation of each inflammatory marker. Results The intra-individual variation (low ICC) was largest for PTX-3 [ICC 0.44; 95% confidence interval (CI): 0.33–0.55], albumin (ICC 0.58; 95% CI: 0.49–0.67) and CRP (ICC 0.59; 95% CI: 0.51–0.68) and lowest for Hcy (ICC 0.81; 95% CI: 0.77–0.86). During follow-up, 88 patients died. Conclusions PTX-3 measurements are less stable and show higher variation within patients than CRP, albumin and Hcy. Persistently elevated PTX-3 levels are associated with high mortality. Moreover, in multivariate logistic regression we found that stable high PTX-3 adds to the mortality risk, even after inclusion of clinical factors and the three other biomarkers. The associations of decreasing albumin levels as well as low Hcy levels with worse outcome reflect protein-energy wasting. PMID:25852911

  19. Influences of ABO blood group, age and gender on plasma coagulation factor VIII, fibrinogen, von Willebrand factor and ADAMTS13 levels in a Chinese population

    PubMed Central

    Wang, Zongkui; Dou, Miaomiao; Du, Xi; Ma, Li; Sun, Pan; Cao, Haijun; Ye, Shengliang; Jiang, Peng; Liu, Fengjuan; Lin, Fangzhao

    2017-01-01

    Background ABO blood group is a hereditary factor of plasma levels of coagulation factor VIII (FVIII) and von Willebrand factor (VWF). Age and gender have been shown to influence FVIII, VWF, fibrinogen (Fbg), and ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 motif, 13). We investigated the effects of ABO type, age, and gender on plasma levels of FVIII, Fbg, VWF, and ADAMTS13 in a Chinese population. Methods A total of 290 healthy volunteers were eligible for this study. ABO blood group was determined by indirect technique. FVIII:C and Fbg were measured by clotting assays. VWF antigen (VWF:Ag), collagen-binding activity (VWF:CBA), and ADAMTS13 antigen were assessed by ELISA, whereas VWF ristocetin cofactor activity (VWF:Rcof) was performed by agglutination of platelets with ristocetin. Results Mean FVIII:C and VWF levels (VWF:Ag, VWF:CBA, and VWF:Rcof) were significantly higher in non-O than in O type subjects (p < 0.05 for all comparison). ADAMTS13 antigen decreased with increasing age, whereas the other parameters increased. Other than ADAMTS13 (p < 0.01), no gender-related variations were observed in the other parameters. Moreover, FVIII:C, Fbg, VWF:Ag, VWF:CBA, and VWF:Rcof showed significant and positive relationships with age (r = 0.421, 0.445, 0.410, 0.401, and 0.589, resp.; all p < 0.001), whereas a negative relationship was observed for ADAMTS13 antigen (r = 0.306; p = 0.006). Furthermore, FVIII:C were strongly correlated with VWF:Ag, VWF:CBA, and VWF:Rcof (r = 0.746, r = 0.746, and r = 0.576, resp.; p < 0.0001). VWF parameters were also strongly correlated with each other (r = 0.0.847 for VWF:Ag and VWF:CBA; r = 0.722 for VWF:Ag and VWF:Rcof; p < 0.0001). Conclusions ABO blood group, age, and gender showed different effects on plasma levels of FVIII:C, Fbg, VWF:Ag, VWF:CBA, VWF:Rcof, and ADAMTS13 antigen. These new data on a Chinese population are quite helpful to compare with other ethnic groups. PMID

  20. Relationship between homocysteine and intraocular pressure in men and women

    PubMed Central

    Leibovitzh, Haim; Cohen, Eytan; levi, Amos; Kramer, Michal; Shochat, Tzippy; Goldberg, Elad; Krause, Ilan

    2016-01-01

    Abstract The relationship between homocysteine levels and glaucoma has been questioned in previous studies without conclusive results. In the current study, we assessed the relationship between homocysteine levels and intraocular pressure which is one of the main factors in the development of glaucoma in men and women. A retrospective cross-sectional analysis of a database from a screening center in Israel which assessed 11,850 subjects, within an age range 20 to 80 years. The relationship between homocysteine and intraocular pressure has been investigated by comparing intraocular pressure in subjects with elevated and normal homocysteine and by comparing homocysteine levels in subjects with elevated and normal intraocular pressure. In addition, we compared the levels of homocysteine in subjects with and without a confirmed diagnosis of glaucoma. The mean IOP (±SD) in subjects with normal homocysteine levels(≤15 μmol/L) was 13.2 ± 2.3 mm Hg and 13.4 ± 2.4 mm Hg in those with high homocysteine levels (>15 μmol/L) (P < 0.008, 95% confidence interval [CI] 0.3–0.09).Nonetheless, after multivariate adjustment for age, gender, vitamin B12, and folic acid statistical significance was no longer demonstrated (P = 0.37). Mean homocysteine levels (±SD) in subjects with normal intraocular pressure of ≤ 21 mm Hg was 11.7 ± 5.5 μmol/L and 12.09 ± 3.43 μmol/L in those with elevated intraocular pressure (P = 0.4, 95%CI 1.1–1.8). Mean homocysteine levels (±SD) in subjects with glaucoma were 11.2 ± 3.5 μmol/L compared to 11.7 ± 5.5 μmol/L in subjects without glaucoma and normal intraocular pressure ≤ 21 mm Hg (P = 0.4, 95% CI 1.2–2.1). The current study displays no clinical correlation between the homocysteine level and the intraocular pressure. Homocysteine may not be used as a predictive parameter to recognize those subjects prone to develop elevated intraocular pressure. PMID:27661027

  1. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen.

    PubMed Central

    Stamler, J S; Osborne, J A; Jaraki, O; Rabbani, L E; Mullins, M; Singel, D; Loscalzo, J

    1993-01-01

    Elevated levels of homocysteine are associated with an increased risk of atherosclerosis and thrombosis. The reactivity of the sulfhydryl group of homocysteine has been implicated in molecular mechanisms underlying this increased risk. There is also increasingly compelling evidence that thiols react in the presence of nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) to form S-nitrosothiols, compounds with potent vasodilatory and antiplatelet effects. We, therefore, hypothesized that S-nitrosation of homocysteine would confer these beneficial bioactivities to the thiol, and at the same time attenuate its pathogenicity. We found that prolonged (> 3 h) exposure of endothelial cells to homocysteine results in impaired EDRF responses. By contrast, brief (15 min) exposure of endothelial cells, stimulated to secrete EDRF, to homocysteine results in the formation of S-NO-homocysteine, a potent antiplatelet agent and vasodilator. In contrast to homocysteine, S-NO-homocysteine does not support H2O2 generation and does not undergo conversion to homocysteine thiolactone, reaction products believed to contribute to endothelial toxicity. These results suggest that the normal endothelium modulates the potential, adverse effects of homocysteine by releasing EDRF and forming the adduct S-NO-homocysteine. The adverse vascular properties of homocysteine may result from an inability to sustain S-NO formation owing to a progressive imbalance between the production of NO by progressively dysfunctional endothelial cells and the levels of homocysteine. PMID:8380812

  2. Influence of training volume and acute physical exercise on the homocysteine levels in endurance-trained men: interactions with plasma folate and vitamin B12.

    PubMed

    König, D; Bissé, E; Deibert, P; Müller, H-M; Wieland, H; Berg, A

    2003-01-01

    The interrelation between physical exercise and plasma levels of homocysteine (Hcy), vitamin B(12), and folic acid has not been examined. Therefore, we investigated the influence of extensive endurance training and acute intense exercise on plasma concentrations of total Hcy, vitamin B(12), and folic acid in 42 well-trained male triathletes. Examinations and blood sampling took place before and after a 30-day endurance training period as well as before and 1 and 24 h after a competitive exercise (sprint triathlon). Following the training period, no significant change in Hcy levels could be detected for the whole group. Subgroup analysis in quartiles of training volume revealed that - as compared with the lowest quartile (low-training group: 9.1 h training/week) - athletes in the highest training quartile (high-training group: 14.9 h training/week) exhibited a significant decrease in Hcy levels (from 12.7 +/- 2.3 to 11.7 +/- 2.4 micromol/l as compared with levels of 12.5 +/- 1.5 and 12.86 +/- 1.5 micromol/l in the low-training group; p < 0.05). The plasma folate levels were significantly higher in the high-training group at all points of examination (p < 0.05). 1 h and 24 h after competition, the Hcy concentration increased in all athletes independent of the previous training volume (24 h: 12.3 +/- 1.8 vs. 13.5 +/- 2.6 micromol/l; p < 0.001), although the increase was decisively stronger in the low-training group. 1 h after competition, the plasma folate concentration increased (7.03 +/- 2.1 vs. 8.33 +/- 2.1 ng/ml; p < 0.05) in all athletes. Multivariate analysis showed that the exercise-induced increase in the Hcy levels was dependent on baselines levels of folate and training volume, but not on the vitamin B(12) levels. In conclusion, although intense exercise acutely increased the Hcy levels, chronic endurance exercise was not associated with higher Hcy concentrations. Moreover, athletes with the highest training volume, exhibiting also the highest plasma folate

  3. Fibrinogen Metabolic Responses to Trauma

    DTIC Science & Technology

    2009-01-13

    intravascular coagulation (DIC), and thrombotic complications [8,10-12]. Based on the limited data avail- able at present, changes in fibrinogen...water at 4°C [48]. Temperature of 32°C was used based on the fact that 100% mortality was observed when the temperature in trauma patients dropped...study. The amount of fibrinogen transfused was calculated based on fibrinogen amount within each blood product, such as fresh whole blood

  4. The levels of vitamın B12, folate and homocysteine in mothers and their babies with neural tube defects.

    PubMed

    Peker, Erdal; Demir, Nihat; Tuncer, Oğuz; Üstyol, Lokman; Balahoroğlu, Ragıp; Kaba, Sultan; Karaman, Kamuran

    2016-09-01

    The aim of the present study was to determine the serum levels of vitamin B12, folate, and homocysteine (Hcy) in mothers and their babies, and to assess the association between these levels and neural tube defect (NTD). The study group included 92 baby-mother pairs, where the babies had NTD, and the control group included 102 pairs, where the babies had no NTD, from May 2012 to May 2015. Plasma vitamin B12, folate, and Hcy levels of the babies and mothers were measured, and compared with each other. NTD was diagnosed in 2.6% of our babies. The vitamin B12 levels in the mothers and the babies in the study group were determined as 166.2 ± 63.7 pg/mL and 240.3 ± 120.3 pg/mL, and in the control group as 1 9 0 ± 80.2 pg/mL and 299.5 ± 151.4 pg/mL, respectively. There was a significant difference between the two groups in terms of both the mothers' and the babies' vitamin B12 levels (p = 0.024 and p = 0.003, respectively). The plasma folate levels of the mothers in the study group (5.2 ± 3 ng/mL) were significantly lower than control group (6.4 ± 4.3 ng/mL, p = 0.032).The plasma Hcy level of the mothers in the study group (9.3 ± 3.8 μmol/L) was significantly higher than the control group (7 ± 3.8 μmol/L, p < 0.001). High plasma Hcy levels and low plasma folate and vitamin B12 levels are risk factors for NTD. Our results show that the risk for NTD can be decreased by fortification of mothers-to-be, particularly in rural areas with folate and vitamin B12 deficiency, which would lower the plasma Hcy level.

  5. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells.

    PubMed Central

    Tsai, J C; Wang, H; Perrella, M A; Yoshizumi, M; Sibinga, N E; Tan, L C; Haber, E; Chang, T H; Schlegel, R; Lee, M E

    1996-01-01

    Homocysteine is an important and independent risk factor for arteriosclerosis. We showed previously that homocysteine stimulates vascular smooth muscle cell proliferation, a hallmark of arteriosclerosis. We show here that homocysteine and serum increased DNA synthesis synergistically in both human and rat aortic smooth muscle cells (RASMCs). Treatment of quiescent RASMCs with 1 mM homocysteine or 2% calf serum for 36 h increased cyclin A mRNA levels by 8- and 14-fold, respectively, whereas homocysteine plus serum increased cyclin A mRNA levels by 40-fold, indicating a synergistic induction of cyclin A mRNA. Homocysteine did not increase the half-life of cyclin A mRNA (2.9 h), but it did increase the transcriptional rate of the cyclin A gene in nuclear run-on experiments. The positive effect of homocysteine on cyclin A gene transcription was confirmed by our finding that homocysteine increased cyclin A promoter activity and ATF-binding protein levels in RASMCs. Finally, 1 mM homocysteine increased cyclin A protein levels and cyclin A-associated kinase activity by threefold. This homocysteine-induced expression lesions by promoting proliferation of vascular smooth muscle cells. PMID:8550827

  6. Risk Factors for Postoperative Fibrinogen Deficiency after Surgical Removal of Intracranial Tumors.

    PubMed

    Wei, Naili; Jia, Yanfei; Wang, Xiu; Zhang, Yinian; Yuan, Guoqiang; Zhao, Baotian; Wang, Yao; Zhang, Kai; Zhang, Xinding; Pan, Yawen; Zhang, Jianguo

    2015-01-01

    Higher levels of fibrinogen, a critical element in hemostasis, are associated with increased postoperative survival rates, especially for patients with massive operative blood loss. Fibrinogen deficiency after surgical management of intracranial tumors may result in postoperative intracranial bleeding and severely worsen patient outcomes. However, no previous studies have systematically identified factors associated with postoperative fibrinogen deficiency. In this study, we retrospectively analyzed data from patients who underwent surgical removal of intracranial tumors in Beijing Tiantan Hospital date from 1/1/2013to12/31/2013. The present study found that patients with postoperative fibrinogen deficiency experienced more operative blood loss and a higher rate of postoperative intracranial hematoma, and they were given more blood transfusions, more plasma transfusions, and were administered larger doses of hemocoagulase compared with patients without postoperative fibrinogen deficiency. Likewise, patients with postoperative fibrinogen deficiency had poorer extended Glasgow Outcome Scale (GOSe), longer hospital stays, and greater hospital expenses than patients without postoperative fibrinogen deficiency. Further, we assessed a comprehensive set of risk factors associated with postoperative fibrinogen deficiency via multiple linear regression. We found that body mass index (BMI), the occurrence of postoperative intracranial hematoma, and administration of hemocoagulasewere positively associated with preoperative-to-postoperative plasma fibrinogen consumption; presenting with a malignant tumor was negatively associated with fibrinogen consumption. Contrary to what might be expected, intraoperative blood loss, the need for blood transfusion, and the need for plasma transfusion were not associated with plasma fibrinogen consumption. Considering our findings together, we concluded that postoperative fibrinogen deficiency is closely associated with postoperative

  7. [Effect of homocysteine on the structure and functions of human placenta trophoblasts].

    PubMed

    Martseniuk, O P; Romanets', K L; Obolens'ka, M Iu; Huppertz, B

    2009-01-01

    Elevated level of homocysteine in blood serum of pregnant women is the risk factor for placental malfunction and fetal abnormalities. Our study has shown the activation of apoptosis, inhibition of proliferation, destruction of placental trophoblast and activation of the transsulfuration pathway under elevated homocysteine level in the incubation medium in the range of 20-80 microM. The activation of the transsulfuration pathway indicates that placenta may to some extent withstand elevated homocysteine level.

  8. Associations of plasma natriuretic peptide, adrenomedullin, and homocysteine levels with alterations in arterial stiffness: The Framingham Heart Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Experimental studies suggest that the natriuretic peptides influence lipid and fatty acid metabolism. Although it has been shown that obese individuals have reduced natriuretic peptide levels, conflicting data exist on the relation of natriuretic peptide levels to other metabolic risk factors. We ex...

  9. Zinc antagonizes homocysteine-induced fetal heart defects in rats.

    PubMed

    He, Xiaoyu; Hong, Xinru; Zeng, Fang; Kang, Fenhong; Li, Li; Sun, Qinghua

    2009-09-01

    It has been suggested that zinc may have a protective role against heart defects during fetal development. We investigated the effects of zinc on the development of fetal cardiac malformations induced by homocysteine. Pregnant Sprague-Dawley rats were randomized into one of five groups: control (C), homocysteine (H), homocysteine + zinc (Z), homocysteine + folic acid (F), or homocysteine + zinc + folic acid (ZF) (each n = 8). Homocysteine (8 nmol/day) was administered intraperitoneally in the H, Z, F, and ZF groups on gestation days (GD) 8, 9, and 10. Zinc (30 mg/kg day), folic acid (30 mg/kg day), or both (30 mg/kg day each) were administered intragastrically daily in the Z, F, and ZF groups, respectively, throughout the pregnancy. In each group, two fetuses were removed on GD 13, 15, 17, and 19 and examined for cardiac malformations; maternal copper/zinc-containing-superoxide dismutase (Cu/Zn-SOD) activity and metallothionein type I (MT-1) mRNA expression were measured simultaneously. The prevalence of cardiac malformations was significantly higher in group H than in group C, and significantly lower in group Z than in group H at the studied time points. Cu/Zn-SOD activity and MT-1 mRNA levels were significantly lower in group H than in group C, and significantly higher in group Z than in group H. Our data suggest that zinc antagonizes homocysteine-induced teratogenic effects on the fetal heart, possibly via the inhibition of excessive peroxidation.

  10. Plasma homocysteine in late pregnancies complicated with preeclampsia and in newborns.

    PubMed

    Baksu, Alparslan; Taskin, Mehtap; Goker, Nimet; Baksu, Basak; Uluocak, Aygul

    2006-01-01

    The aim of this study was to determine the relationship between maternal serum homocysteine levels in preeclampsia and the severity of the disease, neonatal serum homocysteine levels, maternal complications, and fetal outcome. Fifty pregnant women were included in this prospective study, of which 25 were severe (group I) and 25 were non-severe preeclamptic (group II). Maternal and neonatal serum homocysteine levels were measured by the fluorescence polarization immunoassay (FPIA) method. Maternal homocysteine levels in both groups were compared. The association of maternal and neonatal serum homocysteine levels with maternal complications and fetal outcome was investigated. When the maternal serum homocysteine cut-off value was accepted as 15 micromol/L, significant differences in relation to maternal (eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome) and fetal (in utero mort fetalis, low birthweight) complications were observed between the group with maternal serum homocysteine level > 15 micromol/L and the group with maternal serum homocysteine level < or = 15 micromol/L ( p < 0.05). Hyperhomocysteinemia during pregnancy is a risk factor for both development of preeclampsia and its complications. Given that the diagnosis and treatment of hyperhomocysteinemia is possible, clinical trials to determine whether treatment to reduce homocysteine would be valuable in the prevention of both maternal and fetal complications in preeclampsia should be designed.

  11. Relationship of MTHFR Gene 677C→T Polymorphism, Homocysteine, and Estimated Glomerular Filtration Rate Levels With the Risk of New-Onset Diabetes

    PubMed Central

    Qin, Xianhui; Li, Youbao; Yuan, Hui; Xie, Di; Tang, Genfu; Wang, Binyan; Wang, Xiaobin; Xu, Xin; Xu, Xiping; Hou, Fanfan

    2015-01-01

    Abstract East Asian patients with diabetes have a higher risk for renal complications and strokes than Europeans. We aimed to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) gene 677C→T polymorphism, which was associated with a higher stroke risk and was common in the Chinese population, as well as homocysteine and estimated glomerular filtration rate (eGFR) levels on the risk of new-onset diabetes (NOD). A total of 2422 subjects without diabetes were followed-up for 7 years. NOD was defined as fasting plasma glucose ≥7.0 mmol/L or self-reported physician diagnosis of diabetes. Compared with subjects with MTHFR 677CC genotype, those with TT genotype had a higher risk of NOD in females (odds ratio 2.78, 95% confidence interval 1.39–5.56) but not in males (0.80, 0.40–1.61, P for interaction = 0.008). Furthermore, MTHFR 677C→T polymorphism was more strongly associated with the risk of NOD among females with higher body mass index (BMI, ≥23 vs <23 kg/m2, P for interaction = 0.009) or lower high-density lipoprotein-cholesterol (HDL-C, <1.3 vs ≥1.3 mmol/L, P for interaction = 0.015) levels. Hyperhomocysteinemia (≥16 vs <10 μmol/L) was not significantly associated with NOD in males (0.88, 0.42–1.85) or females (1.52, 0.65–3.57). However, mildly decreased eGFR (<90 vs 90–120 mL/min/1.73 m2) was associated with NOD mainly in males (1.96, 1.01–3.78; females, 0.74, 0.32–1.72, P for interaction = 0.134). Females with MTHFR 677TT genotype had a significantly higher risk of NOD, particularly those with higher BMI or low HDL-C levels. The higher risk of NOD associated with mildly decreased eGFR also warrants more investigation. Our results provide insights into the ethnic differences of diabetic complications between East Asian patients and Europeans. PMID:25700330

  12. A Protein Extract from Chicken Reduces Plasma Homocysteine in Rats.

    PubMed

    Lysne, Vegard; Bjørndal, Bodil; Vik, Rita; Nordrehaug, Jan Erik; Skorve, Jon; Nygård, Ottar; Berge, Rolf K

    2015-06-04

    The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), with a low methionine/glycine ratio, on plasma homocysteine and metabolites related to homocysteine metabolism. Male Wistar rats were fed either a control diet with 20% w/w casein as the protein source, or an experimental diet where 6, 14 or 20% w/w of the casein was replaced with the same amount of CP for four weeks. Rats fed CP had reduced plasma total homocysteine level and markedly increased levels of the choline pathway metabolites betaine, dimethylglycine, sarcosine, glycine and serine, as well as the transsulfuration pathway metabolites cystathionine and cysteine. Hepatic mRNA level of enzymes involved in homocysteine remethylation, methionine synthase and betaine-homocysteine S-methyltransferase, were unchanged, whereas cystathionine gamma-lyase of the transsulfuration pathway was increased in the CP treated rats. Plasma concentrations of vitamin B2, folate, cobalamin, and the B-6 catabolite pyridoxic acid were increased in the 20% CP-treated rats. In conclusion, the CP diet was associated with lower plasma homocysteine concentration and higher levels of serine, choline oxidation and transsulfuration metabolites compared to a casein diet. The status of related B-vitamins was also affected by CP.

  13. Elevated Plasma Homocysteine Concentration in Opium-Addicted Individuals

    PubMed Central

    Masoomi, Mohammad; Azdaki, Nahid; Shahouzehi, Beydolah

    2015-01-01

    Background Although the triggering role of both opium use and elevated plasma homocysteine level for progressing atherosclerosis and, therefore, appearing coronary heart disease has been clearly determined, no study are available with respect to the relation between these to risk profiles. In the present study and for the first time, we hypothesized that the opium addiction can be potentially correlated with elevated homocysteine concentration. Methods 217 persons (103 opium-addicted and 114 non-addicted) were randomly selected from the Kerman Coronary Artery Disease Risk Study (KERCADRS), Iran, as a population-based, epidemiological prospective study. In all participants, an enzyme immunoassay kit was used to measure homocysteine in serum samples. Findings The serum level of homocysteine was significantly higher in the opium-addicted ones compared to non-addicted individuals (11.49 ± 7.45 vs. 8.02 ± 3.87 μmol/l) (P < 0.001). In this regard, 21.3% of the opium users and only 3.2% of the non-users had homocysteine concentration > 15 μmol/l (P < 0.001). On the other hand, individuals addicted to opiates exhibited significantly elevated odds of having homocysteine level higher than 15 [odds ratio (OR) = 8.244, 95% confidence interval (CI) = 3.117-21.806]. Multivariable linear regression model showed that the opium addiction could strongly predict elevated homocysteine level in the study individuals [beta = 3.524, standard error (SE) = 0.852] (P < 0.001). Conclusion Opium consumption can be strongly accompanied with the elevation of plasma homocysteine concentration, and thus opium addiction can exhibit elevated odds of having hyperhomocysteinemia. PMID:26885351

  14. Fibrinogen stability under surfactant interaction.

    PubMed

    Hassan, Natalia; Barbosa, Leandro R S; Itri, Rosangela; Ruso, Juan M

    2011-10-01

    Differential scanning calorimetry (DSC), circular dichroism (CD), difference spectroscopy (UV-vis), Raman spectroscopy, and small-angle X-ray scattering (SAXS) measurements have been performed in the present work to provide a quantitatively comprehensive physicochemical description of the complexation between bovine fibrinogen and the sodium perfluorooctanoate, sodium octanoate, and sodium dodecanoate in glycine buffer (pH 8.5). It has been found that sodium octanoate and dodecanoate act as fibrinogen destabilizer. Meanwhile, sodium perfluorooctanoate acts as a structure stabilizer at low molar concentration and as a destabilizer at high molar concentration. Fibrinogen's secondary structure is affected by all three studied surfactants (decrease in α-helix and an increase in β-sheet content) to a different extent. DSC and UV-vis revealed the existence of intermediate states in the thermal unfolding process of fibrinogen. In addition, SAXS data analysis showed that pure fibrinogen adopts a paired-dimer structure in solution. Such a structure is unaltered by sodium octanoate and perfluoroctanoate. However, interaction of sodium dodecanoate with the fibrinogen affects the protein conformation leading to a complex formation. Taken together, all results evidence that both surfactant hydrophobicity and tail length mediate the fibrinogen stability upon interaction.

  15. Hyperhomocysteinemia as an Early Predictor of Erectile Dysfunction: International Index of Erectile Function (IIEF) and Penile Doppler Ultrasound Correlation With Plasma Levels of Homocysteine.

    PubMed

    Giovannone, Riccardo; Busetto, Gian Maria; Antonini, Gabriele; De Cobelli, Ottavio; Ferro, Matteo; Tricarico, Stefano; Del Giudice, Francesco; Ragonesi, Giulia; Conti, Simon L; Lucarelli, Giuseppe; Gentile, Vincenzo; De Berardinis, Ettore

    2015-09-01

    Erectile dysfunction (ED) is inability to achieve and maintain an erection to permit satisfactory sexual activity. Homocysteine (Hcys) is a sulfur-containing amino acid synthesized from the essential amino acid methionine. Experimental models have elucidated the role of hyperhomocysteinemia (HHcys) as a strong and independent predictor for atherosclerosis progression and impaired cavernosal perfusion. The aim of this study is to investigate the serum levels of Hcys in our cohort of patients with ED, to compare these values with these of control population and to examine Hcys as a predictive marker for those patients who are beginning to complain mild-moderate ED. A total of 431 patients were enrolled in the study. The whole cohort was asked to complete the International Index of Erectile Function (IIEF) questionnaire. The study population was divided in 3 main groups: Group A: 145 patients with no ED serving as a control group; Group B: 145 patients with mild or mild-moderate ED; Group C: 141 patients with moderate or severe ED. Each participant underwent blood analysis. All patients underwent baseline and dynamic penile Doppler ultrasonography. We found in our cohort mean Hcys plasma concentrations significantly higher than the cut-off point in both groups B and C (18.6 ± 4.7 and 28.38 ± 7.8, respectively). Mean IIEF score was 27.9 ± 1.39, 19.5 ± 2.6, and 11.1 ± 2.5 for groups A, B, and C, respectively (P < 0.0001). In the penile Doppler ultrasonography studies, a high significant inverse correlation was detected between the mean values of the 10th minute's peak-systolic velocity (PSV) and Hcys levels for the groups B and C. This establishes a dose-dependent association between Hcys and ED. Furthermore, we showed that Hcys was an earlier predictor of ED than Doppler studies, as the Hcys increase was present in patients with mild ED even before abnormal Doppler values.

  16. [Homocysteine metabolism disorders as a potential predictor of preeclamsia].

    PubMed

    Kajdy, Anna; Niemiec, Tomasz

    2008-11-01

    Preeclampsia is one of the main causes of maternal and fetal mortality. We lack a reliable test that would identify the "at risk" group of pregnant women, thus allowing us to implement a specific prevention, management and treatment program. Recently, a number of theories regarding the pathophysiology of preeclampsia has been published. The role of vascular pathology as a result of an increase in homocysteine level is often mentioned. The aim of this paper is to review the current literature related to the pathology of preeclampsia and to evaluate the usefulness of assessment of homocysteine level and homocysteine metabolism disorders as a potential predictor of preeclamsia. Hiperhomocysteinemia is a known risk factor of cardiovascular diseases and hypertension. Different sources report a similar correlation between an increase in homocysteine level and the incidence of preeclampsia. As far as the topic of homocysteine in pregnancy is concerned, numerous questions and problems remain unanswered and unsolved. Although there exists a relationship between an increased values of homocysteine and the incidence of preeclampsia, there is not enough information about what group of patients should be included in the screening test to increase the rate of diagnosis and prevention of the most dangerous sequele.

  17. Homocysteine and Cognitive Performance in Elders with Self-Neglect

    NASA Technical Reports Server (NTRS)

    Burnett, J.; Smith, S.M.; Aung, K.; Dyer, C.

    2009-01-01

    Elevated plasma homocysteine has been associated with altered cognitive performance in older adults. Elders referred to Adult Protective Services (APS) for self-neglect have been reported to have elevated plasma homocysteine levels and to suffer from cognitive impairment. This study assesses the association, if any, between plasma homocysteine and cognitive performance among elders with self-neglect. Methods: Sixty-five community-living adults, 65 years of age and older, reported to Adult Protective Services for self-neglect and 55 matched controls (matched for age, ethnicity, gender and socio-economic status) consented and participated in this study. The research team conducted in-home comprehensive geriatric assessments which included the mini-mental state exam (MMSE), the 15-item geriatric depression scale (GDS), the Wolf-Klein Clock Drawing Tests (CDT) and a comprehensive nutritional biochemistry panel, which included plasma homocysteine. Student s t tests and Pearson correlations were conducted to assess for bivariate associations. Results: Elders with self-neglect had significantly higher plasma homocysteine levels (M=12.68umol/L, sd=4.4) compared to the controls (M=10.40umol/L, sd=3.61;t=3.21, df=127, p=.002). There were no statistically significant associations between cognitive performance and plasma homocysteine in the self-neglect group, however there was a significant correlation between plasma homocysteine and the CDT among the controls (r=-.296, p=.022). Conclusion: Mean plasma homocysteine levels were significantly higher in elders with self-neglect, however, they do not appear to be related to cognitive performance, indicating that cognitive impairment in elder self-neglect involve mechanisms other than hyperhomocysteinemia. These findings warrant further investigation

  18. Predictive value of homocysteine for depression after acute coronary syndrome

    PubMed Central

    Kang, Hee Ju; Stewart, Robert; Bae, Kyung Yeol; Kim, Sung Wan; Shin, Il Seon; Kang, Hyuno; Moon, Won Jin; Hong, Young Joon; Ahn, Youngkeun; Jeong, Myung Ho; Yoon, Jin Sang; Kim, Jae Min

    2016-01-01

    We investigated roles of plasma homocysteine and MTHFR gene in relation to risks and treatment responses of depression in ACS. A sample of 969 patients with recent ACS were recruited and 711 followed 1 year later. In addition, of 378 baseline participants with depressive disorder, 255 were randomized to a 24-week double blind trial of escitalopram (N = 127) or placebo (N = 128). A higher homocysteine concentration was independently associated with prevalent depressive disorder at baseline irrespective of MTHFR genotype; and with both incident and persistent depressive disorder at follow-up only in the presence of TT genotype. MTHFR genotype was not itself associated with depressive disorder after ACS. No associations were found with 24-week antidepressant treatment responses. Plasma homocysteine could be a biomarker for depressive disorder particularly in the acute phase of ACS. Focused interventions for those with higher homocysteine level and MTHFR TT genotype might reduce the risk of later depressive disorder. PMID:27626182

  19. Fibrinogen depletion in trauma: early, easy to estimate and central to trauma-induced coagulopathy

    PubMed Central

    2013-01-01

    Fibrinogen is fundamental to hemostasis and falls rapidly in trauma hemorrhage, although levels are not routinely measured in the acute bleeding episode. Prompt identification of critically low levels of fibrinogen and early supplementation has the potential to correct trauma-induced coagulation and improve outcomes. Early estimation of hypofibrinogenemia is possible using surrogate markers of shock and hemorrhage; for example, hemoglobin and base excess. Rapid replacement with fibrinogen concentrate or cryoprecipitate should be considered a clinical priority in major trauma hemorrhage. PMID:24063404

  20. Fibrinogen depletion in trauma: early, easy to estimate and central to trauma-induced coagulopathy.

    PubMed

    Davenport, Ross; Brohi, Karim

    2013-09-24

    Fibrinogen is fundamental to hemostasis and falls rapidly in trauma hemorrhage, although levels are not routinely measured in the acute bleeding episode. Prompt identification of critically low levels of fibrinogen and early supplementation has the potential to correct trauma-induced coagulation and improve outcomes. Early estimation of hypofibrinogenemia is possible using surrogate markers of shock and hemorrhage; for example, hemoglobin and base excess. Rapid replacement with fibrinogen concentrate or cryoprecipitate should be considered a clinical priority in major trauma hemorrhage.

  1. Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals

    SciTech Connect

    Beyerle, Andrea; Nolte, Marc W.; Solomon, Cristina; Herzog, Eva; Dickneite, Gerhard

    2014-10-01

    Fibrinogen, a soluble 340 kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.5–2.0 g/l. Plasma-derived human fibrinogen concentrate has been available for therapeutic use since 1956. The overall aim of the comprehensive series of non-clinical investigations presented was to evaluate i) the pharmacodynamic and pharmacokinetic characteristics and ii) the safety and tolerability profile of human fibrinogen concentrate Haemocomplettan P® (RiaSTAP®). Pharmacodynamic characteristics were assessed in rabbits, pharmacokinetic parameters were determined in rabbits and rats and a safety pharmacology study was performed in beagle dogs. Additional toxicology tests included: single-dose toxicity tests in mice and rats; local tolerance tests in rabbits; and neoantigenicity tests in rabbits and guinea pigs following the introduction of pasteurization in the manufacturing process. Human fibrinogen concentrate was shown to be pharmacodynamically active in rabbits and dogs and well tolerated, with no adverse events and no influence on circulation, respiration or hematological parameters in rabbits, mice, rats and dogs. In these non-clinical investigations, human fibrinogen concentrate showed a good safety profile. This data adds to the safety information available to date, strengthening the current body of knowledge regarding this hemostatic agent. - Highlights: • A comprehensive series of pre-clinical investigations of human fibrinogen concentrate. • Human fibrinogen concentrate was shown to be pharmacodynamically active. • Human fibrinogen concentrate was well tolerated

  2. Homocysteine and B vitamins.

    PubMed

    Cook, S; Hess, O M

    2005-01-01

    Homocysteine (tHcy) is an intermediate sulfur-containing amino acid which acts as a methyl group donor for methionine metabolism. Increased serum concentrations (=hyperhomocysteinemia, >10 micromol/l) have been associated with an increased cardiovascular risk. Homocystinuria, an infrequent genetic disease usually due to lack of cystathione beta-synthase, has been found with severely elevated serum homocysteine values (>150 micromol/l). Functional gene polymorphisms of key enzymes (e.g., N5,N10-methylene-tetrahydrofolate reductase) and dietary B-vitamin deficiencies in the elderly are, however, frequent in the 'Western' population. Hyperhomocysteinemia has been associated with other vascular effects such as atherothrombosis and endothelial dysfunction due to its auto-oxidative potential, thereby increasing the production of reactive oxygen species. Other effects may involve neurodegenerative diseases such as Alzheimer or dementia praecox of the elderly. Therapeutic interventions lowering tHcy may therefore offer novel tools for the prevention and treatment of atherosclerosis. B-vitamin supplementation (folic acid=vitamin B9, vitamin B6 and vitamin B12) is an efficient and safe tHcy-lowering therapy, decreases tHcy by 30%-50% and has been shown to lower cardiovascular morbidity and mortality. Furthermore, folic acid supplementation has been shown to reduce or even almost eliminate neurotubular birth defects (spina bifida) and to markedly decrease the rate of megaloblastic anemia. Thus, fortification of flour with folic acid in the USA was advocated several years ago in order to prevent these entities.

  3. May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

    PubMed

    Olas, Beata; Kołodziejczyk, Joanna; Malinowska, Joanna

    2010-06-01

    Homocysteine (Hcys) may be implicated in different diseases, especially in cardiovascular illnesses. The most reactive form of Hcys is its cyclic thioester-homocysteine thiolactone (HTL), which is formed in plasma and represents up to 0.29% of plasma total Hcys. Recently, it has been observed that Hcys and HTL may modify plasma proteins, including albumin, hemoglobin or fibrinogen, but the role of this process is not yet well known. The aim of our study in vitro was to investigate the modifications of human plasma total proteins after incubation with the reduced form of Hcys in concentrations 10-100 micromol/l, and HTL in concentrations 1-0.1 micromol/l, which correspond to levels found in human plasma during hyperhomocysteinemia in vivo. The aim of our study was also to explain the effects of Hcys and HTL on coagulation activity of human plasma. We showed that in model system in vitro Hcys and HTL change the level of thiol, amino and carbonyl groups in plasma total proteins. Moreover, our studies reported that not only Hcys (10-100 micromol/l), but also HTL (at lower concentrations than Hcys) modulates the coagulation properties of human plasma.

  4. B Vitamins, Homocysteine and Bone Health

    PubMed Central

    Fratoni, Valentina; Brandi, Maria Luisa

    2015-01-01

    Nutrition is one of the most important modifiable factors involved in the development and maintenance of good bone health. Calcium and Vitamin D have confirmed and established roles in the maintenance of proper bone health. However, other nutritional factors could also be implicated. This review will explore the emerging evidence of the supporting role of certain B Vitamins as modifiable factors associated with bone health. Individuals with high levels of homocysteine (hcy) exhibit reduced bone mineral density (BMD), alteration in microarchitecture and increased bone fragility. The pathophysiology caused by high serum homocysteine is not completely clear regarding fractures, but it may involve factors, such as bone mineral density, bone turnover, bone blood flow and collagen cross-linking. It is uncertain whether supplementation with B Vitamins, such as folate, Vitamin B1, and Vitamin B6, could decrease hip fracture incidence, but the results of further clinical trials should be awaited before a conclusion is drawn. PMID:25830943

  5. Concentration-dependent effect of fibrinogen on IgG-specific antigen binding and phagocytosis.

    PubMed

    Boehm, Tobias Konrad; Sojar, Hakimuddin; Denardin, Ernesto

    2010-01-01

    In this paper, we aim to characterize fibrinogen-IgG interactions, and explore how fibrinogen alters IgG-mediated phagocytosis. Using enzyme-linked binding assays, we found that fibrinogen binding to IgG is optimized for surfaces coated with high levels of IgG. Using a similar method, we have shown that for an antigen unable to specifically bind fibrinogen, fibrinogen enhances binding of antibodies towards that antigen. For binding of IgG antibodies to cells expressing Fc receptors, we found a bimodal binding response, where low levels of fibrinogen enhance binding of antibody to Fc receptors and high levels reduce it. This corresponds to a bimodal effect on phagocytosis of IgG-coated particles, which is inhibited in the presence of excess IgG during coating of the particles with antibodies and fibrinogen. We conclude that fibrinogen can modulate phagocytosis of IgG-coated particles in vitro by changing IgG binding behavior, and that high fibrinogen levels could negatively affect phagocytosis.

  6. Comparative studies on homocysteine and its metabolite-homocysteine thiolactone action in blood platelets in vitro.

    PubMed

    Olas, B; Kedzierska, M; Wachowicz, B

    2008-11-01

    Homocysteine (Hcy), an intermediate formed during the catabolism of the essential dietary amino acid methionine, and its cyclic thioester, homocysteine thiolactone (TL) formed from Hcy in plasma, may be implicated in pathological haemostasis and atherosclerosis. The mechanism by which TL exerts the prothrombotic effect and influences blood platelets remains unclear. Activation of blood platelets plays an important role in prothrombotic events. The aim of our study was to establish and compare the influence of a reduced form of homocysteine (at final doses of 10-100 microM) and its cyclic thioester, homocysteine thiolactone (0.1-1 microM), on platelet activation induced by thrombin (platelet aggregation), on platelet protein modifications (determined by parameters such as level of protein carbonyl groups, 3-nitrotyrosine residues in proteins) and on superoxide anion radicals ( O2-*) generation using the model system in vitro. We have observed that TL, like its precursor, Hcy, stimulates the generation of O2* in platelets and causes an augmentation of platelet aggregation induced by thrombin. Our present results in vitro also demonstrate that Hcy (10-100 microM) and TL at lower doses than Hcy (0.1-1 microM) cause modification of platelet proteins: diminished formation of carbonyl groups and distinctly decreased tyrosine nitration in platelet proteins after thrombin stimulation, but increased platelet aggregation induced by thrombin. TL like Hcy (at concentrations corresponding to concentrations in blood during hyperhomocysteinemia) modifies platelet responses to an important physiological agonist--thrombin.

  7. Evaluation of serum fibrinogen, plasminogen, α2-anti-plasmin, and plasminogen activator inhibitor levels (PAI) and their correlation with presence of retinopathy in patients with type 1 DM.

    PubMed

    Polat, Sefika Burcak; Ugurlu, Nagihan; Yulek, Fatma; Simavli, Huseyin; Ersoy, Reyhan; Cakir, Bekir; Erel, Ozcan

    2014-01-01

    BACKGROUND. Diabetic retinopathy (DR) is the leading cause of blindness in the world. Retinopathy can still progress despite optimal metabolic control. The aim of the study was to determine whether different degrees of DR (proliferative or nonproliferative) were associated with abnormally modulated hemostatic parameters in patients with T1DM. METHOD. 52 T1DM patients and 40 healthy controls were enrolled in the study. Patients were subdivided into three categories. Group I was defined as those without retinopathy, group II with NPRP, and group III with PRP. We compared these subgroups with each other and the control group (Group IV) according to the serum fibrinogen, plasminogen, alpha2-anti-plasmin ( α2-anti-plasmin), and PAI. RESULTS. We detected that PAI-1, serum fibrinogen, and plasminogen levels were similar between the diabetic and control groups (P = 0.209, P = 0.224, and P = 0.244, resp.), whereas α2-anti-plasmin was higher in Groups I, II, and III compared to the control group (P < 0.01, P < 0.05, and P < 0.001, resp.). There was a positive correlation between serum α2-anti-plasmin and HbA1c levels (r = 0,268, P = 0.031). CONCLUSION. To our knowledge there is scarce data in the literature about α2-anti-plasmin levels in type 1 diabetes. A positive correlation between α2-anti-plasmin with HbA1c suggests that fibrinolytic markers may improve with disease regulation and better glycemic control.

  8. Plasma fibrinogen lever and risk of coronary heart disease among Chinese population: a systematic review and meta-analysis.

    PubMed

    Song, Bin; Shu, Ying; Xu, Yuan Ning; Fu, Ping

    2015-01-01

    Coronary heart disease (CHD) remains the leading causes of death and disability for men and women in most developed countries. It may soon become the leading cause of death in developing countries. Several studies have examined the role of fibrinogen levels in the prediction of atherosclerosis and CHD events. The aim of this study was to explore the effects of plasma fibrinogen levels in Chinese patients with CHD and to examine the relationship of fibrinogen. We performed this meta-analysis of prospective studies of plasma fibrinogen level in relation to CHD risk in electronic database of Medline, EMBase, the Cochrane Library and CNKI (China National Knowledge Infrastructure). Plasma fibrinogen levels were calculated by mean difference with 95% confidence intervals (CI) in patients with CHD and related controls without CHD. The selected 23 studies included 2984 CHD cases and 2279 controls. Our results found that plasma fibrinogen levels of patients were significantly higher than control group (P<0.0001). The predicted odds ratio (OR) for a 1 g/L higher plasma fibrinogen level was 0.94 (95% CI=0.78-1.10). Furthermore, fibrinogen levels were slightly related to age-related CHD patients. The plasma fibrinogen lever was correlated with CHD in the Chinese population, and may be a risk factor and predictor of CHD. Further studies assessing any causal relevance of fibrinogen levels to disease are required.

  9. Chronic homocysteine exposure causes changes in the intrinsic electrophysiological properties of cultured hippocampal neurons.

    PubMed

    Schaub, Christina; Uebachs, Mischa; Beck, Heinz; Linnebank, Michael

    2013-04-01

    Homocystinuria is an inborn error of metabolism characterized by plasma homocysteine levels up to 500 μM, premature vascular events and mental retardation. Mild elevations of homocysteine plasma levels up to 25 μM, which are common in the general population, are associated with vascular disease, cognitive impairment and neurodegeneration. Several mechanisms of homocysteine neurotoxicity have been investigated. However, information on putative effects of hyperhomocysteinemia on the electrophysiology of neurons is limited. To screen for such effects, we examined primary cultures of mouse hippocampal neurons with the whole-cell patch-clamp technique. Homocysteine was applied intracellularly (100 μM), or cell cultures were incubated with 100 μM homocysteine for 24 h. Membrane voltage was measured in current-clamp mode, and action potential firing was induced with short and prolonged current injections. Single action potentials induced by short current injections (5 ms) were not altered by acute application or incubation of homocysteine. When we elicited trains of action potentials with prolonged current injections (200 ms), a broadening of action potentials during repetitive firing was observed in control neurons. This spike broadening was unaltered by acute application of homocysteine. However, it was significantly diminished when incubation with homocysteine was extended to 24 h prior to recording. Furthermore, the number of action potentials elicited by low current injections was reduced after long-term incubation with homocysteine, but not by the acute application. After 24 h of homocysteine incubation, the input resistance was reduced which might have contributed to the observed alterations in membrane excitability. We conclude that homocysteine exposure causes changes in the intrinsic electrophysiological properties of cultured hippocampal neurons as a mechanism of neurological symptoms of hyperhomocysteinemia.

  10. Fibrinogen: A Marker in Predicting Diabetic Foot Ulcer Severity

    PubMed Central

    Li, X. H.; Guan, L. Y.; Lin, H. Y.; Wang, S. H.; Cao, Y. Q.; Jiang, X. Y.

    2016-01-01

    Aims. To examine whether fibrinogen levels are a valuable biomarker for assessing disease severity and monitoring disease progression in patients with diabetic foot ulcer (DFU). Methods. A retrospective study was designed to examine the utility of fibrinogen in estimating disease severity in patients with DFU admitted to our hospital between January 2015 and January 2016. In total, 152 patients with DFU were enrolled in the study group, and 52 age and gender matched people with diabetes but no DFU were included as the control group. DFU severity was assessed using Wagner criteria. Results. Patients with DFU were divided into 2 subgroups based on the Wagner criteria. Mean fibrinogen values were significantly higher in patients with DFU grade ≧ 3 compared to those with DFU grades 1-2 (5.23 ± 1.37 g/L versus 3.61 ± 1.04 g/L). Using ROC statistic, a cut-off value of 5.13 g/L indicated the possible amputation with a sensitivity of 81.8% and a specificity of 78.9% (positive predictive value [PPV] 78.6%, negative predictive value [89.0%]). Fibrinogen values were found to be correlated with CRP levels, neutrophil, and WBC count. Conclusions. Fibrinogen levels might be a valuable tool for assessing the disease severity and monitoring the disease progression in patients with DFU. PMID:28044140

  11. A cross-sectional study to find out the relationship of methylenetetrahydrofolate reductase (MTHFR) C677T genotype with plasma levels of folate and total homocysteine by daily folate intake in Japanese.

    PubMed

    Fukuda, Nana; Hamajima, Nobuyuki; Wakai, Kenji; Suzuki, Koji

    2014-01-01

    In those with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, enzyme activity is lowered. Therefore, these individuals might require an increased intake of folate to maintain or control blood levels of plasma folate or total homocysteine (tHcy). We examined associations of dietary folate intake with fasting plasma folate and total homocysteine (tHcy) according to genotype among 554 Japanese (207 men and 347 women aged 39-89 y) recruited in 2009. Intake of folate was estimated with a food frequency questionnaire. The MTHFR polymorphism was genotyped by a polymerase chain reaction with confronting two-pair primers. The log-transformed concentration of folate or tHcy was regressed on energy-adjusted folate intake in a linear regression analysis. Higher folate intake was associated with higher plasma folate among those with the CC (β=0.165, p=0.066) or CT (β=0.248, p<0.001) genotypes, and with lower tHcy levels only among those with the CC (β=-0.141, p=0.013) genotype. Plasma folate was significantly and inversely associated with tHcy, irrespective of MTHFR genotype. When the analysis was restricted to those with tHcy levels higher than the reference range (≥13.5 nmol/mL, n=20), these significant associations were not found. The interaction between folate intake or plasma folate and genotype was not significant in any analysis. In conclusion, dietary folate intake was positively associated with plasma folate among those with the CC or CT genotypes and inversely associated with tHcy among those with the CC genotype, but the associations were not clear among those with higher levels of tHcy.

  12. Clinical and Prognostic Effect of Plasma Fibrinogen in Renal Cell Carcinoma: A Meta-Analysis

    PubMed Central

    Hong, Mei; Jing, Suoshi; Liu, Xingchen; Wang, Hanzhang; Wang, Xinping; Kaushik, Dharam; Rodriguez, Ronald

    2017-01-01

    Background. Although numerous studies have shown that plasma fibrinogen is linked to renal cell carcinoma (RCC) risk, the consistency and magnitude of the effect of plasma fibrinogen are unclear. The aim of the study was to explore the association between plasma fibrinogen and RCC prognosis. Methods. An electronic search of Embase, PubMed/MEDLINE, and the Cochrane databases was performed to identify relevant studies published prior to June 1, 2016. Results. A total of 3744 patients with RCC from 7 published studies were included in the meta-analysis. The prognostic and clinical relevance of plasma fibrinogen are evaluated in RCC patients. Statistical significance of the combined hazard ratio (HR) was detected for overall survival, cancer-specific survival, and disease-free survival. Our pooled results showed that elevated plasma fibrinogen was significantly associated with clinical stage and Fuhrman grading. The level of plasma fibrinogen was not found to be associated with tumor type and gender. Conclusions. Elevated plasma fibrinogen is a strong indicator of poorer prognosis of patients with RCC, whereas the plasma fibrinogen is not significantly associated with tumor type. Therefore, plasma fibrinogen could be used in patients with RCC for risk stratification and decision providing a proper therapeutic strategy. PMID:28154828

  13. Clinical and Prognostic Effect of Plasma Fibrinogen in Renal Cell Carcinoma: A Meta-Analysis.

    PubMed

    Tian, Yuejun; Hong, Mei; Jing, Suoshi; Liu, Xingchen; Wang, Hanzhang; Wang, Xinping; Kaushik, Dharam; Rodriguez, Ronald; Wang, Zhiping

    2017-01-01

    Background. Although numerous studies have shown that plasma fibrinogen is linked to renal cell carcinoma (RCC) risk, the consistency and magnitude of the effect of plasma fibrinogen are unclear. The aim of the study was to explore the association between plasma fibrinogen and RCC prognosis. Methods. An electronic search of Embase, PubMed/MEDLINE, and the Cochrane databases was performed to identify relevant studies published prior to June 1, 2016. Results. A total of 3744 patients with RCC from 7 published studies were included in the meta-analysis. The prognostic and clinical relevance of plasma fibrinogen are evaluated in RCC patients. Statistical significance of the combined hazard ratio (HR) was detected for overall survival, cancer-specific survival, and disease-free survival. Our pooled results showed that elevated plasma fibrinogen was significantly associated with clinical stage and Fuhrman grading. The level of plasma fibrinogen was not found to be associated with tumor type and gender. Conclusions. Elevated plasma fibrinogen is a strong indicator of poorer prognosis of patients with RCC, whereas the plasma fibrinogen is not significantly associated with tumor type. Therefore, plasma fibrinogen could be used in patients with RCC for risk stratification and decision providing a proper therapeutic strategy.

  14. Simultaneous determination of plasma total homocysteine and methionine by liquid chromatography-tandem mass spectrometry.

    PubMed

    Jiang, Yi; Mistretta, Brandon; Elsea, Sarah; Sun, Qin

    2017-01-01

    The sulfur-containing amino acid homocysteine is a cardiac risk factor and a biomarker for several inborn errors of metabolism in methionine synthesis. A simple LC-MS/MS method was developed and validated for determination of homocysteine and methionine in human plasma. Rapid separation was achieved using a reverse phase liquid chromatography. Mass spectrometry identification was performed in positive electrospray ionization mode for homocysteine and methionine. Accuracy, precision, linearity, recovery and sample stability were evaluated in the method validation. The test is applied in diagnosis of homocystinuria and monitoring total homocysteine levels. Moreover, simultaneous measurement of methionine helps in the differentiation of homocystinuria and some cobalamin disorders (such as cblC and cblD defects) without additional amino acid testing. Lastly, this assay is sensitive to detect reduced total homocysteine levels that are possibly seen in sulfocysteinuria and molybdenum cofactor deficiencies.

  15. Venous ulceration, fibrinogen and fibrinolysis.

    PubMed Central

    Leach, R. D.

    1984-01-01

    The effect of long and short-term venous hypertension upon lymph fibrinogen concentrations was studied in an attempt to explain the peri-capillary deposition of fibrin reported in patients with post-phlebitic syndromes. The clearance of radioactive fibrinogen/thrombin clots from the subcutaneous tissues of rats and human volunteers was also studied. Both long- and short-term venous hypertension were found to increase fibrinogen transport across the interstitial space by more than 600%. Not only was there evidence of fibrinolytic activity in the lymph but after long-term venous hypertension alpha 2 antiplasmin activity was also detectable. Skin biopsies from the venous hypertensive ankles showed deposition of interstitial fibrin. The clearance of radioactive fibrinogen/thrombin clots from the subcutaneous tissues of the rat was found to be delayed if the rats were given epsilon amino caproic acid but it could not be increased with stanozolol. In human subjects it was found that patients with lipodermatosclerosis had delayed clot clearance and retarded blood fibrinolytic activity when compared with normal volunteers and patients with uncomplicated varicose veins. The principle cause why tall men are more subject to ulcers than short men, Dr Young conceived to be then length of the column of blood in their veins; which by its pressure, renders the legs less able to recover when hurt by any violence. Images Fig. 1 Fig. 2 Fig. 5 PMID:6742738

  16. Fluorescein Tri-Aldehyde Promotes the Selective Detection of Homocysteine.

    PubMed

    Barve, Aabha; Lowry, Mark; Escobedo, Jorge O; Thainashmuthu, Josephrajan; Strongin, Robert M

    2016-03-01

    Elevated homocysteine levels are a well-known independent risk factor for cardiovascular disease. To date, relatively few selective fluorescent probes for homocysteine detection have been reported. The lack of sensing reagents and remaining challenges largely derive from issues of sensitivity and/or selectivity. For example, homocysteine is a structural homologue of the more abundant (ca, 20-25 fold) aminothiol cysteine, differing only by an additional methylene group side chain. Fluorescein tri-aldehyde, described herein, has been designed and synthesized as a sensitive and selective fluorophore for the detection of homocysteine in human plasma samples. It responds to analytes selectively via a photoinduced electron transfer (PET) inhibition process that is modulated by predictable analyte-dye product hybridization and ionization states. Mulliken population analysis of fluorescein tri-aldehyde and its reaction products reveals that the characteristic formation of multiple cationic of homocysteine-derived heterocycles leads to enhanced relative negative charge build up on the proximal phenolate oxygen of the fluorophore as a contributing factor to selective emission enhancement.

  17. A Prospective Study on Serum Methylmalonic Acid and Homocysteine in Pregnant Women.

    PubMed

    Choi, Rihwa; Choi, Sunkyu; Lim, Yaeji; Cho, Yoon Young; Kim, Hye Jeong; Kim, Sun Wook; Chung, Jae Hoon; Oh, Soo-Young; Lee, Soo-Youn

    2016-12-08

    This study aimed to investigate serum methylmalonic acid (MMA) and homocysteine levels and to assess their effects on pregnancy and neonatal outcomes. Serum MMA and homocysteine levels in 278 pregnant Korean women, determined by liquid chromatography-tandem mass spectrometry in each trimester, were compared with those of previous studies in other ethnic groups. We investigated the association between MMA and homocysteine status with pregnancy and neonatal events: gestational diabetes, preeclampsia, gestational age at delivery, preterm birth, small for gestational age, neonatal birth weight, and congenital abnormalities. The median (range) MMA level was 0.142 (0.063-0.446) µmol/L and homocysteine level was 10.6 (4.4-38.0) µmol/L in pregnant women. MMA levels were significantly higher in the third trimester than during other trimesters (p < 0.05), while homocysteine levels were not. No significant association was observed between MMA or homocysteine levels and any of the maternal or neonatal outcomes examined. Future studies are needed to assess the associations among maternal serum concentrations of MMA and homocysteine, and maternal and neonatal outcomes.

  18. A Prospective Study on Serum Methylmalonic Acid and Homocysteine in Pregnant Women

    PubMed Central

    Choi, Rihwa; Choi, Sunkyu; Lim, Yaeji; Cho, Yoon Young; Kim, Hye Jeong; Kim, Sun Wook; Chung, Jae Hoon; Oh, Soo-young; Lee, Soo-Youn

    2016-01-01

    This study aimed to investigate serum methylmalonic acid (MMA) and homocysteine levels and to assess their effects on pregnancy and neonatal outcomes. Serum MMA and homocysteine levels in 278 pregnant Korean women, determined by liquid chromatography–tandem mass spectrometry in each trimester, were compared with those of previous studies in other ethnic groups. We investigated the association between MMA and homocysteine status with pregnancy and neonatal events: gestational diabetes, preeclampsia, gestational age at delivery, preterm birth, small for gestational age, neonatal birth weight, and congenital abnormalities. The median (range) MMA level was 0.142 (0.063–0.446) µmol/L and homocysteine level was 10.6 (4.4–38.0) µmol/L in pregnant women. MMA levels were significantly higher in the third trimester than during other trimesters (p < 0.05), while homocysteine levels were not. No significant association was observed between MMA or homocysteine levels and any of the maternal or neonatal outcomes examined. Future studies are needed to assess the associations among maternal serum concentrations of MMA and homocysteine, and maternal and neonatal outcomes. PMID:27941633

  19. Recombinant human fibrinogen and sulfation of the. gamma. prime chain

    SciTech Connect

    Farrell, D.H.; Huang, S.; Chung, D.W.; Davie, E.W. ); Mulvihill, E.R. )

    1991-10-01

    Human fibrinogen and the homodimeric {gamma}{prime}-chain-containing variant have been expressed in BHK cells using cDNAs coding for the {alpha},{beta}, and {gamma} (or {gamma}{prime}) chains. The fibrinogens were secreted at levels greater than 4 {mu}g (mg of total cell protein){sup {minus}1}day{sup {minus}1} and were biologically active in clotting assays. Recombinant fibrinogen containing the {gamma}' chain incorporated {sup 35}SO{sub 4} into its chains during biosynthesis, while no incorporation occurred in the protein containing the {gamma} chain. The identity of the sulfated {gamma}{prime} chain was verified by its ability to form dimers during clotting. In addition, carboxypeptidase {Upsilon} digestion of the recombinant fibrinogen containing the {gamma}{prime} chain released 96% of the {sup 35}S label from the sulfated chain, and the radioactive material was identified as tyrosine O-sulfate. These results clarify previous findings of the sulfation of tyrosine in human fibrinogen.

  20. Alcohol consumption and plasma homocysteine.

    PubMed

    Sakuta, Hidenari; Suzuki, Takashi

    2005-10-01

    A few reports show that consumption of spirits and of wine correlate with elevated plasma total homocysteine (tHcy), which is associated with the risk of cardiovascular disease. We analyzed the relation between tHcy and current daily ethanol consumption cross-sectionally in middle-aged Japanese men (n = 974, age 51-59 years). Plasma tHcy was positively associated with consumption of whiskey but not with consumption of shochu (Japanese spirits), sake, beer, or wine. Odds ratios of an increase in daily intake of 30 ml ethanol (approximately 1 standard deviation) for hyperhomocysteinemia (>14.0 micromol/l) were 2.58 (95% confidence interval, 1.29-5.14) for whiskey, 1.08 (0.78-1.50) for shochu, 0.99 (0.59-1.66) for sake, 0.98 (0.58-1.63) for beer, and 1.70 (0.31-9.50) for wine in a multivariate logistic regression analysis adjusted for the daily number of cigarettes smoked, physical activity, vegetable consumption, and serum creatinine levels. After inclusion of plasma folate and vitamin B12 in the multivariate analysis model, the association between whiskey ethanol consumption and hyperhomocysteinemia remained significant with odds ratio of 2.79 (1.36-5.72). These results suggest that whiskey consumption correlates with hyperhomocysteinemia independently of plasma folate or vitamin B12 or lifestyle factors in the population studied.

  1. Homocysteine and bone loss in epilepsy.

    PubMed

    Elliott, John O; Jacobson, Mercedes P; Haneef, Zulfi

    2007-01-01

    Epidemiological studies reveal fracture incidence in epilepsy is twice that of the normal population. Much interest has been focused on Vitamin D, however, considering mixed results on non-enzyme inducing anti-epileptic drugs (AEDs) and bone mineral density (BMD) additional metabolic effects may be to blame. AEDs increase serum homocysteine (s-Hcy) by lowering blood folate levels. An association between elevated homocysteine, BMD and increased fracture incidence has been found in non-epilepsy populations. Additionally, folate and Vitamin B12 levels are independently related to bone mineral density in various non-epilepsy populations. This study supports previous research, which found elevated s-Hcy in subjects taking AEDs and that bone loss is related to the use of enzyme-inducing AEDs and changes in alkaline phosphatase. By one-way ANOVA, subjects on phenytoin monotherapy had significantly higher levels of s-Hcy than those on other AEDs (F=5.89, p=.016). Regression analyses revealed homocysteine, fracture history, length of years on AEDs, ethnicity were predictors of spine T scores. Weight and BMI were predictors of both BMD and DEXA T scores. Use of enzyme-inducing AEDs was a negative predictor of spine BMD and T scores, while phenytoin monotherapy was a positive predictor of spine BMD. Lamotrigine was found to be a negative predictor of spine T score. Ambulatory status, menopause and alcohol consumption were predictors of BMD but not T scores. In this study, persons with epilepsy who take nutritional supplementation have 25% lower s-Hcy levels than those who do not. Supplementation continues to be important in preventative epilepsy care.

  2. Homocysteine and its thiolactone impair plasmin activity induced by urokinase or streptokinase in vitro.

    PubMed

    Kolodziejczyk-Czepas, Joanna; Talar, Beata; Nowak, Pawel; Olas, Beata; Wachowicz, Barbara

    2012-04-01

    Mechanisms of homocysteine (Hcy) contribution to thrombosis are complex and only partly recognized. The available data suggest that the prothrombotic activity of homocysteine may be not only a result of the changes in coagulation process and endothelial dysfunction, but also the dysfunction of fibrinolysis. The aim of the present work was to assess the effects of homocysteine (10-100 μM mM) and its thiolactone (HTL, 0.1-1 μM) on plasminogen and plasmin functions in vitro. The amidolytic activity of generated plasmin in Hcy or HTL-treated plasminogen and plasma samples was measured by the hydrolysis of chromogenic substrate. Effects of Hcy and HTL on proteolytic activity of plasmin were monitored electrophoretically, by using of fibrinogen as a substrate. The exposure of human plasma and purified plasminogen to Hcy or HTL resulted in the decrease of urokinase-induced plasmin activity. In plasminogen samples treated with the highest concentration of homocysteine (100 μM) or thiolactone (1 μM), the activity of plasmin was inhibited by about 50%. In plasma samples, a reduction of amidolytic activity by about 30% (for 100 μM Hcy) and 40% (for 1 μM HTL), was observed. Both Hcy and HTL were also able to diminish the streptokinase-induced proteolytic activity of plasmin. In conclusion, the results obtained in this study demonstrate that Hcy and HTL may affect fibrinolytic properties of plasminogen and plasma, leading to the decrease of plasmin activity.

  3. A study on human serum albumin influence on glycation of fibrinogen

    SciTech Connect

    Kielmas, Martyna; Szewczuk, Zbigniew; Stefanowicz, Piotr

    2013-09-13

    Highlights: •The glycation of fibrinogen was investigated by isotopic labeling method. •The potential glycation sites in fibrinogen were identified. •Human serum albumin (HSA) inhibits the glycation of fibrinogen. •The effect of HSA on fibrinogen glycation is sequence-dependent. -- Abstract: Although in vivo glycation proceeds in complex mixture of proteins, previous studies did not take in consideration the influence of protein–protein interaction on Maillard reaction. The aim of our study was to test the influence of human serum albumin (HSA) on glycation of fibrinogen. The isotopic labeling using [{sup 13}C{sub 6}] glucose combined with LC-MS were applied as tool for identification possible glycation sites in fibrinogen and for evaluation the effect of HSA on the glycation level of selected amino acids in fibrinogen. The obtained data indicate that the addition of HSA protects the fibrinogen from glycation. The level of glycation in presence of HSA is reduced by 30–60% and depends on the location of glycated residue in sequence of protein.

  4. Optimized microturbidimetric assay for fibrinogen.

    PubMed

    Macart, M; Koffi, A; Henocque, G; Mathieu, J F; Guilbaud, J C

    1989-02-01

    In this assay we measure the turbidity produced by precipitation of plasma fibrinogen with a reagent composed of ammonium sulfate, EDTA, and guanidine hydrochloride. The two-step reagent addition, and use of fixed reaction times, eliminates interference from bilirubin, hemoglobin, and chylomicrons. We checked 135 monoclonal proteins for interference, finding the probability of encountering major interference in samples from adults to be very low, P = 0.0002. The method is calibrated with purified fibrinogen and the response is linear over the range 0-10 g/L. Within-run precision (CV) is less than 2% from 1 to 10 g/L. Correlations with the immunoturbidimetric (r = 0.99), chronometric (r = 0.99), and clotting (r = 0.97) methods were extremely high.

  5. Update on cobalamin, folate, and homocysteine.

    PubMed

    Carmel, Ralph; Green, Ralph; Rosenblatt, David S; Watkins, David

    2003-01-01

    is a risk factor for vascular and thrombotic disease. In Section II, Dr. Green notes that the interactions of metabolism and clinical risk are not well understood and a causative relationship remains unproven despite new reports that lowering homocysteine levels may reduce vascular complications. Genetic and acquired influences may interact in important ways that are still being sorted out. The use of vitamins, especially folate, often reduces homocysteine levels but also carries potential disadvantages and even risks. Folate fortification of the diet and supplement use have also markedly reduced the frequency of folate deficiency, and cobalamin deficiency is now the more common deficiency state, especially among the elderly. Although genetic disorders are rare, they illuminate important metabolic mechanisms and pose diagnostic challenges, especially when clinical presentation occurs later in life. In Section III, Drs. Rosenblatt and Watkins use selected disorders to illustrate the subject. Imerslund-Gräsbeck syndrome, a hereditary disorder of cobalamin absorption at the ileal level, demonstrates genetic heterogeneity. Finnish patients show mutation of the gene for cubilin, the multiligand receptor for intrinsic factor. Surprisingly, Norwegian and other patients have been found recently to have mutations of the AMN (amnionless) gene, mutations that are lethal in mice at the embryonic stage. Two disorders of cobalamin metabolism, cblG and cblE, are now known to arise from mutations of the methionine synthase and methionine synthase reductase genes, respectively. These disorders feature megaloblastic anemia and neurologic manifestations. The folate disorder selected for illustration, methylenetetrahydrofolate reductase (MTHFR) deficiency, paradoxically causes neurological problems but no megaloblastic anemia. This rare deficiency is the most common inborn error of folate metabolism. It is distinct from the very common MTHFR gene polymorphisms, mutations that cause

  6. Effects of methyl-deficient diets on methionine and homocysteine metabolism in the pregnant rat.

    PubMed

    Wilson, Fiona A; Holtrop, Grietje; Calder, A Graham; Anderson, Susan E; Lobley, Gerald E; Rees, William D

    2012-06-15

    Although the importance of methyl metabolism in fetal development is well recognized, there is limited information on the dynamics of methionine flow through maternal and fetal tissues and on how this is related to circulating total homocysteine concentrations. Rates of homocysteine remethylation in maternal and fetal tissues on days 11, 19, and 21 of gestation were measured in pregnant rats fed diets with limiting or surplus amounts of folic acid and choline at two levels of methionine and then infused with L-[1-(13)C,(2)H(3)-methyl]methionine. The rate of homocysteine remethylation was highest in maternal liver and declined as gestation progressed. Diets deficient in folic acid and choline reduced the production of methionine from homocysteine in maternal liver only in the animals fed a methionine-limited diet. Throughout gestation, the pancreas exported homocysteine for methylation within other tissues. Little or no methionine cycle activity was detected in the placenta at days 19 and 21 of gestation, but, during this period, fetal tissues, especially the liver, synthesized methionine from homocysteine. Greater enrichment of homocysteine in maternal plasma than placenta, even in animals fed the most-deficient diets, shows that the placenta did not contribute homocysteine to maternal plasma. Methionine synthesis from homocysteine in fetal tissues was maintained or increased when the dams were fed folate- and choline-deficient methionine-restricted diets. This study shows that methyl-deficient diets decrease the remethylation of homocysteine within maternal tissues but that these rates are protected to some extent within fetal tissues.

  7. Relationship between homocysteine and intraocular pressure in men and women: A population-based study.

    PubMed

    Leibovitzh, Haim; Cohen, Eytan; Levi, Amos; Kramer, Michal; Shochat, Tzippy; Goldberg, Elad; Krause, Ilan

    2016-09-01

    The relationship between homocysteine levels and glaucoma has been questioned in previous studies without conclusive results. In the current study, we assessed the relationship between homocysteine levels and intraocular pressure which is one of the main factors in the development of glaucoma in men and women.A retrospective cross-sectional analysis of a database from a screening center in Israel which assessed 11,850 subjects, within an age range 20 to 80 years. The relationship between homocysteine and intraocular pressure has been investigated by comparing intraocular pressure in subjects with elevated and normal homocysteine and by comparing homocysteine levels in subjects with elevated and normal intraocular pressure. In addition, we compared the levels of homocysteine in subjects with and without a confirmed diagnosis of glaucoma.The mean IOP (±SD) in subjects with normal homocysteine levels(≤15 μmol/L) was 13.2 ± 2.3 mm Hg and 13.4 ± 2.4 mm Hg in those with high homocysteine levels (>15 μmol/L) (P < 0.008, 95% confidence interval [CI] 0.3-0.09).Nonetheless, after multivariate adjustment for age, gender, vitamin B12, and folic acid statistical significance was no longer demonstrated (P = 0.37). Mean homocysteine levels (±SD) in subjects with normal intraocular pressure of ≤ 21 mm Hg was 11.7 ± 5.5 μmol/L and 12.09 ± 3.43 μmol/L in those with elevated intraocular pressure (P = 0.4, 95%CI 1.1-1.8). Mean homocysteine levels (±SD) in subjects with glaucoma were 11.2 ± 3.5 μmol/L compared to 11.7 ± 5.5 μmol/L in subjects without glaucoma and normal intraocular pressure ≤ 21 mm Hg (P = 0.4, 95% CI 1.2-2.1).The current study displays no clinical correlation between the homocysteine level and the intraocular pressure. Homocysteine may not be used as a predictive parameter to recognize those subjects prone to develop elevated intraocular pressure.

  8. Vitamin B6 suppresses apoptosis of NM-1 bovine endothelial cells induced by homocysteine and copper.

    PubMed

    Endo, Naoko; Nishiyama, Kazuo; Okabe, Masaaki; Matsumoto, Mitsuharu; Kanouchi, Hiroaki; Oka, Tatsuzo

    2007-04-01

    Hyperhomocysteinemia is an important risk factor for atherosclerosis. We previously reported that formation of early atherosclerosis in the rat aorta was associated with hyperhomocysteinemia and reduction of antioxidant activity caused by low concentration of vitamin B(6)in vivo. In the present study, we examined effects of vitamin B(6) on apoptosis of bovine endothelial cells (NM-1 cells) treated with homocysteine and copper. Homocysteine and copper induced extracellular hydrogen peroxide, intracellular ROS and cellular lipid peroxide levels. Cell viability was reduced to 30% compared to that of control cells. On the other hand, pyridoxal treatment as well as EDTA treatment increased viability of NM-1 cells treated with homocysteine and copper to about 60%, and significantly decreased extracellular hydrogen peroxide, intracellular ROS and cellular lipid peroxide levels. The treatment of catalase recovered cell viability and reduced the level of extracellular hydrogen peroxide and intracellular ROS. Cell death by homocysteine and copper was confirmed to be due to apoptosis by evaluation of DNA fragmentation and by TUNEL assay. However, apoptosis of NM-1 cells induced by homocysteine and copper was due to a caspase-independent pathway as it was not inhibited by the caspase inhibitor, Z-VAD-fmk. Apoptosis of NM-1 cells induced by homocysteine and copper accompanied with mitochondrial permeability but not cytochrome c release. These results suggest that pyridoxal treatment suppresses apoptosis of NM-1 cells induced by homocysteine and copper, most likely through antioxidant effects.

  9. Effect of a Klamath algae product ("AFA-B12") on blood levels of vitamin B12 and homocysteine in vegan subjects: a pilot study.

    PubMed

    Baroni, Luciana; Scoglio, Stefano; Benedetti, Serena; Bonetto, Chiara; Pagliarani, Silvia; Benedetti, Yanina; Rocchi, Marco; Canestrari, Franco

    2009-03-01

    Vitamin B12 is a critical nutrient that is often inadequate in a plant-based (vegan) diet, thus the inclusion of a reliable vitamin B12 source in a vegan diet is recommended as essential. Unfortunately, many natural sources of vitamin B12 have been proven to contain biologically inactive vitamin B12 analogues, inadequate for human supplementation. The aim of this non-randomized open trial was to determine whether supplementation with a natural Klamath algae-based product ("AFA-B12", Aphanizomenon flos-aquae algae plus a proprietary mix of enzymes) could favorably affect the vitamin B12 status of a group of 15 vegan subjects. By assessing blood concentration of vitamin B12, folate, and more importantly homocysteine (Hcy, a reliable marker in vegans of their B12 absorption), the vitamin B12 status of the participants at the end of the 3-month intervention period, while receiving the Klamath-algae supplement (T2), was compared with their vitamin B12 status at the end of the 3-month control period (T1), when they were not receiving any supplement, having stopped taking their usual vitamin B12 supplement at the beginning of the study (T0). Compared to the control period, in the intervention period participants improved their vitamin B12 status, significantly reducing Hcy blood concentration (p=0.003). In conclusion, the Klamath algae product AFA-B12 appears to be, in a preliminary study, an adequate and reliable source of vitamin B12 in humans.

  10. DNA methylation profiling of the fibrinogen gene landscape in human cells and during mouse and zebrafish development.

    PubMed

    Vorjohann, Silja; Pitetti, Jean-Luc; Nef, Serge; Gonelle-Gispert, Carmen; Buhler, Leo; Fish, Richard J; Neerman-Arbez, Marguerite

    2013-01-01

    The fibrinogen genes FGA, FGB and FGG show coordinated expression in hepatocytes. Understanding the underlying transcriptional regulation may elucidate how their tissue-specific expression is maintained and explain the high variability in fibrinogen blood levels. DNA methylation of CpG-poor gene promoters is dynamic with low methylation correlating with tissue-specific gene expression but its direct effect on gene regulation as well as implications of non-promoter CpG methylation are not clear. Here we compared methylation of CpG sites throughout the fibrinogen gene cluster in human cells and mouse and zebrafish tissues. We observed low DNA methylation of the CpG-poor fibrinogen promoters and of additional regulatory elements (the liver enhancers CNC12 and PFE2) in fibrinogen-expressing samples. In a gene reporter assay, CpG-methylation in the FGA promoter reduced promoter activity, suggesting a repressive function for DNA methylation in the fibrinogen locus. In mouse and zebrafish livers we measured reductions in DNA methylation around fibrinogen genes during development that were preceded by increased fibrinogen expression and tri-methylation of Histone3 lysine4 (H3K4me3) in fibrinogen promoters. Our data support a model where changes in hepatic transcription factor expression and histone modification provide the switch for increased fibrinogen gene expression in the developing liver which is followed by reduction of CpG methylation.

  11. Homocysteine, folate and pregnancy outcomes.

    PubMed

    Kim, M W; Hong, S-C; Choi, J S; Han, J-Y; Oh, M-J; Kim, H J; Nava-Ocampo, A; Koren, G

    2012-08-01

    The purpose of this study is to evaluate the relationship between maternal and/or cord blood folate/homocysteine concentrations and adverse pregnancy outcomes. The study population included a random sample of singleton pregnant women in whom we measured total homocysteine and folic acid in maternal or cord blood at deliveries. A total of 227 pregnant women were enrolled. The concentration of folate in maternal blood tended to be significantly lower in pre-term birth than in full-term delivery group (median (95% CI), 14.4 (3.6-73) vs 25 (7.3-105.5) p < 0.01). The total homocysteine in maternal and cord blood was significantly higher in the pre-eclampsia than in the normotensive group (7.9 (1.7-28.2) vs 5.9 (1.8-14.6) μmol/ml, p < 0.05; and 5.8 (2.6-14.4) vs 4.2 (0.7-7.9) ng/ml, p < 0.05, respectively). Lower maternal serum folate concentration is associated with pre-term delivery and higher maternal plasma homocysteine concentration with pre-eclampsia.

  12. Crotalus atrox venom preconditioning increases plasma fibrinogen and reduces perioperative hemorrhage in a rat model of surgical brain injury

    PubMed Central

    Kim, Cherine H.; McBride, Devin W.; Raval, Ronak; Sherchan, Prativa; Hay, Karen L.; Gren, Eric C. K.; Kelln, Wayne; Lekic, Tim; Hayes, William K.; Bull, Brian S.; Applegate, Richard; Tang, Jiping; Zhang, John H.

    2017-01-01

    Perioperative bleeding is a potentially devastating complication in neurosurgical patients, and plasma fibrinogen concentration has been identified as a potential modifiable risk factor for perioperative bleeding. The aim of this study was to evaluate preconditioning with Crotalus atrox venom (Cv-PC) as potential preventive therapy for reducing perioperative hemorrhage in the rodent model of surgical brain injury (SBI). C. atrox venom contains snake venom metalloproteinases that cleave fibrinogen into fibrin split products without inducing clotting. Separately, fibrinogen split products induce fibrinogen production, thereby elevating plasma fibrinogen levels. Thus, the hypothesis was that preconditioning with C. atrox venom will produce fibrinogen spilt products, thereby upregulating fibrinogen levels, ultimately improving perioperative hemostasis during SBI. We observed that Cv-PC SBI animals had significantly reduced intraoperative hemorrhage and postoperative hematoma volumes compared to those of vehicle preconditioned SBI animals. Cv-PC animals were also found to have higher levels of plasma fibrinogen at the time of surgery, with unchanged prothrombin time. Cv-PC studies with fractions of C. atrox venom suggest that snake venom metalloproteinases are largely responsible for the improved hemostasis by Cv-PC. Our findings indicate that Cv-PC increases plasma fibrinogen levels and may provide a promising therapy for reducing perioperative hemorrhage in elective surgeries. PMID:28102287

  13. The down-regulation of IL-6-stimulated fibrinogen steady state mRNA and protein levels by human recombinant IL-1 is not PGE2-dependent: effects of IL-1 receptor antagonist (IL-1RA).

    PubMed

    Conti, P; Bartle, L; Barbacane, R C; Reale, M; Sipe, J D

    1995-01-26

    Infections, trauma and inflammatory processes induce a host response with increases in a large group of structurally and functionally diverse plasma proteins. Parental administration of foreign proteins also induce an increase in plasma fibrinogen. Interleukin-6 (IL-6) is a monocyte-derived mediator and has regulatory effects on acute phase protein genes which result in the induction of fibrinogen synthesis in primary hepatocytes, while the addition of interleukin-1 (IL-1) exerts a negative modulating influence on the IL-6-stimulated fibrinogen. In order to understand the mechanisms by which IL-1 inhibits IL-6-stimulated fibrinogen transcription and translation, and since IL-1 is believed to act through PGE2 stimulation, we have studied the influence of PGE2 in IL-6 or IL-1, alone and in combination, on Fg mRNA expression (by Northern blot analysis) and the influence of PGE2, indomethacin, and arachidonic acid on Fg secretion. Moreover, since human recombinant interleukin-1 receptor antagonist (hrIL-1ra) is a strong inhibitor of IL-1 induced IL-1 transcription and translation and has an inhibitory effect on PGE2, we have studied the effects of IL-1ra on the down-regulation of IL-6 stimulated fibrinogen by IL-1, using an Fg ELISA method.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Genetic and environmental sources of fibrinogen variability in Israeli families: the Kibbutzim Family Study.

    PubMed Central

    Friedlander, Y; Elkana, Y; Sinnreich, R; Kark, J D

    1995-01-01

    Genetic and environmental determinants of plasma fibrinogen were investigated in a sample of 82 kindreds residing in kibbutz settlements in Israel. The sample included 223 males and 229 females ages 15-97 years. Fibrinogen levels were first adjusted for variability in sex and age. There was a significant familial aggregation of adjusted fibrinogen levels, as indicated by inter- and intraclass correlation coefficients significantly different from zero. Commingling analysis implied that in this population a mixture of two normal distributions fit the adjusted fibrinogen levels better than did a single normal distribution. Complex segregation analysis was first applied to these sex- and age-adjusted data. Heterogeneous etiologies for individual differences were suggested. There was evidence for a nontransmitted environmental major factor in addition to polygenic genes that explained the mixture of distributions. In parallel, a single recessive locus with a major effect that explained the adjusted variation in fibrinogen could not be rejected. However, when the regression model for sex and age allowed coefficients to be ousiotype (class)-specific, the recessive genetic model was rejected and the mixed environmental one was not. These results suggested that particular ousiotypes determined by the major environmental factor are associated with a steeper increase of fibrinogen with age. While at the age of 20 years, the major environmental factor contributed 10% to fibrinogen variability, and 48% was explained by polygenic loci, at 80 years of age, the major factor explained 64% and only approximately 20% was explained by polygenic factors. PMID:7726177

  15. Insufficient fibrinogen response following free flap surgery is associated with bleeding complications

    PubMed Central

    Kolbenschlag, Jonas; Diehm, Yannick; Daigeler, Adrien; Kampa, David; Fischer, Sebastian; Kapalschinski, Nicolai; Goertz, Ole; Lehnhardt, Marcus

    2016-01-01

    Background: Microvascular tissue transfer has become a safe and reliable tool in the reconstructive armamentarium, yielding high success rates. However, little is known about the changes in coagulation after free tissue transfer and their potential impact on morbidity. Methods: Fibrinogen concentration and platelet count among other values were available and assessed in 139 undergoing free tissue transfer before, immediately after, and 1–3 as well as 8–11 days after surgery. In patients undergoing urgent revision for either bleeding or microvascular thrombosis, blood samples were drawn directly before re-exploration. Results: In the patients without any surgical revision and in those with thrombosis of the microvascular pedicle, both fibrinogen concentration and platelet count increased significantly during the early and late post-operative window. Patients that developed bleeding necessitating re-exploration showed an inadequate increase in fibrinogen levels, resulting in significantly lower concentrations compared to the other two groups. There were no significant differences in platelet count or PTT between these groups. Conclusion: Free flap surgery induces acute and subacute changes in coagulation, comparable to other major surgeries and severe injuries. This leads to an increase in platelet count and fibrinogen over the post-operative course. Patients that developed bleeding requiring surgical re-exploration showed an insufficient increase in fibrinogen, resulting in significantly lower fibrinogen levels. Therefore, monitoring and correction of fibrinogen levels might aid in preventing or treating bleeding complications following free flap surgery. PMID:27975041

  16. Homocysteine Is an Oncometabolite in Breast Cancer, Which Promotes Tumor Progression and Metastasis

    DTIC Science & Technology

    2014-09-01

    tissues and compare the expression levels in normal mouse mammary gland . For this, we used biological triplicates by preparing RNA from tumor tissues...homocysteine to be increased 4.5-fold in MMTV-HRAS mouse breast tumor tissues compared to age-matched wild type mouse mammary tissues. Similarly, the...levels of homocysteine went up 7.3-fold in MMTV-PyMT mouse breast cancer tissues 3 compared to age-matched wild type mouse mammary tissues

  17. Mutational and nucleotide sequence analysis of S-adenosyl-L-homocysteine hydrolase from Rhodobacter capsulatus.

    PubMed Central

    Sganga, M W; Aksamit, R R; Cantoni, G L; Bauer, C E

    1992-01-01

    The genetic locus ahcY, encoding the enzyme S-adenosyl-L-homocysteine hydrolase (EC 3.3.1.1) from the bacterium Rhodobacter capsulatus, has been mapped by mutational analysis to within a cluster of genes involved in regulating the induction and maintenance of the bacterial photosynthetic apparatus. Sequence analysis demonstrates that ahcY encodes a 51-kDa polypeptide that displays 64% sequence identity to its human homolog. Insertion mutants in ahcY lack detectable S-adenosyl-L-homocysteine hydrolase activity and, as a consequence, S-adenosyl-L-homocysteine accumulates in the cells, resulting in a 16-fold decrease in the intracellular ratio of S-adenosyl-L-methionine to S-adenosyl-L-homocysteine as compared to wild-type cells. The ahcY disrupted strain fails to grow in minimal medium; however, growth is restored in minimal medium supplemented with methionine or homocysteine or in a complex medium, thereby indicating that the hydrolysis of S-adenosyl-L-homocysteine plays a key role in the metabolism of sulfur-containing amino acids. The ahcY mutant, when grown in supplemented medium, synthesizes significantly reduced levels of bacteriochlorophyll, indicating that modulation of the intracellular ratio of S-adenosyl-L-methionine to S-adenosyl-L-homocysteine may be an important factor in regulating bacteriochlorophyll biosynthesis. PMID:1631127

  18. Elevated plasma fibrinogen level shows superior prognostic value than Epstein–Barr virus DNA load for stage IVA/B nasopharyngeal carcinoma patients in the intensity-modulated radiotherapy era

    PubMed Central

    Huang, Ying; Mao, Minjie; Han, Fei; Liao, Junfang; Deng, Meiling; Duan, Zhijun; Zheng, Lie; Wu, Shaoxiong; Lu, Taixiang; Jian, Yutao

    2016-01-01

    Purpose Effective prognostic factors for patients with stage IVA/B nasopharyngeal carcinoma (NPC) who are susceptible to distant metastases are limited. We aim to investigate the prognostic value of pretreatment plasma fibrinogen (FIB) level and Epstein–Barr virus DNA (EBV-DNA) load in these patients in the era of intensity-modulated radiotherapy (IMRT). Results The 5-year DSS, DFS and DMFS rates of the entire cohort were 72.7%, 66.8%, 80.0%, respectively. High FIB level was identified as a negative prognostic factor for survival: the 5-year DSS, DFS and DMFS rates for patients with high FIB (> 4.0 g/L) and normal FIB (≤ 4.0 g/L) were 60.3% vs. 76.0%, 56.0% vs. 69.9%, and 59.4% vs. 85.5%, respectively (all P < 0.001). Subgroup analysis demonstrated that DSS, DFS and DMFS decreased as FIB gradually increased, even within the normal range. The risk of distant metastasis in patients with high FIB was over 3-fold than patients with normal FIB. EBV-DNA was not an independent prognostic factor for any survival outcomes in multivariate analysis. Conclusion High pretreatment FIB level shows superior prognostic value than EBV-DNA load for stage IVA/B NPC patients in the era of IMRT. Materials and Methods A total of 755 patients with newly-diagnosed stage IVA/B NPC treated with definitive IMRT between January 2007 and December 2011 were enrolled. Plasma FIB and EBV-DNA were measured before treatment. Disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method; differences were compared using the log-rank test. PMID:27323828

  19. A comparison of the fibrinogen receptor distribution on adherent platelets using both soluble fibrinogen and fibrinogen immobilized on gold beads.

    PubMed

    Estry, D W; Mattson, J C; Mahoney, G J; Oesterle, J R

    1991-04-01

    The distribution of fibrinogen receptors was determined on the surface of adherent platelets using both direct labeling with the ligand fibrinogen which was immobilized on gold particles (Fg-Au) and indirect immunogold (Ig-Au) labeling of bound soluble fibrinogen identified with a rabbit polyclonal anti-fibrinogen antibody. Two distinctly different patterns of labeling were obtained and appeared to depend on whether solid phase fibrinogen (Fg-Au) or soluble phase released fibrinogen were bound to the membrane receptor. The membrane-bound Fg-Au reorganized in patterns that closely mimicked the organization of the underlying cytoskeleton. In approximately 18% of the adherent platelets, Fg-Au was seen in channels or vesicle-like structures lying deep to the platelet surface suggesting internalization into the open canalicular system and/or endocytosis. The labeling pattern obtained when identifying the location of membrane-bound soluble released fibrinogen by Ig-Au was diffuse and lacked the organizational patterns characteristic of Fg-Au. Unlike the Fg-Au probe, early dendritic platelets were heavily labeled by the soluble phase fibrinogen using the Ig-Au technique. Although the label covered the entire exposed platelet membrane in fully spread platelets, labeling over the peripheral web was more dense than that over the intermediate or granulomere zone. The diffuse organization and heavier peripheral distributional pattern of the glycoprotein IIb-IIIa (GP IIb-IIIa) receptor in fixed, adherent platelets, was also seen with the GP IIb-IIIa receptor-specific antibody AP-2. The binding of both the Fg-Au and Ig-Au were inhibited using the tetrapeptide Arg-Gly-Asp-Ser (RGDS) (93% and 98% inhibition, respectively), AP-2 (98% and 97%, respectively) and platelets from patients with Glanzmann's thrombasthenia (GT) (99% and 98%, respectively). The data presented provides the first report that receptor reorganization, following binding of fibrinogen, appears to be related to

  20. Homocysteine and the pathogenesis of atherosclerosis.

    PubMed

    McCully, Kilmer S

    2015-03-01

    The homocysteine theory of arteriosclerosis was discovered by study of arteriosclerotic plaques occurring in homocystinuria, a disease caused by deficiencies of cystathionine synthase, methionine synthase or methylenetetrahydrofolate reductase. According to the homocysteine theory, metabolic and nutritional abnormalities leading to elevation of plasma homocysteine cause atherosclerosis in the general population without these rare enzymatic abnormalities. Through studies of metabolism of homocysteine thiolactone, the anhydride of homocysteine, in cell cultures from homocystinuric children, the pathway for synthesis of sulfate was found to be dependent upon thioretinamide, the amide formed from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide form the complex thioretinaco with cobalamin, and oxidative phosphorylation is catalyzed by reduction of oxygen, which is bound to thioretinaco ozonide, by electrons from electron transport particles. Atherogenesis is attributed to formation of aggregates of homocysteinylated lipoproteins with microorganisms, which obstruct the vasa vasorum during formation of arterial vulnerable plaques.

  1. Homocysteine and non-cardiac vascular disease.

    PubMed

    Katsiki, Niki; Perez-Martinez, Pablo; Mikhailidis, Dimitri P

    2017-03-17

    Elevated homocysteine (Hcy) levels are predictors of cardiovascular disease (CVD). Hyperhomocysteinemia has also been associated with total and CVD mortality. However, whether Hcy is just a marker or plays a causal role in CVD remains to be elucidated. In this narrative review, we discuss the associations between Hcy and non-cardiac vascular diseases, namely stroke, peripheral artery disease (PAD), carotid artery disease, chronic kidney disease (CKD), atherosclerotic renal artery stenosis (ARAS), abdominal aortic aneurysm (AAA) and erectile dysfunction (ED). The effects of several drugs on Hcy levels are also considered. Folic acid, vitamin B6 and B12 supplementation can significantly decrease circulating Hcy concentrations but their effects on CVD risk reduction are conflicting. No current guidelines recommend the routine screening of Hcy levels in patients with non-cardiac vascular diseases. Therefore, further research is needed to elucidate the use of Hcy in the clinical practice.

  2. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine.

    PubMed

    Starkebaum, G; Harlan, J M

    1986-04-01

    We have examined whether the toxic effects of homocysteine on cultured endothelial cells could result from the formation and action of hydrogen peroxide. In initial experiments with a cell-free system, micromolar amounts of copper were found to catalyze an oxygen-dependent oxidation of homocysteine. The molar ratio of homocysteine oxidized to oxygen consumed was approximately 4.0, which suggests that oxygen was reduced to water. The addition of catalase, however, decreased oxygen consumption by nearly one-half, which suggests that H2O2 was formed during the reaction. Confirming this hypothesis, H2O2 formation was detected using the horseradish peroxidase-dependent oxidation of fluorescent scopoletin. Ceruloplasmin was also found to catalyze oxidation of homocysteine and generation of H2O2 in molar amounts equivalent to copper sulfate. Finally, homocysteine oxidation was catalyzed by normal human serum in a concentration-dependent manner. Using cultured human and bovine endothelial cells, we found that homocysteine plus copper could lyse the cells in a dose-dependent manner, an effect that was completely prevented by catalase. Homocystine plus copper was not toxic to the cells. Specific injury to endothelial cells was seen only after 4 h of incubation with homocysteine plus copper. Confirming the biochemical studies, ceruloplasmin was also found to be equivalent to Cu++ in its ability to cause injury to endothelial cells in the presence of homocysteine. Since elevated levels of homocysteine have been implicated in premature development of atherosclerosis, these findings may be relevant to the mechanism of some types of chronic vascular injury.

  3. Over 50 Years of Fibrinogen Concentrate

    PubMed Central

    Hochleitner, Gerald; Wendt, Michael; Teruya, Alexandre; Spahn, Donat R.

    2015-01-01

    March 2013 represented the 50th anniversary of the first license granted for a fibrinogen concentrate. In this review, we look at the history of bleeding management that led to the development of fibrinogen concentrate, discuss its current use, and consider future developments for this product. PMID:26294722

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

    PubMed Central

    Deminice, Rafael; Ribeiro, Diogo Farias; Frajacomo, Fernando Tadeu Trevisan

    2016-01-01

    Background Although 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. Objective The aim of this meta-analysis was to ascertain the effects of acute exercise and exercise training on homocysteine levels in the blood. Method A 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. Results Given 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

  5. Fibrinogen

    MedlinePlus

    ... its attachment to the uterus wall ( placenta abruptio ). Risks There is very little risk involved with having ... urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows ...

  6. Homocysteine imbalance: a pathological metabolic marker.

    PubMed

    Schalinske, Kevin L; Smazal, Anne L

    2012-11-01

    Perturbations in methyl group metabolism and homocysteine balance have emerged over the past few decades as having defining roles in a number of pathological conditions. Numerous nutritional, hormonal, and genetic factors that are characterized by elevations in circulating homocysteine concentrations are also associated with specific pathological conditions, including cancer development, autoimmune diseases, vascular dysfunction, and neurodegenerative disease. Although much remains to be explored, our understanding of the relationship between disease, methyl balance, and epigenetic control of gene expression has steadily progressed. However, homocysteine balance and its role in health and disease are not as clearly understood. This review presents our current understanding of homocysteine metabolism and its link to specific pathologies.

  7. Fibrinogen-related proteins in ixodid ticks

    PubMed Central

    2011-01-01

    Background Fibrinogen-related proteins with lectin activity are believed to be part of the tick innate immune system. Several fibrinogen-related proteins have been described and characterised mainly on the basis of their cDNA sequences while direct biochemical evidence is missing. One of them, the haemolymph lectin Dorin M from the tick Ornithodoros moubata was isolated and characterised in more depth. Results Several fibrinogen-related proteins were detected in the haemolymph of ixodid ticks Dermacentor marginatus, Rhipicephalus appendiculatus, R. pulchellus, and R. sanguineus. These proteins were recognised by sera directed against the tick lectin Dorin M and the haemagglutination activity of the ticks R. appendiculatus and D. marginatus. Cross-reactivity of the identified proteins with antibodies against the fibrinogen domain of the human ficolin was also shown. The carbohydrate-binding ability of tick haemolymph was confirmed by haemagglutination activity assays, and this activity was shown to be inhibited by neuraminic acid and sialylated glycoproteins as well as by N-acetylated hexosamines. The fibrinogen-related proteins were shown to be glycosylated and they were localised in salivary glands, midguts, and haemocytes of D. marginatus. Hemelipoglycoprotein was also recognised by sera directed against the fibrinogen-related proteins in all three Rhipicephalus species as well as in D. marginatus. However, this protein does not contain the fibrinogen domain and thus, the binding possibly results from the structure similarity between hemelipoglycoprotein and the fibrinogen domain. Conclusions The presence of fibrinogen-related proteins was shown in the haemolymph of four tick species in high abundance. Reactivity of antibodies directed against ficolin or fibrinogen-related proteins with proteins which do not contain the fibrinogen domain points out the importance of sequence analysis of the identified proteins in further studies. Previously observed expression of

  8. Interactions among methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) polymorphisms - a cross-sectional study: multiple heterozygosis as a risk factor for higher homocysteine levels and vaso-occlusive episodes.

    PubMed

    Amaral, F M; Miranda-Vilela, A L; Lordelo, G S; Ribeiro, I F; Daldegan, M B; Grisolia, C K

    2017-02-23

    High plasma homocysteine (Hcy) ​​levels may be responsible for vaso-occlusive episodes and may have acquired and/or genetic causes. This cross-sectional study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C) and cystathionine-β-synthase (CBS; T833C/844ins68, G919A) polymorphisms in serum levels of folic acid, vitamin B12 and Hcy, and to verify a possible association between these polymorphisms and the clinical variability. Blood samples of Brazilian patients with a diagnosis of thrombosis were submitted to genotyping by PCR-based methods and serum dosages of folic acid, vitamin B12 and Hcy. Except for the CBS G919A polymorphism, all other genetic markers were in Hardy-Weinberg equilibrium. An increased risk for venous thrombosis was found for the MTHFR 1298CC carriers (OR = 1.688; 95%CI = 0.839-3.398, P = 0.018) and those homozygously mutant for the CBS haplotype 844ins68/T833C (OR = 2.488; 95%CI = 0.501-12.363, P = 0.031), while heterozygous for this CBS haplotype showed an increased risk for higher Hcy levels (OR = 5.900; 95%CI = 1.003-34.691, P = 0.030). Significant interactions were observed among the MTHFR C677T, MTHFR A1298C and CBS haplotype 844ins68/T833C polymorphisms in the results for Hcy levels (P = 0.000), where heterozygous had higher values. Interactions among these polymorphisms can affect serum Hcy levels, where multiple heterozygosis could be a risk factor for vaso-occlusive episodes.

  9. Three cases of congenital dysfibrinogenemia in unrelated Chinese families: heterozygous missense mutation in fibrinogen alpha chain Argl6His.

    PubMed

    Luo, Meiling; Deng, Donghong; Xiang, Liqun; Cheng, Peng; Liao, Lin; Deng, Xuelian; Yan, Jie; Lin, Faquan

    2016-09-01

    Congenital dysfibrinogenemia (CD) is a qualitative fibrinogen disorder caused by an abnormal fibrinogen molecule structure, leading to dysfunctional blood coagulation. This study describes 3 cases of dysfibrinogenemia identified in the unrelated Chinese pedigrees.Routine coagulation screening tests were performed on the probands and their families. The antigens and functionality of fibrinogen was measured using an immunoturbidimetry assay and the Clauss method, respectively. To identify the genetic mutation responsible for these dysfibrinogens, genomic DNA extracted from the blood was analyzed using PCR amplification and direct sequencing. The presence of the mutant chains was determined using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectroscopy. Purified plasma fibrinogen of 3 probands was analyzed using SDS-PAGE, fibrinogen clottability, fibrin polymerization, fibrinopeptide release, and scanning electron microscopy (SEM).The 3 probands had a long thrombin time. Levels of functional fibrinogen were found to be very low, while the fibrinogen antigen was within the normal range. DNA sequencing revealed a heterozygous Arg16His substitution in the fibrinogen Aα chain (FGA). The mutant chains were found to be expressed using MALDI-TOF mass spectroscopy. SDS-PAGE did not reveal any difference in the molecular weights of 3 polypeptide chains between normal and abnormal fibrinogens. Fibrinogen clottability showed a slower fibrin clot formation than the healthy control. Fibrin polymerization, after addition of thrombin, showed a prolonged lag phase and decreased final turbidity. The kinetics of fibrinopeptides release revealed a decreased amount of the released fibrinopeptide A. SEM of the patient's fibrin clot was found to be abnormal.Results indicate that the 3 probands with dysfibrinogenemia were caused by mutations of Aα chain Arg16His. Mutation of this fibrinogen induced dysfunction of plasma fibrinogen.

  10. Three cases of congenital dysfibrinogenemia in unrelated Chinese families: heterozygous missense mutation in fibrinogen alpha chain Argl6His

    PubMed Central

    Luo, Meiling; Deng, Donghong; Xiang, Liqun; Cheng, Peng; Liao, Lin; Deng, Xuelian; Yan, Jie; Lin, Faquan

    2016-01-01

    Abstract Congenital dysfibrinogenemia (CD) is a qualitative fibrinogen disorder caused by an abnormal fibrinogen molecule structure, leading to dysfunctional blood coagulation. This study describes 3 cases of dysfibrinogenemia identified in the unrelated Chinese pedigrees. Routine coagulation screening tests were performed on the probands and their families. The antigens and functionality of fibrinogen was measured using an immunoturbidimetry assay and the Clauss method, respectively. To identify the genetic mutation responsible for these dysfibrinogens, genomic DNA extracted from the blood was analyzed using PCR amplification and direct sequencing. The presence of the mutant chains was determined using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectroscopy. Purified plasma fibrinogen of 3 probands was analyzed using SDS–PAGE, fibrinogen clottability, fibrin polymerization, fibrinopeptide release, and scanning electron microscopy (SEM). The 3 probands had a long thrombin time. Levels of functional fibrinogen were found to be very low, while the fibrinogen antigen was within the normal range. DNA sequencing revealed a heterozygous Arg16His substitution in the fibrinogen Aα chain (FGA). The mutant chains were found to be expressed using MALDI-TOF mass spectroscopy. SDS–PAGE did not reveal any difference in the molecular weights of 3 polypeptide chains between normal and abnormal fibrinogens. Fibrinogen clottability showed a slower fibrin clot formation than the healthy control. Fibrin polymerization, after addition of thrombin, showed a prolonged lag phase and decreased final turbidity. The kinetics of fibrinopeptides release revealed a decreased amount of the released fibrinopeptide A. SEM of the patient's fibrin clot was found to be abnormal. Results indicate that the 3 probands with dysfibrinogenemia were caused by mutations of Aα chain Arg16His. Mutation of this fibrinogen induced dysfunction of plasma fibrinogen. PMID

  11. In vivo investigation of homocysteine metabolism to polyamines by high-resolution accurate mass spectrometry and stable isotope labeling.

    PubMed

    Ruseva, Silviya; Lozanov, Valentin; Markova, Petia; Girchev, Radoslav; Mitev, Vanio

    2014-07-15

    Polyamines are essential polycations, playing important roles in mammalian physiology. Theoretically, the involvement of homocysteine in polyamine synthesis via S-adenosylmethionine is possible; however, to our knowledge, it has not been established experimentally. Here, we propose an original approach for investigation of homocysteine metabolites in an animal model. The method is based on the combination of isotope-labeled homocysteine supplementation and high-resolution accurate mass spectrometry analysis. Structural identity of the isotope-labeled metabolites was confirmed by accurate mass measurements of molecular and fragment ions and comparison of the retention times and tandem mass spectrometry fragmentation patterns. Isotope-labeled methionine, spermidine, and spermine were detected in all investigated plasma and tissue samples. The induction of moderate hyperhomocysteinemia leads to an alteration in polyamine levels in a different manner. The involvement of homocysteine in polyamine synthesis and modulation of polyamine levels could contribute to a better understanding of the mechanisms connected with homocysteine toxicity.

  12. Congenital hypofibrinogenemia associated with novel homozygous fibrinogen Aα and heterozygous Bβ chain mutations.

    PubMed

    Castaman, Giancarlo; Rimoldi, Valeria; Giacomelli, Sofia H; Duga, Stefano

    2015-07-01

    We report the molecular characterisation of two novel cases of inherited hypofibrinogenemia. After sequencing all coding regions and intron-exon boundaries of the three fibrinogen genes (FGA, FGB, and FGG), two different novel mutations were found, one homozygous and one heterozygous. The first patient, with a mild bleeding history and mild discrepancy between functional and immunological fibrinogen, showed a novel homozygous nonsense mutation in exon 5 of FGA (p.Trp373*, p.Trp354* according to the mature protein) caused by a G>A transition at nucleotide position 1,119. The resulting truncation in the Aα chain is likely to reduce the efficiency of fibrinogen assembly and secretion. The second patient, referred after ischemic stroke (functional fibrinogen 77mg/dL), had a novel heterozygous splicing mutation in intron 5 of FGB (IVS5+2T>A or c.832+2T>A), which we demonstrated to cause either exon 5 skipping or the inclusion of 75bp belonging to intron 5. Neither splicing defect alters the reading frame: one results in a 38-residue deletion and the other in a 25-residue insertion in the D domain of fibrinogen Bβ chain. This report confirms that genetically determined partial deficiencies of fibrinogen with levels greater than 50mg/dL are rarely associated with significant bleeding symptoms and that homozygous null mutations removing a significant portion of the Aα chain may be associated with mild fibrinogen deficiency.

  13. Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency.

    PubMed

    Asselta, Rosanna; Platè, Manuela; Robusto, Michela; Borhany, Munira; Guella, Ilaria; Soldà, Giulia; Afrasiabi, Abdolreza; Menegatti, Marzia; Shamsi, Tahir; Peyvandi, Flora; Duga, Stefano

    2015-03-01

    Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aα, Bβ, and γ, encoded by the FGA, FGB, and FGG gene, respectively). Congenital afibrinogenaemia and hypofibrinogenaemia are rare bleeding disorders characterised by abnormally low levels of functional and immunoreactive fibrinogen in plasma, associated with haemorrhagic manifestations of variable severity. While afibrinogenaemia is caused by mutations in the homozygous or compound heterozygous state in one of the three fibrinogen genes, hypofibrinogenaemia is generally due to heterozygous mutations, and is usually characterised by a milder phenotype. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations often affecting fibrinogen assembly and/or secretion. Here we report the clinical and molecular characterisation of 13 unrelated afibrinogenaemic and eight hypofibrinogenaemic patients, leading to the identification of 17 different mutations (10 hitherto unknown). All the newly-identified missense and splicing mutations werein vitro expressed to verify their pathogenic role. Our data increase the number of mutations causing quantitative fibrinogen deficiencies by about 7 %. The high number of private mutations identified in the analysed probands indicates that the full mutational screening of the three fibrinogen genes is still required for molecular diagnosis.

  14. A method to measure thrombin activity in a mixture of fibrinogen and thrombin powders

    PubMed Central

    DeAnglis, Ashley P.; Nur, Israel; Gorman, Anne J.; Meidler, Roberto

    2017-01-01

    Thrombin and fibrinogen powders are the active components of advanced surgical hemostasis products including the EVARREST Fibrin Sealant Patch. Measuring the enzymatic activity of thrombin in the presence of fibrinogen is challenging, as hydration of the powders in a neutral aqueous environment will cause the enzyme to rapidly react with the fibrinogen to form a fibrin clot, which in turn binds and entraps the enzyme thus preventing subsequent measurement of thrombin activity. A novel approach has been developed to overcome this challenge. After isolation of the mixture of powders, an alkaline carbonate solution is used to solubilize the proteins, while reversibly inhibiting the activity of thrombin and preventing clot formation. Once the powders have been fully solubilized, thrombin activity can be restored by neutralization in a buffered fibrinogen solution resulting in fibrin clot formulation. The rate of clot formation can be quantified in a coagulometer to determine the thrombin activity of the original powder. Samples coated with powders containing fibrinogen and varying amounts of thrombin were tested using the method described herein. The results demonstrated that the method could consistently measure the activity of (alpha) thrombin in the presence of fibrinogen over a broad range of thrombin activity levels. The test was successfully validated according to International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines and thus is suitable for use as part of a commercial manufacturing process. A method has been developed that enables thrombin activity to be measured in a mixture of fibrinogen and thrombin powders. PMID:26991860

  15. Implication of homocysteine in diabetes and impact of folate and vitamin B12 in diabetic population.

    PubMed

    Mursleen, M Tahir; Riaz, Samreen

    2016-12-13

    Diabetes mellitus is an acutely debilitating ailment affecting a large population of the world. At present, over 415 million people around the world including 7 million people in Pakistan suffering from diabetes. Homocysteine is an amino acid that is inversely related to vitamin B12 and folate, and raised level of homocysteine is implicated in many adverse health conditions. In this study, the potential role of homocysteine in diabetes and the epidemiology of hyperhomocysteinaemia, and vitamin B12 and folate deficiency is reviewed along with the impact of folate and vitamin B12 in regulation of homocysteine level. Deficiency of vitamin B12 and folate is rare in developed countries and the countries which adopted fortification programs, but deficiency of these vitamins is found to be highly prevalent in developing world, particularly in Pakistan. Several studies have found an association of high homocysteine levels and diabetes, but a few studies found contrary results. Hence, further epidemiological studies are recommended for homocysteine involvement in diabetes and vitamin B12 and folate deficiency, so that an urgent action can be taken to control the hyperhomocysteinaemia and consequently the ever increasing burden of disease and specifically diabetes.

  16. NADPH oxidase 4 regulates homocysteine metabolism and protects against acetaminophen-induced liver damage in mice.

    PubMed

    Murray, Thomas V A; Dong, Xuebin; Sawyer, Greta J; Caldwell, Anna; Halket, John; Sherwood, Roy; Quaglia, Alberto; Dew, Tracy; Anilkumar, Narayana; Burr, Simon; Mistry, Rajesh K; Martin, Daniel; Schröder, Katrin; Brandes, Ralf P; Hughes, Robin D; Shah, Ajay M; Brewer, Alison C

    2015-12-01

    Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic detoxification of xenobiotics and other environmental toxins. Hepatic glutathione is also a major systemic store for other organs and thus impacts on pathologies such as Alzheimer's disease, Sickle Cell Anaemia and chronic diseases associated with aging. Glutathione levels are determined in part by the availability of cysteine, generated from homocysteine through the transsulfuration pathway. The partitioning of homocysteine between remethylation and transsulfuration pathways is known to be subject to redox-dependent regulation, but the underlying mechanisms are not known. An association between plasma Hcy and a single nucleotide polymorphism within the NADPH oxidase 4 locus led us to investigate the involvement of this reactive oxygen species- generating enzyme in homocysteine metabolism. Here we demonstrate that NADPH oxidase 4 ablation in mice results in increased flux of homocysteine through the betaine-dependent remethylation pathway to methionine, catalysed by betaine-homocysteine-methyltransferase within the liver. As a consequence NADPH oxidase 4-null mice display significantly lowered plasma homocysteine and the flux of homocysteine through the transsulfuration pathway is reduced, resulting in lower hepatic cysteine and glutathione levels. Mice deficient in NADPH oxidase 4 had markedly increased susceptibility to acetaminophen-induced hepatic injury which could be corrected by administration of N-acetyl cysteine. We thus conclude that under physiological conditions, NADPH oxidase 4-derived reactive oxygen species is a regulator of the partitioning of the metabolic flux of homocysteine, which impacts upon hepatic cysteine and glutathione levels and thereby upon defence against environmental toxins.

  17. 5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle-southern Italian adults.

    PubMed

    Zappacosta, Bruno; Graziano, Mirella; Persichilli, Silvia; Di Castelnuovo, Augusto; Mastroiacovo, Pierpaolo; Iacoviello, Licia

    2014-01-01

    Two genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) can influence the plasma homocysteine (Hcy) levels, especially in the presence of an inadequate folate status. The aim of this study was to evaluate the frequencies of C677T and of A1298C MTHFR polymorphisms and their correlation with Hcy and serum folate concentrations in a population of blood donors living in a region of middle-southern Italy (the Molise Region). One hundred ninety seven blood donors were studied for total plasma Hcy, serum folate and C677T and A1298C MTHFR genotypes. The frequency of C677T genotypes was 20.8% (CC), 49.8% (CT) and 29.4% (TT); for the A1298C genotypes: 48.7% (AA), 43.7% (AC) and 7.6% (CC). Hcy and serum folate concentrations were significantly different among genotypes of the C677T polymorphism (CC versus CT versus TT: <0.0001 both for Hcy and folate), with Hcy values increasing, and serum folate decreasing, from CC to TT subjects. Regarding to A1298C polymorphism, the difference among genotypes (AA versus AC versus CC; p: 0.026 for Hcy and 0.014 for serum folate), showed an opposite trend for both parameters, with Hcy higher in the wild-type and lower in the homozygotes and serum folate higher in CC than in AA subjects. In conclusion, we found a high frequency of MTHFR allele associated with high level of Hcy and low levels of folate in an Italian southern population.

  18. The model homologue of the partially defective human 5,10-methylenetetrahydrofolate reductase, considered as a risk factor for stroke due to increased homocysteine level, can be protected and reactivated by heat shock proteins.

    PubMed

    Grabowski, Michał; Banecki, Bogdan; Kadziński, Leszek; Jakóbkiewicz-Banecka, Joanna; Gabig-Cimińska, Magdalena; Węgrzyn, Alicja; Węgrzyn, Grzegorz; Banecka-Majkutewicz, Zyta

    2016-10-01

    The A222 V substitution in the human MTHFR gene product (5,10-methylenetetrahydrofolate reductase) is responsible for a decreased activity of this enzyme. This may cause an increased homocysteine level, considered as a risk factor for arteriosclerosis and stroke. The bacterial homologue of the human enzyme, MetF, has been found to be a useful model in genetic and biochemical studies. The similarity of Escherichia coli MetF and human MTHFR proteins is so high that particular mutations in the corresponding human gene can be reflected by the bacterial mutants. For example, the A222 V substitution in MTHFR (caused by the C667T substitution in the MTHFR gene) can be ascribed to the A117 V substitution in MetF. Here, it is reported that a temperature-sensitive MetF117 (A117 V) protein can be partially protected from a thermal inactivation by the heat shock proteins from the Hsp70/100 systems. Moreover, activity of the thermally denatured enzyme can be partially restored by the same heat shock proteins. High temperature protein G (HtpG) had no effect on MetF117 activity in both experimental systems. The presented results indicate that functions of heat shock proteins may be required for maintenance of the MetF117 function. This may have implications for the mechanisms of arteriosclerosis and stroke, especially in the light of previous findings that the A222 V MTHFR polymorphism may be a risk factor for stroke, as well as recently published results which demonstrated the increased levels of antibodies against heat shock proteins in stroke patients.

  19. [A correlation study on homocysteine metabolism in pregnant women and neural tube defects in urban and rural areas].

    PubMed

    Zhan, S; Hu, Y; Li, L

    1997-07-01

    Serum levels of homocysteine, folic acid and vitamin B12 in pregnant women in urban and rural areas were compared to study the relationship between homocysteine metabolism and neural tube defects. Four hundred and eleven serum specimens were sampled randomly from a serum bank for women with early pregnancy in Beijing area, 195 from urban and 216 from rural. Their levels of homocysteine were determined by high performance liquid chromatography combined with electrochemical methods, and those of folic acid and vitamin B12 by radioimmunoassay. Results showed that level of homocysteine was significantly higher in rural pregnant women than that in urban, with 9.31 mumol/L and 5.73 mumol/L, respectively, level of vitamin B12 was lower in rural than that in urban women, with 210.09 pmol/L and 233.35 pmol/L, respectively, and level of folic acid was higher in rural than that in urban women, but no significant difference in deficiency of folic acid between rural and urban was found. The average ratio of folic acid to homocysteine and that of vitamin B12 to homocysteine were higher in rural than those in urban women. It suggests that abnormal metabolism of homocysteine usually correlates with high incidence of neural tube defects in rural area.

  20. Analysis of biological properties of selected elements of haemostasis after treatment with the oxidized form of homocysteine in vitro.

    PubMed

    Malinowska, Joanna; Olas, Beata

    2011-01-01

    The elevated level of homocysteine (Hcys; hyperhomocysteinemia, in relation to the total plasma Hcys concentration, >15 µM) is associated with different diseases in human, including cardiovascular diseases. In plasma, Hcys occurs in various forms (the reduced Hcys, the oxidized Hcys, homocysteine thiolactone (HTL) and a component of proteins as a result of N- or S-homocysteinylation). The mechanisms by which hyperhomocysteinemia contributes to changes of haemostasis are complex and unclear. The role of different forms of Hcys, which may be involved in the modulation of haemostatic process during hyperhomocysteinemia is also not yet well-known. Our previous works have shown that both Hcys in the reduced form and the most reactive form of Hcys-its thiolactone may modify fibrinolysis, coagulation process and biological activity of blood platelets. The mechanism by which the oxidized Hcys exerts the prothrombotic effect and influences on blood platelets or plasma remains unclear. The aim of our study in vitro was to establish and compare the influence of the oxidized Hcys (at final doses of 0.01-1 mM), the reduced Hcys (at final doses of 0.01-1 mM) and HTL (at final doses of 0.1-1 µM) on selected haemostatic properties of blood platelets (platelet aggregation and platelet microparticle formation measured by flow cytometry) and plasma (fibrin polymerization and lysis). Here, our results indicate that the oxidized Hcys, like the reduced Hcys or HTL-augmented blood platelet aggregation, stimulated polymerization of fibrinogen and reduced the fibrin lysis in plasma. But, we suggest that the most reactive form of Hcys may be HTL (at lower concentrations than Hcys) during hyperhomocysteinemia-induced cardiovascular diseases.

  1. High homocysteine induces betaine depletion

    PubMed Central

    Imbard, Apolline; Benoist, Jean-François; Esse, Ruben; Gupta, Sapna; Lebon, Sophie; de Vriese, An S; de Baulny, Helene Ogier; Kruger, Warren; Schiff, Manuel; Blom, Henk J.

    2015-01-01

    Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI—LC–MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte. PMID:26182429

  2. High homocysteine induces betaine depletion.

    PubMed

    Imbard, Apolline; Benoist, Jean-François; Esse, Ruben; Gupta, Sapna; Lebon, Sophie; de Vriese, An S; de Baulny, Helene Ogier; Kruger, Warren; Schiff, Manuel; Blom, Henk J

    2015-04-28

    Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI-LC-MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.

  3. Surface plasmon resonance analysis of immobilized fibrinogen and fibrin and their interaction with thrombin and fibrinogen

    NASA Astrophysics Data System (ADS)

    Dyr, Jan E.; Jirouskova, Marketa; Rysava, Jitka; Tichy, Ivo; Tobiska, Petr; Slavik, Radan; Homola, Jiri; Suttnar, Jiri

    1999-01-01

    The exploitation of surface plasmon resonance optical sensor for the study of the interaction of immobilized fibrinogen and fibrin monomer with soluble fibrinogen and thrombin is reported. Soluble fibrinogen was mostly reversible, the bound thrombin could be inhibited by milimolar concentration of phenylmethylsulphonyl fluoride (PMSF). At lease three sets of different thrombin binding sites were found. There was a residual fraction of thrombin bound to washed fibrin (ogin) (to about a five to ten percent of fibron monomer units) suggesting that a known naturally occurring fibrinogen variant differing in the gamma chain was the target. Surface bound fibrinogen was converted by thrombin to fibrin monomer that interacted with fibrinogen in solution. At low fibrin monomer surface density the second layer was formed that contained about the same amount of protein as the first layer, at higher fibrin monomer concentration less than one molecule of fibrinogen per molecule of fibrin monomer was captured. Starting with surface-bound fibrinogen and alternating addition of thrombin and fibrinogen a fibrin network of predetermined composition, size, and arrangement could be formed.

  4. Quantitative assessment of fibrinogen cross-linking by epsilon aminocaproic acid in patients with end-stage liver disease.

    PubMed

    Quach, Thien; Tippens, Melissa; Szlam, Fania; Van Dyke, Rebecca; Levy, Jerrold H; Csete, Marie

    2004-01-01

    Analysis of the effectiveness of antifibrinolytic therapy for liver transplant recipients is hampered by lack of quantitative assays for assessing drug effects. We adapted chemical engineering tools used in polymerization studies to quantify fibrinogen cross-linking by plasma from liver transplant patients obtained before and after epsilon aminocaproic acid (EACA) therapy. A target fluorescein isothiocyanate-fibrinogen (FITC-fibrinogen) molecule was constructed; it fluoresces in a quantifiable pattern when in solution, and undergoes cross-linking in the presence of plasmin inhibitors. Cross-linking quenches the fluorescent signal, and the quenching is a quantifiable endpoint. Thus fluorescence from this reporter molecule can be used to assess functional improvement in fibrinogen cross-linking as a result of antifibrinolytic therapies, and it is sensitive to picomolar amounts of plasmin inhibitors and activators. Cross-linking of FITC-fibrinogen by patient plasma, before and after EACA therapy, was assessed using fluorescence spectrometry. Fluorescence patterns from FITC-fibrinogen indicated no significant cross-linking of the target fibrinogen as a consequence of EACA in posttreatment plasma. When the fibrinogen-FITC target was assayed without plasma in the presence of EACA at concentrations that bracket therapeutic levels (100 and 400 microg/ml), significant fluorescence quenching (target FITC-fibrinogen cross-linking) was achieved. These results suggest that fibrinogen-FITC fluorescence is sensitive enough to detect EACA activity in clinically relevant ranges, but that EACA given in usual doses is insufficient to promote fibrinogen cross-linking in patients with end-stage liver disease.

  5. Lipoprotein(a), homocysteine, and retinal arteriosclerosis

    PubMed Central

    Javadzadeh, Alireza; Argani, Hassan; Nezami, Nariman; Rashtchizadeh, Nadereh; Rafeey, Mandana; Rohbaninoubar, Mohammad; Rahimi-Ardabili, Babak

    2008-01-01

    Purpose Elevated levels of lipoprotein(a) [Lp(a)] and homocysteine (Hcy) have been implicated as risk factors for vascular diseases. The study was performed to explore the possible relationship between retinal arteriosclerosis and serum Lp(a) and Hcy levels. Methods Study subjects consisted of 80 nonsmoking male patients with retinal arteriosclerosis and 54 healthy nonsmoker males as controls. Retinal arteriosclerosis was graded according to the Scheie classification. Serum levels of lipids, lipoproteins, Lp(a), and Hcy were measured by standard methods. Results The serum level of Hcy was higher in patients (24.2±8.1 μmol/l) than controls (10.5±4.1 μmol/l); p<0.01. Serum levels of Lp(a) in patients (47.9±33.1 mg/dl) was also higher than controls (11.7±7.6 mg/dl); p<0.01. There was a significant direct linear correlation between the degree of retinal arteriosclerosis and Lp(a) level (r=0.61, p<0.01), the degree of retinal arteriosclerosis and Hcy level (r=0.72, p<0.01), and also between Lp(a) and Hcy levels (r=0.67, p<0.01). Conclusions The association between retinal arteriosclerosis and serum Lp(a) and Hcy levels suggests that Lp(a) as well as Hcy could play a role in the development of retinal arteriosclerosis. PMID:18806883

  6. [Homocystein--an independent risk factor for cardiovascular and thrombotic diseases].

    PubMed

    Fowler, B

    2005-09-01

    Over the last 20 years homocysteine has taken on increasing importance as an independent, potentially modifiable risk factor for various forms of vascular disease including peripheral and cerebral vascular disease, coronary heart disease and thrombosis. This association has been ascertained in many retrospective and prospective studies but the strength of risk is not yet firmly established although it is clearly dependent on several modifying factors such as other risk factors, nutrition and genetic polymorphisms. Generally it is estimated that hyperhomocysteinaemia is responsible for about 10% of all risks. Homocysteine is formed from the dietary amino acid methionine and plays a pivotal role in folate metabolism and methyl group transfer. Its concentrations in tissues and plasma are influenced by many genetic and environmental factors, especially vitamins such as folate, B12 and B6 as well as certain medications and even life style factors. Nowadays the measurement of plasma homocysteine is freely available although care has to be taken in sample handling and interpretation of results. Final proof that homocysteine is a causal agent and not just a marker for cardiovascular disease and that reduction of plasma homocysteine by vitamin treatment reduces risk of cardiovascular disease is still awaited. Therefore at the present time neither wide-scale screening for homocysteine levels nor general prophylaxis with high dose vitamins is justified. However most experts recommend homocysteine determination in individuals with existing or high risk for arterial or venous blood vessel disease and their relatives. Elevated homocysteine can be lowered in such cases with a combination of folic acid, vitamin B12 vitamin B6. The results of ongoing trials on the impact of such treatment on risk of vascular disease are awaited with great interest.

  7. [Interaction of fibrinogen with magnetite nanoparticles].

    PubMed

    Bychkova, A V; Sorokina, O N; Kovarskiĭ, A L; Shapiro, A B; Leonova, V B; Rozenfel'd, M A

    2010-01-01

    The interaction between fibrinogen and magnetite nanoparticles in solution has been studied by the methods of spin labeling, ferromagnetic resonance, dynamic and Rayleigh light scattering. It was shown that protein molecules adsorb on the surface of nanoparticles to form multilayer protein covers. The number of molecules adsorbed on one nanoparticle amounts to approximately 65 and the thickness of the adsorption layer amounts to approximately 27 nm. Separate nanoparticles with fibrinogen covers (clusters) form aggregates due to interactions of the end D-domains of fibrinogen. Under the influence of direct magnetic field, nanoparticles with adsorbed proteins form linear aggregates parallel to force lines. It was shown that the rate of protein coagulation during the formation of fibrin gel under the action of thrombin on fibrinogen decreases approximately 2 times in the presence of magnetite nanoparticles, and the magnitude of the average fiber mass-length ratio grows.

  8. Interactions of Bacteroides gingivalis with fibrinogen.

    PubMed Central

    Lantz, M S; Rowland, R W; Switalski, L M; Höök, M

    1986-01-01

    Results of previous studies from our laboratory have shown that a strain of Bacteroides intermedius isolated originally from a patient with acute necrotizing ulcerative gingivitis binds and degrades human fibrinogen (M.S. Lantz, L.M. Switalski, K.S. Kornman, and M. Hook, J. Bacteriol. 163:623-628, 1985). We report that strains of Bacteroides gingivalis, an organism implicated in the etiology of several forms of periodontitis, also bind and degrade fibrinogen. The binding is rapid, reversible, saturable, and specific. The number of fibrinogen-binding sites per cell varies from 500 to 1,500 in different batches of bacteria, and the dissociation constant for the complex is on the order of 10(-8) M. B. gingivalis possesses cell-associated fibrinogenolytic activity that is activated by dithiothreitol and blocked by thiol protease inhibitors. Interaction with fibrinogen may mediate colonization and establishment of these organisms in the periodontal microbiota. Images PMID:3096886

  9. Plasma circulating fibrinogen stability and moderate beer consumption.

    PubMed

    Gorinstein, Shela; Caspi, Abraham; Zemser, Marina; Libman, Imanuel; Goshev, Ivan; Trakhtenberg, Simon

    2003-12-01

    MODERATE BEER CONSUMPTION (MBC) IS CARDIOPROTECTIVE: it positively influences plasma lipid levels and plasma antioxidant activity in beer-consuming individuals. The connection between MBC and blood coagulation is not clearly defined. Forty-two volunteers were equally divided into experimental (EG) and control (CG) groups following coronary bypass surgery. For 30 consecutive days, only patients of the EG consumed 330 mL of beer per day (about 20 g of alcohol). A comprehensive clinical investigation of 42 patients was done. Blood samples were collected before and after the investigation for a wide range of laboratory tests. The plasma fibrinogen was denatured with 8 M urea and intrinsic fluorescence (IF), hydrophobicity and differential scanning calorimetry (DSC) were used to reveal possible qualitative changes. After 30 days of moderate beer consumption, positive changes in the plasma lipid levels, plasma anticoagulant and plasma antioxidant activities were registered in patients of the EG group. In 17 out of 21 patients of the same group, differences in plasma circulating fibrinogen's (PCF), secondary and tertiary structures were found. The stability of fibrinogen, expressed in thermodynamic parameters, has shown that the loosening of the structure takes place under ethanol and urea denaturation. Also fluorescence stability of PCF was decreased. No changes in the lipid levels, anticoagulant and antioxidant activity or changes in PCF were detected in patients of CG. In conclusion, for the first time after a short term of moderate beer consumption some qualitative changes in the plasma circulating fibrinogen were detected: differences in the emission peak response, fluorescence intensity and all thermodynamic data. Together, with the decrease in the PCF concentration it may lead to an elevation of the blood anticoagulant activity.

  10. Insulin resistance is not related to plasma homocysteine concentration in healthy premenapausal women.

    PubMed

    Tanrikulu-Kiliç, F; Bekpinar, S; Unlüçerçi, Y; Orhan, Y

    2006-01-01

    This study was performed to test whether plasma homocysteine concentrations are related to insulin resistance in healthy premenopausal women. For this purpose, the relationship between insulin resistance (as assessed by HOMA index) and fasting plasma homocysteine level was determined in 83 healthy volunteers. The results indicated that homocysteine concentrations did not vary as a function of HOMA index (r = -0.147). Plasma homocysteine concentrations also did not vary as a function of other parameters of insulin resistance such as HDL-cholesterol and triglycerides, which they correlated inversely with body mass index (BMI). Furthermore, when individuals were classified according to quartiles of insulin resistance (HOMA index), plasma homocysteine concentrations from the lowest to the highest quartiles were not significantly different. On the other hand, the HOMA index correlated significantly with triglyceride concentrations (r = 0.377, p< 0.001), HDL-cholesterol (r = -0.310, p< 0.01) and BMI (r = 0.468, p< 0.001). These results suggest that plasma homocysteine concentrations are not related to insulin resistance and/or metabolic abnormalities associated with it in premenopausal women.

  11. The role of fibrinogen: a new paradigm in the treatment of coagulopathic bleeding.

    PubMed

    Sørensen, Benny; Tang, Mariann; Larsen, Ole H; Laursen, Peter N; Fenger-Eriksen, Christian; Rea, Catherine J

    2011-01-01

    Fibrinogen is involved in both primary and secondary hemostasis, playing an important role in platelet aggregation and the establishment of a fibrin network. Recent evidence suggests that very high levels of fibrinogen act as antithrombin and can reduce endogenous thrombin potential and compromise clot stability, particularly following a low tissue factor stimulus. Several laboratory methods for measuring plasma fibrinogen concentrations are available, but results vary depending on the type of method and the use of artificial colloid plasma expanders. Adopting only the Clauss method can provide erroneously high levels when used in patients who have received colloid plasma expanders. This may contribute to a hazardous delay or complete lack of treatment. Multiple in vitro experiments, animal studies, and proof-of-principle randomized, clinical studies have recently suggested that hemostatic intervention with a fibrinogen concentrate may be efficient and safe in controling perioperative bleeding. In particular, fibrinogen concentrate has a key role in improving clotting function and reducing blood loss in settings such as trauma and cardiothoracic surgery. However, prospective studies are needed to determine the clinical efficacy and safety of fibrinogen concentrate when used as a hemostatic intervention for patients with massive bleeding due to trauma or surgery.

  12. Fibrinogen and factor VIIag in healthy adolescents: the Floren-teen (Florence teenager) Study.

    PubMed

    Prisco, D; Fedi, S; Brunelli, T; Cellai, A P; Hagi, M I; Gianni, R; Santoro, E; Cappelletti, C; Pepe, G; Gensini, G F; Abbate, R

    1996-05-01

    At least five studies based on more than twenty thousand healthy subjects indicated that fibrinogen is an independent risk factor for cardiovascular events; less clear-cut is the relation between factor VII and risk for arterial thrombotic disorders, which was demonstrated in two of the three studies investigating this association. However, no study has investigated the behaviour of fibrinogen and factor VII in an adolescent population. In a study of Preventive Medicine and Education Program, fibrinogen (clotting method) and factor VIIag (ELISA), in addition to other metabolic parameters, life-style and familial history, were investigated in 451 students (313 females and 138 males, age 15-17 years) from two high schools of Florence. Fibrinogen levels were significantly higher in women than in men, whereas factor VIIag levels did not significantly differ. Both fibrinogen and factor VIIag significantly correlated with total cholesterol (p < 0.05) while only fibrinogen correlated with body mass index (p < 0.01). Factor VIIag was significantly correlated with systolic blood pressure (p < 0.001). This study provides information on coagulation risk factors in a population of adolescents which may be of importance in planning coronary heart disease prevention programs.

  13. Homocysteine, Cortisol, Diabetes Mellitus, and Psychopathology

    PubMed Central

    Kontoangelos, K.; Papageorgiou, C. C.; Raptis, A. E.; Tsiotra, P.; Lambadiari, V.; Papadimitriou, G. N.; Rabavilas, A. D.; Dimitriadis, G.; Raptis, S. A.

    2015-01-01

    Objective. This study investigates the association of homocysteine and cortisol with psychological factors in type 2 diabetic patients. Method. Homocysteine, cortisol, and psychological variables were analyzed from 131 diabetic patients. Psychological factors were assessed with the Eysenck Personality Questionnaire (EPQ), Hostility and Direction of Hostility Questionnaire (HDHQ), the Symptom Checklist 90-R (SCL 90-R), the Zung Self-Rating Depression Scale (ZDRS), and the Maudsley O-C Inventory Questionnaire (MOCI). Blood samples were taken by measuring homocysteine and cortisol in both subgroups during the initial phase of the study (T0). One year later (T1), the uncontrolled diabetic patients were reevaluated with the use of the same psychometric instruments and with an identical blood analysis. Results. The relation of psychoticism and homocysteine is positive among controlled diabetic patients (P value = 0.006 < 0.05) and negative among uncontrolled ones (P value = 0.137). Higher values of cortisol correspond to lower scores on extraversion subscale (rp = −0.223, P value = 0.010). Controlled diabetic patients showed a statistically significant negative relationship between homocysteine and the act-out hostility subscale (rsp = −0.247, P = 0.023). There is a statistically significant relationship between homocysteine and somatization (rsp = −0.220, P = 0.043). Conclusions. These findings support the notion that homocysteine and cortisol are related to trait and state psychological factors in patients with diabetes mellitus type 2. PMID:25722989

  14. Vitamin Status as a Determinant of Serum Homocysteine Concentration in Type 2 Diabetic Retinopathy

    PubMed Central

    Raptis, Athanasios; Apergis, George; Dimitriadis, George; Vergados, Ioannis; Theodossiadis, Panagiotis

    2014-01-01

    We investigated the association of serum homocysteine levels and vitamin status with type 2 diabetic retinopathy. This study included 65 patients with and 75 patients without diabetic retinopathy. Patients with diabetic retinopathy had significantly higher serum homocysteine levels (P < 0.001), higher prevalence of hyperhomocysteinemia (P < 0.001), lower serum folic acid (P < 0.001), and vitamin B12 (P = 0.014) levels than those without diabetic retinopathy. Regression analysis revealed that homocysteine was an independent risk factor for diabetic retinopathy and there was a threshold in its serum level (13.7 μmol/L), above which the risk of diabetic retinopathy greatly increases (OR = 1.66, P = 0.001). Folic acid was associated with decreased odds for diabetic retinopathy (OR = 0.73, P < 0.001). There was a threshold in serum vitamin B12 level (248.4 pg/mL), below which serum homocysteine concentration significantly increases with decreasing serum vitamin B12 (P = 0.003). Our findings suggest that hyperhomocysteinemia is an independent risk factor for the development and progression of diabetic retinopathy. Decreased serum levels of folic acid and vitamin B12, through raising serum homocysteine concentrations, may also affect the diabetic retinopathy risk. PMID:25006590

  15. Effect of Sclerovit on endothelial dysfunction, hemorheological parameters, platelet aggregation, plasma concentration of homocysteine and progression of atherosclerosis in patients with vascular diseases.

    PubMed

    Horvath, Beata; Szapary, Laszlo; Debreceni, Laszlo; Feher, Gergely; Kenyeres, Peter; Fulop, Adrienn; Battyani, Istvan; Toth, Kalman

    2009-01-01

    In our prospective study the effect of Sclerovit (0.8 mg folic acid, 20 mug vitamin B12,5 mg vitamin B6,100 mg vitamin E) on inflammatory markers, hemorheological parameters, platelet aggregation, von Willebrand factor activity as a marker of endothelium dysfunction, plasma lipids, plasma levels of folic acid, vitamin B12 and homocysteine (hcy), flow mediated vasodilatation (FMD) and thickness of carotis intima-media after 1 and 6 months of treatment in patients with vascular diseases (10 patients took 1 capsule, 10 patients 2 capsules of Sclerovit and 10 patients placebo) was determined.Plasma level of vitamin B12, folic acid and elongation index of red blood cells (RBC) increased significantly (p<0.05-0.001), hcy and triglyceride concentrations decreased significantly (p<0.05-0.001) in patients taking Sclerovit. HDL-cholesterol, RBC count, hematocrit, plasma and whole blood viscosity increased significantly (p<0.05-0.001) both in patients taking placebo or vitamins. Fibrinogen and CRP showed a significant (p<0.05-0.01) increase in patients on placebo, but did not change in patients on Sclerovit therapy. FMD showed a significant (p<0.05) amelioration in patients on 1 capsule of Sclerovit.Beside the favorable effects of Sclerovit on some of the measured parameters, the observed deterioration in hemorheological parameters can correlate with the contradictory results of large prospective studies with vitamins.

  16. Testing for homocysteine in clinical practice.

    PubMed

    Nichols, John

    2017-03-01

    The theory that raised blood homocysteine is a major factor in the development of cardiovascular disease was initially rejected by the medical establishment. Trials of a treatment to lower homocysteine in moderately advanced disease have failed to show benefits (except in those not treated with anti-platelet drug), but there is mounting evidence for a role in treatment of very early disease and as a preventive strategy. Recent evidence has shown that lowering of high blood homocysteine significantly slows cognitive decline and the brain shrinkage associated with Alzheimer's disease. This is a test that should be done more frequently by National Health Service (NHS) general practitioners and private practitioners.

  17. [The role of post-translational modification of fibrinogen in the pathogenesis of thrombosis].

    PubMed

    Tadeusiewicz, Justyna; Nowak, Paweł

    2015-02-01

    Fibrinogen is a precursor of fibrin, which is the main component of the blood clot. The opposite of coagulation is fibrinolysis. The proper functioning of both systems allow to maintain a hemostasis. Increasing level of fibrinogen is an important risk factor for myocardial infarction or ischemic stroke. Reactive oxygen, nitrogen and chlorine species are created in inflammatory conditions, ischemia and tissues reperfusion. They can modify the fibrinogen molecule. The most important changes are associated with nitration and chlorination of tyrosine residues, oxidation of methionine, histidine and tryptophan residues, as well as formation dityrosine and carbonyl groups. Moreover, structure of fibrinogen is modified by glycation and homocysteinylation in hyperglycemia and hyperhomocysteinemia conditions. Non-enzymatic posttranslational modifications of fibrinogen contribute to formation of thrombogenic fibrin structure. The degree of fibrinogen modification is responsible for fiber structure, packing and susceptibility of fibrin clots to fibrinolysis. Additionally, the viscoelastic properties are changed. Resistance to fibrinolysis is largely associated with the modification of lysine residues in the protein molecule. Each of these alternations may contribute to increased risk of arterial and venous thrombosis.

  18. Effect of Fibrinogen on Platelet Reactivity Measured by the VerifyNow P2Y12 Assay.

    PubMed

    Dobrovolsky, A B; Laguta, P S; Guskova, E V; Yarovaya, E B; Titaeva, E V; Storozhilova, A N; Panchenko, E P

    2016-05-01

    The VerifyNow assay is based upon the ability of activated platelets to cross-link beads coated with fibrinogen. However, fibrinogen is an abundant protein of blood, and therefore it may affect test results by competing with fibrinogen of beads for binding to platelets. To test this assumption, we assessed the influence of artificial alteration of fibrinogen level in blood samples obtained from donors (n = 9) and patients on clopidogrel therapy (n = 8) on the results of the VerifyNow P2Y12 assay. Fibrinogen level was altered by adding to blood samples 1/10 volume of fibrinogen solution (10.56 g/liter) or corresponding buffer. Relative to baseline, addition of buffer significantly increased platelet reactivity, whereas addition of fibrinogen decreased it. Analysis of the relationship between change in platelet reactivity values (dBase and dPRU) and change in fibrinogen concentration (dFg) revealed strong negative correlations: dBase = -63.3 × dFg - 27.1 (r = -0.924, p < 0.0005) and dPRU = -54.4 × dFg - 21.8 (r = -0.764, p < 0.0005). Thus, the results of our experiments suggest that: (i) blood fibrinogen strongly influences results of the VerifyNow P2Y12 assay, and (ii) correcting for fibrinogen effect may be needed to improve the accuracy of the test in the measuring of antiplatelet effect of clopidogrel therapy.

  19. Neprilysin Inhibits Coagulation through Proteolytic Inactivation of Fibrinogen

    PubMed Central

    Burrell, Matthew; Henderson, Simon J.; Ravnefjord, Anna; Schweikart, Fritz; Fowler, Susan B.; Witt, Susanne; Hansson, Kenny M.; Webster, Carl I.

    2016-01-01

    Neprilysin (NEP) is an endogenous protease that degrades a wide range of peptides including amyloid beta (Aβ), the main pathological component of Alzheimer’s disease (AD). We have engineered NEP as a potential therapeutic for AD but found in pre-clinical safety testing that this variant increased prothrombin time (PT) and activated partial thromboplastin time (APTT). The objective of the current study was to investigate the effect of wild type NEP and the engineered variant on coagulation and define the mechanism by which this effect is mediated. PT and APTT were measured in cynomolgus monkeys and rats dosed with a human serum albumin fusion with an engineered variant of NEP (HSA-NEPv) as well as in control plasma spiked with wild type or variant enzyme. The coagulation factor targeted by NEP was determined using in vitro prothrombinase, calibrated automated thrombogram (CAT) and fibrin formation assays as well as N-terminal sequencing of fibrinogen treated with the enzyme. We demonstrate that HSA-NEP wild type and HSA-NEPv unexpectedly impaired coagulation, increasing PT and APTT in plasma samples and abolishing fibrin formation from fibrinogen. This effect was mediated through cleavage of the N-termini of the Aα- and Bβ-chains of fibrinogen thereby significantly impairing initiation of fibrin formation by thrombin. Fibrinogen has therefore been identified for the first time as a substrate for NEP wild type suggesting that the enzyme may have a role in regulating fibrin formation. Reductions in NEP levels observed in AD and cerebral amyloid angiopathy may contribute to neurovascular degeneration observed in these conditions. PMID:27437944

  20. Fibrinogen geneva II: a new congenitally abnormal fibrinogen alpha chain (Gly17Asp) with a review of similar mutations resulting in abnormal knob A.

    PubMed

    Casini, Alessandro; De Maistre, Emmanuel; Casini-Stuppi, Virginie; Fontana, Pierre; Neerman-Arbez, Marguerite; de Moerloose, Philippe

    2014-04-01

    Congenital dysfibrinogenemias are characterized by biosynthesis of a structurally abnormal fibrinogen molecule that exhibits reduced functional levels compared with the level of fibrinogen antigen. To date a large number of mutations have been identified in patients with dysfibrinogenemia. Mutations occurring at the thrombin cleavage site (Arg16-Gly17 in the mature alpha-chain) at the amino-terminal end of the fibrinogen alpha chain are a common cause of the disease. These mutations causing abnormal fibrin polymerization are associated with different phenotypes. Here, we report the identification of a novel heterozygous missense mutation of Glycine 17 (Gly17Asp) in a female patient with mild bleeding manifestations, and compare it with other previously reported mutations also resulting in abnormal knob A.

  1. S100B and homocysteine in the acute alcohol withdrawal syndrome.

    PubMed

    Wedekind, Dirk; Neumann, Karolin; Falkai, Peter; Malchow, Berend; Engel, Kirsten Rita; Jamrozinski, Katja; Havemann-Reinecke, Ursula

    2011-03-01

    Elevations of serum homocysteine levels are a consistent finding in alcohol addiction. Serum S100B levels are altered in different neuropsychiatric disorders but not well investigated in alcohol withdrawal syndromes. Because of the close connection of S100B to ACTH and glutamate secretion that both are involved in neurodegeneration and symptoms of alcoholism the relationship of S100B and homocysteine to acute withdrawal variables has been examined. A total of 22 male and 9 female inpatients (mean age 46.9 ± 9.7 years) with an ICD-10 diagnosis of alcohol addiction without relevant affective comorbidity were examined on admission and after 24, 48, and 120 h during withdrawal. S100B and homocysteine levels in serum were collected, and severity of withdrawal symptoms (AWS-scale), applied withdrawal medication, initial serum ethanol levels and duration of addiction were recorded. Serum S100B and homocysteine levels declined significantly (P < .05) over time. Both levels declined with withdrawal syndrome severity. Females showed a trend to a more intense decline in serum S100B levels compared to males at day 5 (P = .06). Homocysteine levels displayed a negative relationship to applied amount of clomethiazole (P < .05) and correlated with age of onset of addiction. No withdrawal seizures were recorded during the trial. As it is known for homocysteine, S100B revealed to decline rapidly over withdrawal treatment in alcoholism. This effect is more pronounced in female patients. S100B could be of relevance in the neurobiology of alcohol withdrawal syndromes. It may be indirectly related to the level of stress level or glutamatergic activity during alcohol withdrawal.

  2. Higher homocysteine associated with thinner cortical gray matter in 803 ADNI subjects

    PubMed Central

    Madsen, Sarah K.; Rajagopalan, Priya; Joshi, Shantanu H.; Toga, Arthur W.; Thompson, Paul M.

    2014-01-01

    A significant portion of our risk for dementia in old age is associated with lifestyle factors (diet, exercise, and cardiovascular health) that are modifiable, at least in principle. One such risk factor – high homocysteine levels in the blood – is known to increase risk for Alzheimer’s disease and vascular disorders. Here we set out to understand how homocysteine levels relate to 3D surface-based maps of cortical gray matter distribution (thickness, volume, surface area) computed from brain MRI in 803 elderly subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Individuals with higher plasma levels of homocysteine had lower gray matter thickness in bilateral frontal, parietal, occipital and right temporal regions; and lower gray matter volumes in left frontal, parietal, temporal, and occipital regions, after controlling for diagnosis, age, and sex, and after correcting for multiple comparisons. No significant within-group associations were found in cognitively healthy people, mild cognitive impairment, or Alzheimer’s disease. These regional differences in gray matter structure may be useful biomarkers to assess the effectiveness of interventions, such as vitamin B supplements, that aim to prevent homocysteine-related brain atrophy by normalizing homocysteine levels. PMID:25444607

  3. The evaluation of serum homocysteine, folic acid, and vitamin B12 in patients complicated with preeclampsia

    PubMed Central

    Shahbazian, Nahid; Jafari, Razieh Mohammad; Haghnia, Sahar

    2016-01-01

    Introduction Increased plasma homocysteine may be associated with adverse pregnancy outcomes, such as preeclampsia. The aim of this study was to determine the plasma homocysteine, serum folate, and vitamin B12 levels in preeclamptic pregnant women. Methods This case-control study was conducted in 2016 in Ahwaz on 51 pregnant women with preeclampsia and 51 healthy pregnant women of the same gestational age, who served as controls. The case group also was subdivided into severe and non-severe preeclampsia. Patients’ data were collected through a questionnaire and medical records. Serum homocysteine, folic acid, and vitamin B12 were analyzed using chemiluminescent assay. The results were compared between two groups. Statistical analyses were done using IBM-SPSS 20.0. A Kolmogorov-Smirnov test, independent samples t-test, Mann-Whitney test, and Chi-square test were used for data analysis. Results No different demographic characteristics were found among the groups. Pregnant women complicated with preeclampsia displayed significantly higher serum homocysteine levels (p < 0.001) and lower serum folate (p = 0.005) and vitamin B12 levels (p < 0.001) compared to controls. A statistically significant inverse correlation was evident between serum homocysteine and serum folate levels in preeclamptic patients (p = 0.005; r = −0.389). In addition, an inverse correlation was identified between homocysteine and serum vitamin B12, but it was not statistically significant (p = 0.160; r = −0.200). Significant differences occurred in serum homocysteine and folate levels between the severe and non-severe subgroups (p < 0.001, p < 0.001). Conclusion Women complicated with preeclampsia displayed higher maternal serum homocysteine and lower serum folate and vitamin B12. Further studies are needed to confirm if the prescription of folic acid and vitamin B12 in women with a deficiency of these vitamins could decrease the level of serum homocysteine and, therefore, reduce the risk of

  4. Improved HPLC method for total plasma homocysteine detection and quantification.

    PubMed

    Sawuła, Wojciech; Banecka-Majkutewicz, Zyta; Kadziński, Leszek; Jakóbkiewicz-Banecka, Joanna; Wegrzyn, Grzegorz; Nyka, Walenty; Banecki, Bogdan

    2008-01-01

    Recent clinical research has pointed at hyperhomocysteinemia as an independent risk factor in a number of cardiovascular and neurological diseases. We have improved a chromatographic method of total plasma homocysteine measurements in order to obtain higher sensitivity, reliability and reproducibility. The method demonstrates excellent linearity (R=0.999), range (<2-100 microM), precision (instrumental RSD 0.06 and method RSD 1.17), accuracy (recovery of 99.92 and RSD 1.27), reproducibility, quantification limit and ruggedness (e.g. pH from 2.0 to 2.5). Because even a small increase in homocysteine level can be a significant risk factor of cardiovascular diseases, such a precise method is required. The constructed method allows the measurement of plasma pyridoxal phosphate, PLP, the co-enzyme form of vitamin B(6), on the same column and similar reagents. The developed method has been successfully applied to measure both total plasma and serum homocysteine in a group of acute stroke patients.

  5. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression.

    PubMed

    Bhatia, Pankaj; Singh, Nirmal

    2015-12-01

    Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression.

  6. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review

    PubMed Central

    2011-01-01

    Introduction Haemostatic therapy in surgical and/or massive trauma patients typically involves transfusion of fresh frozen plasma (FFP). Purified human fibrinogen concentrate may offer an alternative to FFP in some instances. In this systematic review, we investigated the current evidence for the use of FFP and fibrinogen concentrate in the perioperative or massive trauma setting. Methods Studies reporting the outcome (blood loss, transfusion requirement, length of stay, survival and plasma fibrinogen level) of FFP or fibrinogen concentrate administration to patients in a perioperative or massive trauma setting were identified in electronic databases (1995 to 2010). Studies were included regardless of type, patient age, sample size or duration of patient follow-up. Studies of patients with congenital clotting factor deficiencies or other haematological disorders were excluded. Studies were assessed for eligibility, and data were extracted and tabulated. Results Ninety-one eligible studies (70 FFP and 21 fibrinogen concentrate) reported outcomes of interest. Few were high-quality prospective studies. Evidence for the efficacy of FFP was inconsistent across all assessed outcomes. Overall, FFP showed a positive effect for 28% of outcomes and a negative effect for 22% of outcomes. There was limited evidence that FFP reduced mortality: 50% of outcomes associated FFP with reduced mortality (typically trauma and/or massive bleeding), and 20% were associated with increased mortality (typically surgical and/or nonmassive bleeding). Five studies reported the outcome of fibrinogen concentrate versus a comparator. The evidence was consistently positive (70% of all outcomes), with no negative effects reported (0% of all outcomes). Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found to be superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length of intensive care unit and hospital

  7. Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death.

    PubMed

    Hemendinger, Richelle A; Armstrong, Edward J; Brooks, Benjamin Rix

    2011-03-15

    Homocysteine is an excitatory amino acid implicated in multiple diseases including amyotrophic lateral sclerosis (ALS). Information on the toxicity of homocysteine in motor neurons is limited and few studies have examined how this toxicity can be modulated. In NSC-34D cells (a hybrid cell line derived from motor neuron-neuroblastoma), homocysteine induces apoptotic cell death in the millimolar range with a TC₅₀ (toxic concentration at which 50% of maximal cell death is achieved) of 2.2 mM, confirmed by activation of caspase 3/7. Induction of apoptosis was independent of short-term reactive oxygen species (ROS) generation. Methyl Vitamin B12 (MeCbl) and methyl tetrahydrofolate (MTHF), used clinically to treat elevated homocysteine levels, were tested for their ability to reverse homocysteine-mediated motor neuron cell death. MeCbl in the micromolar range was able to provide neuroprotection (2 h pretreatment prior to homocysteine) and neurorescue (simultaneous exposure with homocysteine) against millimolar homocysteine with an IC₅₀ (concentration at which 50% of maximal cell death is inhibited) of 0.6 μM and 0.4 μM, respectively. In contrast, MTHF (up to 10 μM) had no effect on homocysteine-mediated cell death. MeCbl inhibited caspase 3/7 activation by homocysteine in a time- and dose-dependent manner, whereas MTHF had no effect. We conclude that MeCbl is effective against homocysteine-induced cell death in motor neurons in a ROS-independent manner, via a reduction in caspase activation and apoptosis. MeCbl decreases Hcy induced motor neuron death in vitro in a hybrid cell line derived from motor neuron-neuroblastoma and may play a role in the treatment of late stage ALS where HCy levels are increased in animal models of ALS.

  8. Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death

    SciTech Connect

    Hemendinger, Richelle A. Armstrong, Edward J.; Brooks, Benjamin Rix

    2011-03-15

    Homocysteine is an excitatory amino acid implicated in multiple diseases including amyotrophic lateral sclerosis (ALS). Information on the toxicity of homocysteine in motor neurons is limited and few studies have examined how this toxicity can be modulated. In NSC-34D cells (a hybrid cell line derived from motor neuron-neuroblastoma), homocysteine induces apoptotic cell death in the millimolar range with a TC{sub 50} (toxic concentration at which 50% of maximal cell death is achieved) of 2.2 mM, confirmed by activation of caspase 3/7. Induction of apoptosis was independent of short-term reactive oxygen species (ROS) generation. Methyl Vitamin B12 (MeCbl) and methyl tetrahydrofolate (MTHF), used clinically to treat elevated homocysteine levels, were tested for their ability to reverse homocysteine-mediated motor neuron cell death. MeCbl in the micromolar range was able to provide neuroprotection (2 h pretreatment prior to homocysteine) and neurorescue (simultaneous exposure with homocysteine) against millimolar homocysteine with an IC{sub 50} (concentration at which 50% of maximal cell death is inhibited) of 0.6 {mu}M and 0.4 {mu}M, respectively. In contrast, MTHF (up to 10 {mu}M) had no effect on homocysteine-mediated cell death. MeCbl inhibited caspase 3/7 activation by homocysteine in a time- and dose-dependent manner, whereas MTHF had no effect. We conclude that MeCbl is effective against homocysteine-induced cell death in motor neurons in a ROS-independent manner, via a reduction in caspase activation and apoptosis. MeCbl decreases Hcy induced motor neuron death in vitro in a hybrid cell line derived from motor neuron-neuroblastoma and may play a role in the treatment of late stage ALS where HCy levels are increased in animal models of ALS.

  9. Plasma Fibrinogen Correlates with Metastasis and is Associated with Prognosis in Human Nasopharyngeal Carcinoma

    PubMed Central

    He, Sha-Sha; Wang, Yan; Yang, Lin; Chen, Hai-Yang; Liang, Shao-Bo; Lu, Li-Xia; Chen, Yong

    2017-01-01

    Background: The purpose of this observational study was to evaluate the prognostic significance of the pre-treatment plasma fibrinogen level for survival outcomes in nasopharyngeal carcinoma (NPC). Methods: A total of 998 patients with NPC treated at a single centre in China were retrospectively enrolled, of whom 182 (18.2%) developed distant metastasis during follow-up. Survival analyses were performed by the Kaplan-Meier method and Cox regression modelling to measure 3-year overall survival (OS) and distant metastasis-free survival (DMFS). Results: Median OS for the entire cohort was 37.8 months. Using the cut-off value of 3.345 g/L identified in receiver operating curve analysis for fibrinogen, a high pre-treatment plasma fibrinogen level were associated with older age (P = 0.034), advanced TNM stage (P = 0.004) and development of distant metastasis (P < 0.001; Chi-square test). Multivariate Cox proportional hazard analysis demonstrated the pre-treatment plasma fibrinogen level was an independent significant prognostic factor for OS and DMFS in both the entire cohort and also among patients who developed distant metastasis during follow-up. Conclusions: This study suggests the pre-treatment plasma fibrinogen level may serve as an independent prognostic marker to predict the survival outcomes of patients with NPC, including patients with metastatic disease. PMID:28261341

  10. Inverse correlation between fibrinogen and bone mineral density in women: Preliminary findings.

    PubMed

    Chen, Jui-Tung; Kotani, Kazuhiko

    2016-01-01

    Hemostatic factors may be involved in bone health. The present preliminary study investigated the association between plasma fibrinogen and bone mineral density (BMD) in perimenopausal women. A significant inverse correlation between fibrinogen and BMD was observed (correlation coefficient = -0.42, p < 0.01). This correlation appeared to be more clearly observed in the subgroup with a high level of high-sensitivity C-reactive protein than in that with a low level of high-sensitivity C-reactive protein, and in the subgroup with a high level of diacron reactive oxygen metabolites (an oxidative stress marker) than in that with a low level of diacron reactive oxygen metabolites. Thus, fibrinogen may be a possible marker of BMD in this population. More studies on the associations among hemostasis, inflammation, oxidative stress, and bone metabolism are warranted in the clinical setting.

  11. Iron modulates the alpha chain of fibrinogen.

    PubMed

    Nielsen, Vance G; Jacobsen, Wayne K

    2016-04-01

    Iron-bound fibrinogen has been noted to accelerate plasmatic coagulation in patients with divergent conditions involving upregulation of heme oxygenase activity, including hemodialysis, Alzheimer's disease, sickle cell anemia, and chronic migraine. Our goal was to determine if a site of iron-fibrinogen interaction was on the alpha chain. Using thrombelastography, we compared the coagulation kinetic profiles of plasma exposed to 0-10 µM ferric chloride after activation of coagulation with thrombin generated by contact activation of plasma with the plastic sample cup or by exposure to 1 µg/ml of Calloselasma rhodostoma venom (rich in ancrod activity), which causes coagulation via polymerization of alpha chain monomers. Venom mediated coagulation always occurred before thrombin activated thrombus formation, and ferric chloride always diminished the time of onset of coagulation and increased the velocity of clot growth. Iron enhances plasmatic coagulation kinetics by modulating the alpha chain of fibrinogen.

  12. Thrombocytopenia in cirrhosis: Impact of fibrinogen on bleeding risk

    PubMed Central

    Thakrar, Sonali V; Mallett, Susan V

    2017-01-01

    AIM To investigate the relationship between baseline platelet count, clauss fibrinogen, maximum amplitude (MA) on thromboelastography, and blood loss in orthotopic liver transplantation (OLT). METHODS A retrospective analysis of our OLT Database (2006-2015) was performed. Baseline haematological indices and intraoperative blood transfusion requirements, as a combination of cell salvage return and estimation of 300 mls/unit of allogenic blood, was noted as a surrogate for intraoperative bleeding. Two groups: Excessive transfusion (> 1200 mL returned) and No excessive transfusion (< 1200 mL returned) were analysed. All data analyses were conducted using IBM SPSS Statistics version 23. RESULTS Of 322 OLT patients, 77 were excluded due to fulminant disease; redo transplant or baseline haemoglobin (Hb) of < 80 g/L. One hundred and fourteen (46.3%) were classified into the excessive transfusion group, 132 (53.7%) in the no excessive transfusion group. Mean age and gender distribution were similar in both groups. Baseline Hb (P ≤ 0.001), platelet count (P = 0.005), clauss fibrinogen (P = 0.004) and heparinase MA (P = 0.001) were all statistically significantly different. Univariate logistic regression with a cut-off of platelets < 50 × 109/L as the predictor and Haemorrhage as the outcome showed an odds ratio of 1.393 (95%CI: 0.758-2.563; P = 0.286). Review of receiver operating characteristic curves showed an area under the curve (AUC) for platelet count of 0.604 (95%CI: 0.534-0.675; P = 0.005) as compared with AUC for fibrinogen level, 0.678 (95%CI: 0.612-0.744; P ≤ 0.001). A multivariate logistic regression shows United Kingdom model for End Stage Liver Disease (P = 0.006), Hb (P = 0.022) and Fibrinogen (P = 0.026) to be statistically significant, whereas Platelet count was not statistically significant. CONCLUSION Platelet count alone does not predict excessive transfusion. Additional investigations, e.g., clauss fibrinogen and viscoelastic tests, provide more

  13. Homocysteine lowering interventions for preventing cardiovascular events

    PubMed Central

    Martí-Carvajal, Arturo J; Solà, Ivan; Lathyris, Dimitrios; Salanti, Georgia

    2014-01-01

    Background Cardiovascular disease such as coronary artery disease, stroke and congestive heart failure, is a leading cause of death worldwide. A postulated risk factor is elevated circulating total homocysteine (tHcy) levels which is influenced mainly by blood levels of cyanocobalamin (vitamin B12), folic acid (vitamin B9) and pyridoxine (vitamin B6). There is uncertainty regarding the strength of association between tHcy and the risk of cardiovascular disease. Objectives To assess the clinical effectiveness of homocysteine-lowering interventions (HLI) in people with or without pre-existing cardiovascular disease. Search methods We searched The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (issue 3 2008), MEDLINE (1950 to August 2008), EMBASE (1988 to August 2008), and LILACS (1982 to September 2, 2008). We also searched in Allied and Complementary Medicine (AMED; 1985 to August 2008), ISI Web of Science (1993 to August 2008), and the Cochrane Stroke Group Specialised Register (April 2007). We hand searched pertinent journals and the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. Selection criteria We included randomised clinical trials (RCTs) assessing the effects of HLI for preventing cardiovascular events with a follow-up period of 1 year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. Data collection and analysis We independently performed study selection, risk of bias assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using I2. We used a random-effects model to synthesise the findings. Main results We included eight RCTs involving 24,210 participants with a low risk of bias in general terms. HLI did not reduce the risk of non-fatal or fatal myocardial infarction, stroke, or

  14. Sulfheme formation during homocysteine S-oxygenation by catalase in cancers and neurodegenerative diseases

    PubMed Central

    Padovani, Dominique; Hessani, Assia; Castillo, Francine T.; Liot, Géraldine; Andriamihaja, Mireille; Lan, Annaïg; Pilati, Camilla; Blachier, François; Sen, Suvajit; Galardon, Erwan; Artaud, Isabelle

    2016-01-01

    Accumulating evidence suggests that abnormal levels of homocysteine are associated with vascular dysfunctions, cancer cell proliferation and various neurodegenerative diseases. With respect to the latter, a perturbation of transition metal homeostasis and an inhibition of catalase bioactivity have been reported. Herein, we report on some of the molecular bases for the cellular toxicity of homocysteine and demonstrate that it induces the formation of sulfcatalase, an irreversible inactive state of the enzyme, without the intervention of hydrogen sulfide. Initially, homocysteine reacts with native catalase and/or redox-active transition metal ions to generate thiyl radicals that mediate compound II formation, a temporarily inactive state of the enzyme. Then, the ferryl centre of compound II intervenes into the unprecedented S-oxygenation of homocysteine to engender the corresponding sulfenic acid species that further participates into the prosthetic heme modification through the formation of an unusual Fe(II) sulfonium. In addition, our ex cellulo studies performed on cancer cells, models of neurodegenerative diseases and ulcerative colitis suggest the likelihood of this scenario in a subset of cancer cells, as well as in a cellular model of Parkinson's disease. Our findings expand the repertoire of heme modifications promoted by biological compounds and point out another deleterious trait of disturbed homocysteine levels that could participate in the aetiology of these diseases. PMID:27848965

  15. Methoxistasis: integrating the roles of homocysteine and folic acid in cardiovascular pathobiology.

    PubMed

    Joseph, Jacob; Loscalzo, Joseph

    2013-08-15

    Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of folic acid have not demonstrated any benefit in preventing or treating cardiovascular disease. In addition to the fact that these clinical trials may have been shorter in duration than appropriate for modulating chronic disease states, it is likely that reduction of the blood homocysteine level may be an oversimplified approach to a complex biologic perturbation. The methionine-homocysteine cycle and folate metabolism regulate redox and methylation reactions and are, in turn, regulated by redox and methylation status. Under normal conditions, a normal redox-methylation balance, or "methoxistasis", exists, coordinated by the methionine-homocysteine cycle. An abnormal homocysteine level seen in pathologic states may reflect a disturbance of methoxistasis. We propose that future research should be targeted at estimating the deviation from methoxistasis and how best to restore it. This approach could lead to significant advances in preventing and treating cardiovascular diseases, including heart failure.

  16. Homocysteine: overview of biochemistry, molecular biology, and role in disease processes.

    PubMed

    Fowler, Brian

    2005-05-01

    Homocysteine is derived from the essential amino acid methionine and plays a vital role in cellular homeostasis in man. Homocysteine levels depend on its synthesis, involving methionine adenosyltransferase, S-adenosylmethionine-dependent methyltransferases such as glycine N-methyltransferase, and S-adenosylhomocysteine hydrolase; its remethylation to methionine by methionine synthase, which requires methionine synthase reductase, vitamin B (12), and 5-methyltetrahydrofolate produced by methylenetetrahydrofolate reductase or betaine methyltransferase; and its degradation by transsulfuration involving cystathionine beta-synthase. The control of homocysteine metabolism involves changes of tissue content or inherent kinetic properties of the enzymes. In particular, S-adenosylmethionine acts as a switch between remethylation and transsulfuration through its allosteric inhibition of methylenetetrahydrofolate reductase and activation of cystathionine beta-synthase. Mutant alleles of genes for these enzymes can lead to severe loss of function and varying severity of disease. Several defects lead to severe hyperhomocysteinemia, the most common form being cystathionine beta-synthase deficiency, with more than a hundred reported mutations. Less severe elevations of plasma homocysteine are caused by folate and vitamin B (12) deficiency, and renal disease and moderate hyperhomocysteinemia are associated with several common disease states such as cardiovascular disease. Homocysteine toxicity is likely direct or caused by disturbed levels of associated metabolites; for example, methylation reactions through elevated S-adenosylhomocysteine.

  17. Are fibrinogen and complete blood count parameters predictive in incarcerated abdominal hernia repair?

    PubMed

    Kahramanca, Sahin; Kaya, Oskay; Ozgehan, Gulay; Guzel, Hakan; Azili, Cem; Gokce, Emre; Kucukpinar, Tevfik; Kulacoglu, Hakan

    2014-01-01

    Therapeutic delays in cases of external incarcerated hernias typically result in increasing morbidity, mortality, and health expenditures. We investigated the diagnostic role of blood fibrinogen level, white blood count (WBC), mean platelet volume (MPV), and platelet distribution width (PDW) in patients with incarcerated hernia. Two groups, each containing 100 patients, were studied. Group A underwent elective, and group B underwent incarcerated and urgent external hernia repair. We observed high fibrinogen and WBC levels but low MPV and PDW values for patients in group B. Contrary to our expectations, we found lower MPV and PDW values in the complicated group than in the elective group. The morbidity rate and cost burden were higher in group B, and the results were statistically significant. Early operation should be recommended for patients with incarcerated external hernias if their fibrinogen and WBC levels are high.

  18. Utility of plasma fibrinogen in the differential diagnosis of thyrotoxicosis

    PubMed Central

    Ma, Jie; Liu, Rui; Wu, Di; Miao, Wei; Chen, Qian; Li, Yushu; Guan, Haixia

    2015-01-01

    Background: A study had reported that a low TSH level is associated with elevated plasma fibrinogen (FIB) levels. Our purpose was to investigate the role of FIB in the differential diagnosis of thyrotoxicosis. Methods: The data of 104 patients with primary thyrotoxicosis at the First Hospital of China Medical University from July 2010 to March 2011 were analyzed and divided into three groups: 45 cases of subacute thyroiditis, 50 cases of Graves’ disease, and 9 cases of toxic multinodular goiter. The patients with subacute thyroiditis were followed up before and after the treatment. FIB levels of the three groups were compared. Results: There was no significant difference in serum TSH, FT3 and FT4 between the patients with three different causes of thyrotoxicosis (P > 0.05). The proportion of hyperfibrinogenemia in patients with subacute thyroiditis was 98%. The FIB levels of patients with subacute thyroiditis were significantly higher than those with Graves’ disease and toxic multinodular goiter (P < 0.05). Levels of ESR show a similar tendency. The FIB levels returned to normal with the remission of subacute thyroiditis. Conclusions: Elevated plasma fibrinogen is a common manifestation of the active phase of subacute thyroiditis. A FIB test can be used for the differential diagnosis of thyrotoxicosis. We can anticipate the outcome of subacute thyroiditis through the dynamic changes of FIB. PMID:25785116

  19. The effect of reagents mimicking oxidative stress on fibrinogen function.

    PubMed

    Štikarová, Jana; Kotlín, Roman; Riedel, Tomáš; Suttnar, Jiří; Pimková, Kristýna; Chrastinová, Leona; Dyr, Jan E

    2013-01-01

    Fibrinogen is one of the plasma proteins most susceptible to oxidative modification. It has been suggested that modification of fibrinogen may cause thrombotic/bleeding complications associated with many pathophysiological states of organism. We exposed fibrinogen molecules to three different modification reagents-malondialdehyde, sodium hypochlorite, and peroxynitrite-that are presented to various degrees in different stages of oxidative stress. We studied the changes in fibrin network formation and platelet interactions with modified fibrinogens under flow conditions. The fastest modification of fibrinogen was caused by hypochlorite. Fibers from fibrinogen modified with either reagent were thinner in comparison with control fibers. We found that platelet dynamic adhesion was significantly lower on fibrinogen modified with malondialdehyde and significantly higher on fibrinogen modified either with hypochlorite or peroxynitrite reflecting different prothrombotic/antithrombotic properties of oxidatively modified fibrinogens. It seems that, in the complex reactions ongoing in living organisms at conditions of oxidation stress, hypochlorite modifies proteins (e.g., fibrinogen) faster and more preferentially than malondialdehyde. It suggests that the prothrombotic effects of prior fibrinogen modifications may outweigh the antithrombotic effect of malondialdehyde-modified fibrinogen in real living systems.

  20. Molecular characterization of betaine-homocysteine methyltransferase 1 from the liver, and effects of aestivation on its expressions and homocysteine concentrations in the liver, kidney and muscle, of the African lungfish, Protopterus annectens.

    PubMed

    Ong, Jasmine L Y; Woo, Jia M; Hiong, Kum C; Ching, Biyun; Wong, Wai P; Chew, Shit F; Ip, Yuen K

    2015-05-01

    Homocysteine accumulation has numerous deleterious effects, and betaine-homocysteine S-methyltransferase (BHMT) catalyses the synthesis of methionine from homocysteine and betaine. This study aimed to determine homocysteine concentrations, and mRNA expression levels and protein abundances of bhmt1/Bhmt1 in the liver, kidney and muscle of the African lungfish, Protopterus annectens, during the induction (6 days), maintenance (6 months) or arousal (3 days after arousal) phase of aestivation. The homocysteine concentration decreased significantly in the liver of P. annectens after 6 days or 6 months of aestivation, but it returned to the control level upon arousal. By contrast, homocysteine concentrations in the kidney and muscle remained unchanged during the three phases of aestivation. The complete coding cDNA sequence of bhmt1 from P. annectens consisted of 1236 bp, coding for 412 amino acids. The Bhmt1 from P. annectens had a close phylogenetic relationship with those from tetrapods and Callorhinchus milii. The expression of bhmt1 was detected in multiple organs/tissues of P. annectens, and this is the first report on the expression of bhmt1/Bhmt1 in animal skeletal muscle. The mRNA and protein expression levels of bhmt1/Bhmt1 were up-regulated in the liver of P. annectens during the induction and maintenance phases of aestivation, possibly to regulate the hepatic homocysteine concentration. The significant increase in hepatic Bhmt1 protein abundance during the arousal phase could be a response to increased cellular methylation for the purpose of tissue reconstruction. Unlike the liver, Bhmt1 expression in the kidney and muscle of P. annectens was regulated translationally, and its up-regulation could be crucial to prevent homocysteine accumulation.

  1. A prospective study of maternal fatty acids, micronutrients and homocysteine and their association with birth outcome.

    PubMed

    Wadhwani, Nisha S; Pisal, Hemlata R; Mehendale, Savita S; Joshi, Sadhana R

    2015-10-01

    Our earlier studies both in animals and in humans have indicated that micronutrients (folic acid, vitamin B12) and long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), are interlinked in the one-carbon cycle, which plays an important role in fetal 'programming' of adult diseases. The present study examines the levels of maternal and cord plasma fatty acids, maternal folate, vitamin B12 and homocysteine in healthy mothers at various time points during pregnancy and also examine an association between them. A longitudinal study of 106 normal pregnant women was carried out, and maternal blood was collected at three time points, viz., T1 = 16-20th week, T2 = 26-30th week and T3 = at delivery. Cord blood was collected at delivery. Fatty acids were estimated using a gas chromatograph. Levels of folate, vitamin B12 and homocysteine were estimated by the chemiluminescent microparticle immunoassay (CMIA) technology. Maternal plasma folate (P < 0.05), vitamin B12 (P < 0.01) and DHA (P < 0.05) levels were lowest, while maternal homocysteine levels were highest (P < 0.01) at T3. There was a negative association between maternal DHA and homocysteine at T2 (P < 0.05) and T3 (P < 0.01). There was a positive association between plasma DHA in maternal blood at T3 and cord blood. Furthermore, there was a positive association between maternal folate and vitamin B12 at T3 and baby weight, whereas maternal homocysteine at T1 were inversely associated with baby weight at delivery. Our study provides evidence for the associations of folic acid, vitamin B12, homocysteine with DHA and baby weight, suggesting that a balanced dietary supplementation of folate-vitamin B12-DHA during pregnancy may be beneficial.

  2. Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans.

    PubMed

    Jakubowski, Hieronim; Boers, Godfried H J; Strauss, Kevin A

    2008-12-01

    Severely elevated plasma homocysteine (Hcy) levels observed in genetic disorders of Hcy metabolism are associated with pathologies in multiple organs and lead to premature death due to vascular complications. In addition to elevating plasma Hcy, mutations in cystathionine beta-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR) gene lead to markedly elevated levels of circulating Hcy-thiolactone. The thiooester chemistry of Hcy-thiolactone underlies its ability to form isopeptide bonds with protein lysine residues (N-Hcy-protein), which may impair or alter the protein's function. However, it was not known whether genetic deficiencies in Hcy metabolism affect N-Hcy-protein levels in humans. Here we show that plasma N-Hcy-protein levels are significantly elevated in CBS- and MTHFR-deficient patients. We also show that CBS-deficient patients have significantly elevated plasma levels of prothrombotic N-Hcy-fibrinogen. These results provide a possible explanation for increased atherothrombosis observed in CBS-deficient patients.

  3. The influence of homocysteine and oxidative stress on pregnancy outcome.

    PubMed

    Micle, O; Muresan, M; Antal, L; Bodog, F; Bodog, A

    2012-02-22

    Oxidative stress in utero-placental tissues plays an important role in the development of placental-related diseases. Maternal hiperhomocysteinemia is associated with placental mediated diseases, such as preeclampsia, spontaneous abortion and placental abruption. The aim of our study is to appreciate the clinical usefulness of the dosage serum homocysteine and malondialdehyde, as an oxidative stress marker, in the pregnancies complicated with risk of abortion or preterm birth. The study was performed at the Obstetric Gynecology Clinical Hospital Oradea from December 2009 until April 2010. It included 18 patients with risk of abortion (group 1), 22 with preterm birth (group 2). The results were compared with a control group composed by 14 healthy pregnant women. Serum homocysteine level was measured by an enzymatic method, on the instrument Hitachi 912, Roche, reagent: Axis-Shield Enzymatic. For proving the oxidative stress we established the level of malondialdehyde using a method with thiobarbituric acid TBA (Kei Satoh 1978) and the level of ceruloplasmin with the Ravin method .Also AST, ALT,CRP, iron, uric acid, urea were assessed.High level of homocysteine in both groups of study in comparison with the control group was found. The concentration of MDA was significantly higher in pregnancies complicated with risk of abortion and preterm birth compared to the control group (p=0.040, p=0.031). Considerable differences of ceruloplasmin concentration between group 1 and group 2 (p=0.045), and between group 2 and control group (p=0.034), was noticed but not any important differences between group 1 and control group (p=0.683). In women with risk of abortion or with preterm birth an oxidative stress and a hyperhomocysteinemia are present.

  4. Comparison of Protein N-Homocysteinylation in Rat Plasma under Elevated Homocysteine Using a Specific Chemical Labeling Method

    PubMed Central

    Zang, Tianzhu; Pottenplackel, Ligi Paul; Handy, Diane E.; Loscalzo, Joseph; Dai, Shujia; Deth, Richard C.; Zhou, Zhaohui Sunny; Ma, Jisheng

    2017-01-01

    Elevated blood concentrations of homocysteine have been well established as a risk factor for cardiovascular diseases and neuropsychiatric diseases, yet the etiologic relationship of homocysteine to these disorders remains poorly understood. Protein N-homocysteinylation has been hypothesized as a contributing factor; however, it has not been examined globally owing to the lack of suitable detection methods. We recently developed a selective chemical method to label N-homocysteinylated proteins with a biotin-aldehyde tag followed by Western blotting analysis, which was further optimized in this study. We then investigated the variation of protein N-homocysteinylation in plasma from rats on a vitamin B12 deficient diet. Elevated “total homocysteine” concentrations were determined in rats with a vitamin B12 deficient diet. Correspondingly, overall levels of plasma protein N-homocysteinylation displayed an increased trend, and furthermore, more pronounced and statistically significant changes (e.g., 1.8-fold, p-value: 0.03) were observed for some individual protein bands. Our results suggest that, as expected, a general metabolic correlation exists between “total homocysteine” and N-homocysteinylation, although other factors are involved in homocysteine/homocysteine thiolactone metabolism, such as the transsulfuration of homocysteine by cystathionine β-synthase or the hydrolysis of homocysteine thiolactone by paraoxonase 1 (PON1), may play more significant or direct roles in determining the level of N-homocysteinylation. PMID:27617989

  5. Comparison of plasma with whole blood prothrombin time and fibrinogen on the same instrument.

    PubMed

    Amukele, Timothy K; Ferrell, Chris; Chandler, Wayne L

    2010-04-01

    We compared plasma with whole blood (WB) international normalized ratio (INR) and fibrinogen using the same instrument and reagents. WBINRs were 50% higher than plasma INRs. After increasing the WB sample volume 40% and adjusting the International Sensitivity Index, WBINRs were similar to plasma INRs [adjusted WBINR = 0.99(plasma INR) - 0.02; r(2) = 0.98; n = 155], but the average difference in WB vs plasma INR was 4-fold higher than duplicate plasma INRs. Variation in hematocrit was a major determinant of the accuracy of the WBINR, with increased error at high INRs. The WB fibrinogen assay was highly dependent on the sample hematocrit (r(2) = 0.83), even after the sample volume was adjusted. Accurate WB fibrinogen measurements required a mathematical hematocrit correction. We conclude that WBINR and fibrinogen assays can be performed on point-of-care or automated analyzers, but sample volume must be adjusted to account for hematocrit. Accuracy is limited by variations in hematocrit with worsening accuracy for samples with high INRs or low fibrinogen levels.

  6. Gender differences in the expression of erythrocyte aggregation in relation to B beta-fibrinogen gene polymorphisms in apparently healthy individuals.

    PubMed

    Ben Assayag, Einor; Bova, Irena; Berliner, Shlomo; Peretz, Hava; Usher, Sali; Shapira, Itzhak; Bornstein, Natan M

    2006-03-01

    An increased erythrocyte aggregation (EA) is associated with capillary slow flow, tissue hypoxemia and endothelial dysfunction. Fibrinogen is a major determinant in the formation of aggregated red blood cells. It has been suggested that the B beta-fibrinogen -455 G/A polymorphism is associated with erythrocyte hyperaggregability in men with coronary artery disease. The purpose of this study was to investigate the influence of the beta-fibrinogen -455 G/A polymorphism on erythrocyte aggregation in apparently healthy individuals. Plasma fibrinogen, red blood cell count, serum lipids, erythrocyte sedimentation rate, and the genotype of the B beta-fibrinogen -455 G/A polymorphism were examined in a cohort of 545 apparently healthy individuals and those with atherothrombotic risk factors. A whole blood erythrocyte aggregation test was performed by using a simple slide test and image analysis. In men, EA levels and plasma fibrinogen levels were significantly higher in subjects carrying the -455 A allele compared to subjects with the -455 GG genotype. This association did not exist in women carrying the fibrinogen -455 A allele. The -455 GA/AA men presented significantly higher correlation between the plasma fibrinogen concentrations and EA. This observation raises the prospect of possible change in the functional properties of the -455 GA/AA fibrinogen, enhancing its ability to induce EH. This study suggests that the B beta-fibrinogen -455 A allele is related to EH in men only. Putative mechanism could be hyperfibrinogenemia and a functional change in the fibrinogen molecule that alters its ability to interact with red blood cells and supports the aggregability of these cells.

  7. A fibrinogen-based precision microporous scaffold for tissue engineering.

    PubMed

    Linnes, Michael P; Ratner, Buddy D; Giachelli, Cecilia M

    2007-12-01

    Fibrin has been long used as an effective scaffolding material to grow a variety of cells and tissue constructs. It has been utilized mainly as a hydrogel in varying concentrations to provide an environment in which suspended cells work to rearrange the fibers and lay down their own extracellular matrix. For these fibrin hydrogels to be useful in many tissue-engineering applications, the gels must be cultured for long periods of time in order to increase their mechanical strength to the levels of native tissues. High concentrations of fibrinogen increase the mechanical strength of fibrin hydrogels, but at the same time reduce the ability of cells within the scaffold to spread and survive. We present a method to create a microporous, nanofibriliar fibrin scaffold that has controllable pore size, porosity, and microstructure for applications in tissue engineering. Fibrin has numerous advantages as a scaffolding material as it is normally used by the body as temporary scaffolding for tissue regeneration and healing, and can be autologously sourced. We present here a scaffolding process which enhances the mechanical properties of the fibrin hydrogel by forming it surrounding poly(methyl-methacrylate) beads, then removing the beads with acetone to form an interconnected microporous network. The acetone serves the dual purpose of precipitating and fixing the fibrinogen-based scaffolds as well as adding strength to the network during polymer bead removal. Effects of fibrinogen concentration and time in acetone were examined as well as polymerization with thrombin. A natural crosslinker, genipin, was also used to add strength to the scaffolds, producing a Young's modulus of up to 184+/-5 kPa after 36 h of reaction. Using these methods we were able to produce microporous fibrin scaffolds that support cell growth and have mechanical properties similar to many native tissues.

  8. The acute phase reactant, fibrinogen, as a guide to plasma exchange therapy for acute Guillain-Barré syndrome.

    PubMed

    Sanjay, Rashmi; Flanagan, Janice; Sodano, Donata; Gorson, Kenneth C; Ropper, Allan H; Weinstein, Robert

    2006-07-01

    The Guillian Barré syndrome is an acute inflammatory disorder for which plasma exchange is effective treatment. Up to 10% relapse after plasma exchange suggesting that treatment sometimes finishes before disease activity has resolved. We studied whether plasma fibrinogen, an inflammatory marker, might be used to determine when to discontinue plasma exchange in patients with acute Guillain-Barré syndrome. We conducted a post-hoc analysis of apheresis database and hospital records of patients treated with plasma exchange for acute Guillain-Barré syndrome during 1999-2004. Data were analyzed from 28 patients who underwent a total of 29 courses of plasma exchange for acute Guillain-Barré syndrome. The mean (+/-SD) plasma fibrinogen concentration was 422.5 (+/-96.4) mg/dl at the time of presentation and, in 17 of the 29, it was above 400 mg/dl (reference range 200-400). Twenty of the 21 patients whose fibrinogen fell by more than 30% from baseline by the time of the final plasma exchange treatment had neurological improvement. There was improvement in only 3 of the 8 instances where fibrinogen decreased by less than 30% by the end of plasma exchange therapy. A > or =30% decrease in fibrinogen by the conclusion of plasma exchange was significantly associated with sustained neurological improvement (P = 0.0025). The plasma fibrinogen level appears to reflect disease activity in acute Guillain-Barré syndrome. A <30% fall in fibrinogen level despite plasma exchange may indicate the need to continue plasma exchange to maximize the benefit of treatment or minimize the risk of relapse. Therapeutic plasma exchange need not be extended when plasma fibrinogen remains > or =30% below its level at presentation by the time of the final planned plasma exchange procedure.

  9. A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease

    PubMed Central

    Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel; Naitza, Silvia; Dehghan, Abbas; Johnson, Andrew D; Teumer, Alexander; Reiner, Alex P; Folkersen, Lasse; Basu, Saonli; Rudnicka, Alicja R; Trompet, Stella; Mälarstig, Anders; Baumert, Jens; Bis, Joshua C.; Guo, Xiuqing; Hottenga, Jouke J; Shin, So-Youn; Lopez, Lorna M; Lahti, Jari; Tanaka, Toshiko; Yanek, Lisa R; Oudot-Mellakh, Tiphaine; Wilson, James F; Navarro, Pau; Huffman, Jennifer E; Zemunik, Tatijana; Redline, Susan; Mehra, Reena; Pulanic, Drazen; Rudan, Igor; Wright, Alan F; Kolcic, Ivana; Polasek, Ozren; Wild, Sarah H; Campbell, Harry; Curb, J David; Wallace, Robert; Liu, Simin; Eaton, Charles B.; Becker, Diane M.; Becker, Lewis C.; Bandinelli, Stefania; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Fornage, Myriam; Green, David; Gross, Myron; Davies, Gail; Harris, Sarah E; Liewald, David C; Starr, John M; Williams, Frances M.K.; Grant, P.J.; Spector, Timothy D.; Strawbridge, Rona J; Silveira, Angela; Sennblad, Bengt; Rivadeneira, Fernando; Uitterlinden, Andre G; Franco, Oscar H; Hofman, Albert; van Dongen, Jenny; Willemsen, G; Boomsma, Dorret I; Yao, Jie; Jenny, Nancy Swords; Haritunians, Talin; McKnight, Barbara; Lumley, Thomas; Taylor, Kent D; Rotter, Jerome I; Psaty, Bruce M; Peters, Annette; Gieger, Christian; Illig, Thomas; Grotevendt, Anne; Homuth, Georg; Völzke, Henry; Kocher, Thomas; Goel, Anuj; Franzosi, Maria Grazia; Seedorf, Udo; Clarke, Robert; Steri, Maristella; Tarasov, Kirill V; Sanna, Serena; Schlessinger, David; Stott, David J; Sattar, Naveed; Buckley, Brendan M; Rumley, Ann; Lowe, Gordon D; McArdle, Wendy L; Chen, Ming-Huei; Tofler, Geoffrey H; Song, Jaejoon; Boerwinkle, Eric; Folsom, Aaron R.; Rose, Lynda M.; Franco-Cereceda, Anders; Teichert, Martina; Ikram, M Arfan; Mosley, Thomas H; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M.; Sudlow, Cathie L M; Hopewell, Jemma C.; Chambers, John C.; Saleheen, Danish; Kooner, Jaspal S.; Danesh, John; Nelson, Christopher P; Erdmann, Jeanette; Reilly, Muredach P.; Kathiresan, Sekar; Schunkert, Heribert; Morange, Pierre-Emmanuel; Ferrucci, Luigi; Eriksson, Johan G; Jacobs, David; Deary, Ian J; Soranzo, Nicole; Witteman, Jacqueline CM; de Geus, Eco JC; Tracy, Russell P.; Hayward, Caroline; Koenig, Wolfgang; Cucca, Francesco; Jukema, J Wouter; Eriksson, Per; Seshadri, Sudha; Markus, Hugh S.; Watkins, Hugh; Samani, Nilesh J; Wallaschofski, Henri; Smith, Nicholas L.; Tregouet, David; Ridker, Paul M.; Tang, Weihong; Strachan, David P.; Hamsten, Anders; O’Donnell, Christopher J.

    2013-01-01

    Background Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation. Methods and Results We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE. Conclusion We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE. PMID:23969696

  10. Different effects of cabergoline and bromocriptine on metabolic and cardiovascular risk factors in patients with elevated prolactin levels.

    PubMed

    Krysiak, Robert; Okopien, Bogusław

    2015-03-01

    Hyperprolactinaemia is suggested to be associated with metabolic and hormonal complications. No previous study has compared the effect of different dopamine agonists on plasma lipids, carbohydrate metabolism markers and cardiovascular risk factors in patients with elevated prolactin levels. The study included eight bromocriptine-resistant women with prolactinoma (group 1) and twelve matched women with hyperprolactinaemia unrelated to prolactinoma (group 2). Group 1 was then treated with cabergoline, while group 2 with bromocriptine. Plasma lipids, glucose homeostasis markers and plasma levels of prolactin, insulin-like growth factor-1 (IGF-1) and cardiovascular risk factors were assessed before and after 6 months of therapy. Both treatments normalized plasma prolactin levels. Cabergoline reduced triglycerides, 2-hr post-challenge plasma glucose, the homeostatic model assessment of insulin resistance (HOMA-IR), and circulating levels of IGF-1, free fatty acids (FFA), uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine and fibrinogen, as well as increased HDL cholesterol and 25-hydroxyvitamin D. With the exception of a reduction in HOMA-IR, bromocriptine treatment produced no significant effect on the investigated biomarkers. Cabergoline was superior to bromocriptine in affecting 2-hr post-challenge plasma glucose levels, HOMA-IR, as well as circulating levels of IGF-1, FFA, uric acid, hsCRP, homocysteine, fibrinogen and 25-hydroxyvitamin D. Our results may suggest that cabergoline is superior to bromocriptine when it comes to affecting atherogenic dyslipidaemia, insulin sensitivity and circulating levels of cardiovascular risk factors in hyperprolactinaemic patients. These findings seem to support previous observations that cabergoline may be a better treatment for patients with elevated prolactin levels than bromocriptine.

  11. Functional evaluation of an inherited abnormal fibrinogen: fibrinogen “Baltimore”

    PubMed Central

    Beck, Eugene A.; Shainoff, John R.; Vogel, Alfred; Jackson, Dudley P.

    1971-01-01

    The rate of clotting and the rate of development and degree of turbidity after addition of thrombin to plasma or purified fibrinogen from a patient with fibrinogen Baltimore was delayed when compared with normal, especially in the presence of low concentrations of thrombin. Optimal coagulation and development of translucent, rather than opaque, clots occurred at a lower pH with the abnormal fibrinogen than with normal. Development of turbidity during clotting of the abnormal plasma or fibrinogen was less than normal at each pH tested, but was maximal in both at approximately pH 6.4. The physical quality of clots formed from fibrinogen Baltimore was abnormal, as demonstrated by a decreased amplitude on thromboelastography. The morphologic appearance of fibrin strands formed from fibrinogen Baltimore by thrombin at pH 7.4 was abnormal when examined by phase contrast or electron microscopy, but those formed by thrombin at pH 6.4 or by thrombin and calcium chloride were similar to, though less compact, than normal fibrin. The periodicity of fibrin formed from fibrinogen Baltimore was similar to normal and was 231-233 Å. A study of the release of the fibrinopeptides from the patient's fibrinogen and its chromatographic subfractions verified the existence of both a normally behaving and a defective form of fibrinogen in the patient's plasma. The defective form differed from normal in three functionally different ways: (a) the rate of release of fibrinopeptides A and AP was slower than normal; (b) no visible clot formation accompanied either partial or complete release of the fibrinopeptides from the defective form in 0.3 M NaCl at pH 7.4; and (c) the defective component possessed a high proportion of phosphorylated, relative to nonphosphorylated, fibrinopeptide A, while the coagulable component contained very little of the phosphorylated peptide (AP). The high phosphate content of the defective component did not appear to be the cause of the abnormality, but may be the

  12. Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elevated plasma homocysteine (Hcy) levels have been recognized as an independent risk factor for cardiovascular and cerebrovascular diseases. However, the causative mechanisms have not been delineated. Scavenger receptors such as scavenger receptor-AI/II (SR-A), CD36, and lectin-like oxidized LDL ...

  13. Antiadhesive effect of fibrinogen: a safeguard for thrombus stability

    PubMed Central

    Lishko, Valeryi K.; Burke, Timothy; Ugarova, Tatiana

    2007-01-01

    The recruitment of phagocytic leukocytes to sites of vessel wall injury plays an important role in thrombus dissolution by proteases elaborated on their adhesion. However, leukocyte adhesion to the fibrin clot can be detrimental at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss. Adhesion of circulating leukocytes to the insoluble fibrin(ogen) matrix is mediated by integrins and occurs in the presence of a high concentration of plasma fibrinogen. In this study, the possibility that soluble fibrinogen could protect fibrin from excessive adhesion of leukocytes was examined. Fibrinogen was a potent inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which soluble fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated with the fibrin(ogen) substrate. Consequently, leukocytes that engage fibrinogen molecules loosely bound to the surface of fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various cells and performed under static and flow conditions. These findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion and suggest that this mechanism may protect the thrombus from premature dissolution. PMID:16849640

  14. Platelet fibrinogen binding in Basset Hound Hereditary Thrombopathy

    SciTech Connect

    Patterson, W.; Estry, D.; Schwartz, K.; Bell, T.

    1986-03-01

    Platelets from dogs with Basset Hound Hereditary Thrombopathy (BHT) display a thrombasthenia-like aggregation defect but have been shown to have normal amounts of platelet membrane glycoproteins IIb and IIIa (GP IIb-IIIa). In order to investigate the possibility of a functionally abnormal GPIIb-IIIa complex, which might be unable to bind fibrinogen after stimulation, fibrinogen binding in BHT was evaluated. Two canine fibrinogen preparations were used, one from BHT dogs and one from normal control dogs, as well as a human fibrinogen preparation. Platelets from BHT and normal dogs were activated with 1 x 10/sup -5/M ADP in the presence of /sup 125/I-labeled fibrinogen and the surface bound radioactivity quantitated. For all fibrinogen preparations, the amount of fibrinogen bound by BHT platelets was not significantly different than that bound by normal dog platelets. BHT platelets bound 23,972 +/- 3612 and normal dog platelets bound 23,033 +/- 3971 molecules of fibrinogen per platelet. The BHT platelet aggregation defect does not seem to be caused by a functionally abnormal GP IIb-IIIa complex, since BHT platelets bind normal amounts of fibrinogen. The results suggest that fibrinogen binding is not sufficient for platelet aggregation, and other factors, perhaps receptor mobility and membrane phospholipid content should be investigated in BHT.

  15. [Serum folate and homocysteine concentrations in women smoking during pregnancy and in umbilical cord blood of newborns].

    PubMed

    Ambroszkiewicz, Jadwiga; Chełchowska, Magdalena; Lewandowski, Leszek; Gajewska, Joanna; Laskowska-Klita, Teresa

    2007-01-01

    In metabolism of homocysteine several enzymes and vitamin cofactors are involves. Genetic abnormalities in these enzymes or nutritional deficiency vitamins, especially of folate may lead to hyperhomocysteinemia, a known risk factor for some pregnancy complications. High maternal homocysteine and low folate levels correlate with low birth weight. Maternal smoking affected significantly total homocysteine concentration in infants. Studies in this area are still scarce and report on limited number of patients. The aim of our study was to assess serum folate and total homocysteine (tHcy) concentrations in smoking pregnant women and in their newborn infants as compared with nonsmoking. The study consisted of 57 pregnant women, who qualified into two groups: smoking (n=28) and nonsmoking (n=29). The serum concentrations of folate were determined by electrochemiluninescent method and tHcy by fluorescence polarization immunoassay. We shown, that serum homocysteine concentrations were significantly higher in smoking as compared with nonsmoking pregnant women (p<0.05) as well as in umbilical cord blood of their newborns (p<0.001). The folate levels were comparable in serum both groups of mothers, but in infants born to smoking women were lower by 20%. In addition, the maternal serum levels of homocysteine and folate showed a significant positive correlation's with these parameters in newborns. Average birth weight infants born to smoking mother was significantly lower than nonsmoking cigarettes (p<0.05). It seems that tobacco smoking during pregnancy affected folate and homocysteine levels in serum of mothers and their infants. Smoking exposure is also associate with reduced birth weight.

  16. Public health significance of elevated homocysteine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation, which requires folic acid and vitamin B12 coenzymes; and transsulfuration, which requires pyridoxal-5'-phosphate, the vitamin B6 coenzyme. Data from a number of laboratories suggest that m...

  17. Fibrin Fiber Stiffness Is Strongly Affected by Fiber Diameter, but Not by Fibrinogen Glycation.

    PubMed

    Li, Wei; Sigley, Justin; Pieters, Marlien; Helms, Christine Carlisle; Nagaswami, Chandrasekaran; Weisel, John W; Guthold, Martin

    2016-03-29

    The major structural component of a blood clot is a mesh of fibrin fibers. Our goal was to determine whether fibrinogen glycation and fibrin fiber diameter have an effect on the mechanical properties of single fibrin fibers. We used a combined atomic force microscopy/fluorescence microscopy technique to determine the mechanical properties of individual fibrin fibers formed from blood plasma. Blood samples were taken from uncontrolled diabetic patients as well as age-, gender-, and body-mass-index-matched healthy individuals. The patients then underwent treatment to control blood glucose levels before end blood samples were taken. The fibrinogen glycation of the diabetic patients was reduced from 8.8 to 5.0 mol glucose/mol fibrinogen, and the healthy individuals had a mean fibrinogen glycation of 4.0 mol glucose/mol fibrinogen. We found that fibrinogen glycation had no significant systematic effect on single-fiber modulus, extensibility, or stress relaxation times. However, we did find that the fiber modulus, Y, strongly decreases with increasing fiber diameter, D, as Y∝D(-1.6). Thin fibers can be 100 times stiffer than thick fibers. This is unusual because the modulus is a material constant and should not depend on the sample dimensions (diameter) for homogeneous materials. Our finding, therefore, implies that fibrin fibers do not have a homogeneous cross section of uniformly connected protofibrils, as is commonly thought. Instead, the density of protofibril connections, ρPb, strongly decreases with increasing diameter, as ρPb∝D(-1.6). Thin fibers are denser and/or have more strongly connected protofibrils than thick fibers. This implies that it is easier to dissolve clots that consist of fewer thick fibers than those that consist of many thin fibers, which is consistent with experimental and clinical observations.

  18. Fibrinogen salvage during DF Thermo using Evaflux-5A plasma fractionators.

    PubMed

    Nakashima, Momoko; Yasui, Masahide; Ihara, Akira

    2012-10-01

    DF Thermo, a modified form of double-filtration plasmapheresis (DFPP), has been used for the treatment of various indications such as arteriosclerosis obliterans (ASO). In case of ASO, fibrinogen is a substance to be removed by DFPP. On the other hand, plasmapheresis for chronic viral hepatitis C became an insurance covered treatment in Japan in April 2008. Since then DFPP has also become a treatment of chronic viral hepatitis C as an adjunctive therapy for the purpose of improving the effect of medication. Therefore, there has been a growing concern in recent years about patients' low fibrinogen levels due to DFPP treatment. With the aim of improving fibrinogen retention by DF Thermo, we examined by in vitro trial, the effects when recirculating the filtrate and elevating its temperature. The trial was conducted using bovine plasma, run through experimental circuits with the same configuration as the clinical setting of the One-Way method and DF Thermo method. The DF Thermo circuit contained a thermostat, on which the temperature was set to 40°C. Two One-Way method circuits were prepared with different temperature settings, i.e., 20°C and 40°C. With these three different conditions, variance of the fibrinogen retention under different temperatures and the implementation of recirculation were compared. Results show that the DF Thermo circuit tends to have enhanced the fibrinogen retention compared to the One-Way method 20°C and 40°C. The explanation is likely as follows: viscosity of plasma reduces when warmed, which in turn helps maintain the permeability of membrane, and the recirculation of the plasma helps prevent membrane fouling, thus more fibrinogen is retained in the DF Thermo method.

  19. Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid beta-peptide.

    PubMed

    Pak, Kirk J; Chan, Sic L; Mattson, Mark P

    2003-01-01

    Although damage to white matter occurs in the brains of patients with Alzheimer's disease (AD), the underlying mechanisms are unknown. Recent findings suggest that individuals with elevated levels of homocysteine are at increased risk of AD. Here we show that oligodendrocytes from mice expressing a mutant form of presenilin-1 (PS1) that causes familial AD exhibit increased sensitivity to death induced by homocysteine compared to oligodendrocytes from wild-type control mice. Homocysteine also sensitized oligodendrocytes to the cytotoxicity of amyloid beta-peptide. Folate deficiency, which is known to result in elevated levels of homocysteine in vivo, also sensitized oligodendrocytes to the cell-death-promoting actions of mutant PS1 and amyloid beta-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid beta-peptide, consistent with a role for a DNA-damage response in the cell death process. These findings demonstrate an adverse effect of homocysteine on oligodendrocytes, and suggest roles for homocysteine and folate deficiency in the white matter damage in AD and related neurodegenerative disorders.

  20. Physiological regulation of phospholipid methylation alters plasma homocysteine in mice.

    PubMed

    Jacobs, René L; Stead, Lori M; Devlin, Cecilia; Tabas, Ira; Brosnan, Margaret E; Brosnan, John T; Vance, Dennis E

    2005-08-05

    Biological methylation reactions and homocysteine (Hcy) metabolism are intimately linked. In previous work, we have shown that phosphatidylethanolamine N-methyltransferase, an enzyme that methylates phosphatidylethanolamine to form phosphatidylcholine, plays a significant role in the regulation of plasma Hcy levels through an effect on methylation demand (Noga, A. A., Stead, L. M., Zhao, Y., Brosnan, M. E., Brosnan, J. T., and Vance, D. E. (2003) J. Biol. Chem. 278, 5952-5955). We have further investigated methylation demand and Hcy metabolism in liver-specific CTP:phosphocholine cytidylyltransferase-alpha (CTalpha) knockout mice, since flux through the phosphatidylethanolamine N-methyltransferase pathway is increased 2-fold to meet hepatic demand for phosphatidylcholine. Our data show that plasma Hcy is elevated by 20-40% in mice lacking hepatic CTalpha. CTalpha-deficient hepatocytes secrete 40% more Hcy into the medium than do control hepatocytes. Liver activity of betaine:homocysteine methyltransferase and methionine adenosyltransferase are elevated in the knockout mice as a mechanism for maintaining normal hepatic S-adenosylmethionine and S-adenosylhomocysteine levels. These data suggest that phospholipid methylation in the liver is a major consumer of AdoMet and a significant source of plasma Hcy.

  1. Effects of Fibrinogen Concentrate on Thrombin Generation, Thromboelastometry Parameters, and Laboratory Coagulation Testing in a 24-Hour Porcine Trauma Model

    PubMed Central

    Zentai, Christian; Solomon, Cristina; van der Meijden, Paola E. J.; Spronk, Henri M. H.; Schnabel, Jonas; Rossaint, Rolf

    2015-01-01

    Introduction: In a 24-hour porcine model of liver injury, we showed that fibrinogen supplementation does not downregulate endogenous fibrinogen synthesis. Here we report data from the same study showing the impact of fibrinogen on coagulation variables. Materials and Methods: Coagulopathy was induced in 20 German land race pigs by hemodilution and blunt liver injury. Animals randomly received fibrinogen concentrate (100 mg/kg) or saline. Coagulation parameters were assessed and thromboelastometry (ROTEM) was performed. Results: Fibrinogen concentrate significantly reduced the prolongations of EXTEM clotting time, EXTEM clot formation time, and prothrombin time induced by hemodilution and liver injury. A decrease in clot strength was also ameliorated. Endogenous thrombin potential was significantly higher in the fibrinogen group than in the control group, 20 minutes (353 ± 24 vs 289 ± 22 nmol/L·min; P < .05) and 100 minutes (315 ± 40 vs 263 ± 38 nmol/L·min; P < .05) after the start of infusion. However, no significant between-group differences were seen in other thrombin generation parameters or in d-dimer or thrombin–antithrombin levels. Fibrinogen–platelet binding was reduced following liver injury, with no significant differences between groups. No significant between-group differences were observed in any parameter at ∼12 and ∼24 hours. Conclusion: This study suggests that, in trauma, fibrinogen supplementation may shorten some measurements of the speed of coagulation initiation and produce a short-lived increase in endogenous thrombin potential, potentially through increased clotting substrate availability. Approximately 12 and 24 hours after starting fibrinogen concentrate/saline infusion, all parameters measured in this study were comparable in the 2 study groups. PMID:25948634

  2. Comparison of parameters of bone profile and homocysteine in physically active and non-active postmenopausal females

    PubMed Central

    Tariq, Sundus; Lone, Khalid Parvez; Tariq, Saba

    2016-01-01

    Background and objectives: Optimal physical activity is important in attaining a peak bone mass. Physically active women have better bone mineral density and reduce fracture risk as compared to females living a sedentary life. The objective of this study was to compare parameters of bone profile and serum homocysteine levels in physically active and non-active postmenopausal females. Methods: In this cross sectional study postmenopausal females between 50-70 years of age were recruited and divided into two groups: Physically inactive (n=133) performing light physical activity and Physically active (n=34) performing moderate physical activity. Physical activity (in metabolic equivalents), bone mineral density and serum homocysteine levels were assessed. Spearman’s rho correlation was applied to observe correlations. Two independent sample t test and Mann Whitney U test were applied to compare groups. P-value ≤ 0.05 was taken statistically significant. Results: Parameters of bone profile were significantly higher and serum homocysteine levels were significantly lower in postmenopausal females performing moderate physical activity as compared to females performing light physical activity. Homocysteine was not significantly related to T-score and Z-score in both groups. Conclusion: Improving physical activity could be beneficial for improving the quality of bone, decreasing fracture risk and decreasing serum homocysteine levels. PMID:27882033

  3. Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer's Disease Neuroimaging Initiative.

    PubMed

    Madsen, Sarah K; Rajagopalan, Priya; Joshi, Shantanu H; Toga, Arthur W; Thompson, Paul M

    2015-01-01

    A significant portion of our risk for dementia in old age is associated with lifestyle factors (diet, exercise, and cardiovascular health) that are modifiable, at least in principle. One such risk factor, high-homocysteine levels in the blood, is known to increase risk for Alzheimer's disease and vascular disorders. Here, we set out to understand how homocysteine levels relate to 3D surface-based maps of cortical gray matter distribution (thickness, volume, and surface area) computed from brain magnetic resonance imaging in 803 elderly subjects from the Alzheimer's Disease Neuroimaging Initiative data set. Individuals with higher plasma levels of homocysteine had lower gray matter thickness in bilateral frontal, parietal, occipital, and right temporal regions and lower gray matter volumes in left frontal, parietal, temporal, and occipital regions, after controlling for diagnosis, age, and sex and after correcting for multiple comparisons. No significant within-group associations were found in cognitively healthy people, patients with mild cognitive impairment, or patients with Alzheimer's disease. These regional differences in gray matter structure may be useful biomarkers to assess the effectiveness of interventions, such as vitamin B supplements, that aim to prevent homocysteine-related brain atrophy by normalizing homocysteine levels.

  4. Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective.

    PubMed

    Santilli, Francesca; Davì, Giovanni; Patrono, Carlo

    2016-03-01

    Observational studies consistently reported an association between plasma total homocysteine concentrations and the risk of vascular events. In contrast, data from randomized trials largely support the hypothesis that mild elevations in homocysteine level have a modest effect on cardiovascular risk. A substantial body of evidence suggests that platelet activation is, at least in part, a transducer of the effects of high homocysteine in promoting atherothrombosis. The larger treatment effect recorded in several supplementation trials by subjects not on antiplatelet agents may support this hypothesis and justify, at least in part, the success of folate therapy in primary prevention. Circulating folate and homocysteine levels as well as MTHFR genotype, while emerging as major predictors of the risk of vascular events and of the efficacy of folic acid therapy, have also proved to be determinants of an interindividual variability in the degree of lipid peroxidation and platelet activation, and of the extent of their downregulation by folic acid. This may justify a variability in folate requirements, to be further characterized with dose-finding studies using biochemical endpoints. The combination of low-dose aspirin and low-dose folate would appear to be ideally suited for the primary prevention of both coronary and cerebrovascular events, and additional clinical trials should assess the efficacy and safety of these agents.

  5. Elevated homocysteine and the risk of contrast-induced nephropathy: a cohort study.

    PubMed

    Barbieri, Lucia; Verdoia, Monica; Schaffer, Alon; Niccoli, Giampaolo; Perrone-Filardi, Pasquale; Bellomo, Giorgio; Marino, Paolo; Suryapranata, Harry; Luca, Giuseppe De

    2015-04-01

    Contrast-induced nephropathy (CIN) is a common complication in patients with impaired kidney function undergoing coronary angiography/angioplasty. We evaluated whether elevated homocysteine (known to be associated with free radical generation and oxidative stress) increases the risk of CIN. Patients (n = 876) with creatinine clearance <60 mL/min undergoing coronary angiography or percutaneous coronary intervention (PCI) were divided into tertiles of homocysteine levels. Contrast-induced nephropathy was defined as ≥0.5 mg/dL or ≥25% creatinine increase 24 to 48 hours post-PCI. A significant relationship was observed between homocysteine levels and the risk of CIN (P = .033), confirmed after correction for baseline confounding factors, adjusted odds ratio, OR (95% confidence interval, [CI]) = 1.68 (1.09-2.59), P = .019. This association was also significant applying the new definition of contrast-induced acute kidney injury (11.9% in group 1, 10.4% in group 2, and 22.8% in group 3; P < .001), adjusted OR (95% CI) = 1.96 (1.3-2.95), P = .001. Future studies are needed to confirm our findings and to define the role of homocysteine in CIN.

  6. Creatine prevents the imbalance of redox homeostasis caused by homocysteine in skeletal muscle of rats.

    PubMed

    Kolling, Janaína; Scherer, Emilene B S; Siebert, Cassiana; Marques, Eduardo Peil; Dos Santos, Tiago Marcom; Wyse, Angela T S

    2014-07-15

    Homocystinuria is a neurometabolic disease caused by severe deficiency of cystathionine beta-synthase activity, resulting in severe hyperhomocysteinemia. Affected patients present several symptoms including a variable degree of motor dysfunction, being that the pathomechanism is not fully understood. In the present study we investigated the effect of chronic hyperhomocysteinemia on some parameters of oxidative stress, namely 2'7'dichlorofluorescein (DCFH) oxidation, levels of thiobarbituric acid-reactive substances (TBARS), antioxidant enzyme activities (SOD, CAT and GPx), reduced glutathione (GSH), total sulfhydryl and carbonyl content, as well as nitrite levels in soleus skeletal muscle of young rats subjected to model of severe hyperhomocysteinemia. We also evaluated the effect of creatine on biochemical alterations elicited by hyperhomocysteinemia. Wistar rats received daily subcutaneous injection of homocysteine (0.3-0.6 μmol/g body weight), and/or creatine (50mg/kg body weight) from their 6th to the 28th days age. Controls and treated rats were decapitated at 12h after the last injection. Chronic homocysteine administration increased 2'7'dichlorofluorescein (DCFH) oxidation, an index of production of reactive species and TBARS levels, an index of lipoperoxidation. Antioxidant enzyme activities, such as SOD and CAT were also increased, but GPx activity was not altered. The content of GSH, sulfhydril and carbonyl were decreased, as well as levels of nitrite. Creatine concurrent administration prevented some homocysteine effects probably by its antioxidant properties. Our data suggest that the oxidative insult elicited by chronic hyperhomocystenemia may provide insights into the mechanisms by which homocysteine exerts its effects on skeletal muscle function. Creatine prevents some alterations caused by homocysteine.

  7. [Deposition of von Willebrand factor in human endothelial cells HUVEC in the endoplasmic reticulum stress induced by an excess of homocysteine in vitro].

    PubMed

    Ignashkova, T I; Mesitov, M V; Rybakov, A S; Moskovtsev, A A; Sokolovskaia, A A; Kubatiev, A A

    2012-01-01

    Von Willebrand factor (vWF) is an adhesive glycoprotein synthesized and secreted by endothelial cells and megakaryocytes. Violation of vWF secretion by endothelial cells is a characteristic feature of endothelial dysfunction in hyperhomocysteinemia. In our study we examined to clarify the concentration-dependent effect of homocysteine (Hcy) on the expression of vWF. Our studies have shown that homocysteine excess induces changes in the intracellular deposition of von Willebrand factor in cultured human endothelial cells in vitro. Primary cultures of human umbilical vein endothelial cells (HUVEC) were incubated with the various concentrations of D,L-homocysteine (0.025 - 5 mM). Homocysteine at a concentration of 0.025 and 0.25 mM after 18 h incubation caused an increase in the intracellular fraction of vWF in HUVEC cells. High concentrations of homocysteine induced a dose-dependent decrease in the intracellular fraction of vWF. These dose-dependent variations may indicate the modulation by homocysteine of different mechanisms of the deposition, the constitutive secretion and the degradation of vWF in human endothelial cells. We proposed that Endoplasmic reticulum stress, in HUVEC cells by the action of an excess of homocysteine associated with increased intracellular levels of vWF at a relatively low concentration of the inducer. We found decline in intracellular vWF at the same duration but higher concentrations of inducer, which may be due to the ER-associated protein degradation.

  8. Single-molecule surface studies of fibrinogen and DNA on semiconductors

    NASA Astrophysics Data System (ADS)

    Kong, Xianhua

    Understanding of protein adsorption onto non-biological substrates is of fundamental interest in science, but also has great potential technological applications in medical devices and biosensors. This study explores the non-specific interaction, at the single molecule level, of a blood protein and DNA with semiconductor surfaces through the use of a custom built, non rastering electron emission microscope and a scanning probe microscope. The specifics and history of electron emission are described as well as the equipment used in this study. The protein examined in this study is human plasma fibrinogen, which plays an important role in haemostatis and thrombosis, and deoxyribonucleic acid (DNA) is also studied. A novel technique for determining the photothreshold of biomolecules on single molecule level is developed and applied to fibrinogen molecules adsorbed on oxidized silicon surfaces, using photo-electron emission microscopy (PEEM). Three theoretical models are employed and compared to analyze the experimental photothreshold data. The non-specific adsorption of human plasma fibrinogen on oxidized p- and n- type silicon (100) surfaces is investigated to characterize both hydrophobic interactions and electrostatic forces. The experimental results indicate that hydrophobic interactions are one of the driving forces for protein adsorption and the electrostatic interactions also play a role in the height of the fibrinogen molecules adsorbed on the surface. PEEM images establish a photo threshold of 5.0 +/- 0.2 eV for fibrinogen on both n-type and p-type Si (100) surfaces. We suggest that the photothreshold results from surface state associated Fermi level (EF) pinning and there exists negative charge transfer from the adsorbed fibrinogen onto the p-type silicon substrates, while on n-type silicon substrates negative charge is transferred in the opposite direction. The adsorption of deoxyribonucleic acid (DNA) on mica and silicon is studied in liquid and ambient

  9. Human fibrinogen monolayers on latex particles: role of ionic strength.

    PubMed

    Bratek-Skicki, Anna; Żeliszewska, Paulina; Adamczyk, Zbigniew; Cieśla, Michał

    2013-03-19

    The adsorption of human serum fibrinogen on polystyrene latex particles was studied using the microelectrophoretic and concentration depletion methods. Measurements were carried out for pH 3.5 and an ionic strength range of 10(-3) to 0.15 M NaCl. The electrophoretic mobility of latex was determined as a function of the amount of adsorbed fibrinogen (surface concentration). A monotonic increase in the electrophoretic mobility (zeta potential) of the latex was observed, indicating a significant adsorption of fibrinogen on latex for all ionic strengths. No changes in the latex mobility were observed for prolonged time periods, suggesting the irreversibility of fibrinogen adsorption. The maximum coverage of fibrinogen on latex particles was precisely determined using the depletion method. The residual protein concentration after making contact with latex particles was determined by electrokinetic measurements and AFM imaging where the surface coverage of fibrinogen on mica was quantitatively determined. The maximum fibrinogen coverage increased monotonically with ionic strength from 1.8 mg m(-2) for 10(-3) M NaCl to 3.6 mg m(-2) for 0.15 M NaCl. The increase in the maximum coverage was interpreted in terms of the reduced electrostatic repulsion among adsorbed fibrinogen molecules. The experimental data agree with theoretical simulations made by assuming a 3D unoriented adsorption of fibrinogen. The stability of fibrinogen monolayers on latex was also determined in ionic strength cycling experiments. It was revealed that cyclic variations in NaCl concentration between 10(-3) and 0.15 M induced no changes in the latex electrophoretic mobility, suggesting that there were no irreversible molecule orientation changes in the monolayers. On the basis of these experimental data, a robust procedure of preparing fibrinogen monolayers on latex particles of well-controlled coverage was proposed.

  10. [HOMOCYSTEINE AS A PROGNOSTIC MARKER OF ATRIAL REMODELING AND CLINICAL PICTURE IN PATIENTS WITH PAROXYSMAL AND PERSISTENT FORMS OF ATRIAL FIBRILLATION].

    PubMed

    Snezhitsky, V A; Yatskevich, E S; Doroshenko, E M; Smirnov, V Yu; Dolgoshey, T S; Rubinsky, A Yu

    2016-01-01

    The aim of this work was to study prognostic significance of the relationship between the homocysteine level, structural/functional atrial remodeling, and clinical picture of paroxysmal and persistent forms of atrial fibrillation (AF). The study included 75 patients with AF concomitant with coronary heart disease and hypertensive disease without apparent structural changes in myocardium. Group 1 was comprised of 48 patients with paroxysmal AF, group 2 of 27 patients with persistent AF. 19 patients with coronary heart disease and hypertensive disease without AF served as controls. The structural and functional state of the heart was evaluated based on two-dimensional trans-thoracal echocardiography with the use of the formulas for calculating left ventricular characteristics. Blood homocysteine levels were measured The frequency of AF relapses was determined after an 1 year follow-up. The homocysteine level over 11.2 mcmol/l was related to left ventricle enlargement (over 40 mm), high frequency and relapse rate of AF. It is concluded that the relationship between homocysteine levels, left ventricle size, frequency and relapse rate of AF suggests the influence of homocysteine on atrial remodeling. A rise in the homocysteine level above 11 mcmol/l should be regarded as a prognostic factor of increased AF relapse rate.

  11. [Study on the selective removal of plasma low-density lipoprotein and fibrinogen by degraded carrageenan].

    PubMed

    Cong, Haixia; Yin, Liang; Fang, Bo; Du, Longbing; Zhao, Hui; Chen, Jingling; You, Chao

    2010-08-01

    The selective removal of low density lipoprotein (LDL) and fibrinogen (Fib) by degraded carrageenan was studied by the present authors. Degraded carrageenan was prepared by acid with carrageenan as the main material. The effects of acid conditions on the molecular weight were investigated, and the proper reaction conditions were ascertained. The results of infrared spectrometry indicated that the degraded carrageenan is a heparin-like polysaccharide. Then the selective removal of LDL/Fibrinogen by degraded carrageenan was studied. When molecular weight was about 10,000, pH was 5.10 and the concentration of degraded carrageenan was 800 mg/L, the average reduction percentages were 60.0% for total cholesterol(TC), 79.4% for LDL and very low-density lipoprotein (VLDL), and 93.8% for fibrinogen. There were no significant changes with relation to the level of high-density lipoprotein (HDL) and total protein (TP). So, degraded carrageenan was shown to be of good selectivity on plasma LDL/Fibrinogen apheresis.

  12. Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular disease

    PubMed Central

    Lominadze, D.; Dean, W. L.; Tyagi, S. C.; Roberts, A. M.

    2009-01-01

    Fibrinogen (Fg) is a high molecular weight plasma adhesion protein and a biomarker of inflammation. Many cardiovascular and cerebrovascular disorders are accompanied by increased blood content of Fg. Increased levels of Fg result in changes in blood rheological properties such as increases in plasma viscosity, erythrocyte aggregation, platelet thrombogenesis, alterations in vascular reactivity and compromises in endothelial layer integrity. These alterations exacerbate the complications in peripheral blood circulation during cardiovascular diseases such as hypertension, diabetes and stroke. In addition to affecting blood viscosity by altering plasma viscosity and erythrocyte aggregation, growing experimental evidence suggests that Fg alters vascular reactivity and impairs endothelial cell layer integrity by binding to its endothelial cell membrane receptors and activating signalling mechanisms. The purpose of this review is to discuss experimental data, which demonstrate the effects of Fg causing vascular dysfunction and to offer possible mechanisms for these effects, which could exacerbate microcirculatory complications during cardiovascular diseases accompanied by increased Fg content. PMID:19723026

  13. Discriminating Neoantigenic Differences Between Fibrinogen and Fibrin Derivatives

    PubMed Central

    Plow, Edward F.; Edgington, Thomas S.

    1973-01-01

    Discrimination between the physiological cleavage fragments of fibrinogen and fibrin offers an approach to differentiation between fibrinogenolytic processes and fibrinolysis after coagulation. By use of the cleavage-associated neoantigen of fibrinogen (fg-Dneo) as a molecular marker, characteristic differences between the D regions of fibrinogen derivatives and fibrin derivatives can be demonstrated. The expression of fg-Dneo by X, Y, D:E complex, and D-fragments of fibrinogen or fibrin is shown to be quantitative and unitary. Characteristic differences between fg-Dneo sites present on fibrinogen cleavage fragments, as contrasted to fibrin cleavage fragments, are indicated by different competitive inhibition slopes, and appear to reflect differential binding affinity of selected anti-fg-Dneo antibodies for the specific molecular site. There is a linear relationship between the slope of quantitative competitive inhibition and the relative molar ratio of fibrinogen and fibrin derivatives. Identical immunochemical expressions are observed in vitro and in vivo, and support the thesis that cleavage in vivo is produced by plasmin. The differential immunochemical features of fg-Dneo expression may be the result of stable conformational and/or subtle structural differences between the D region of fibrinogen and fibrin cleavage fragments and suggest that precise changes in the D region are associated with the fibrin transition. These molecular features not only provide additional insight into the molecular immunology and structure of fibrinogen, but also appear to offer a new molecular approach to discrimination between fibrinogenolytic mechanisms as contrasted to fibrinolysis secondary to coagulation. PMID:4123931

  14. Protecting fibrinogen with rutin during UVC irradiation for viral inactivation.

    PubMed

    Marx, G; Mou, X; Freed, R; Ben-Hur, E; Yang, C; Horowitz, B

    1996-04-01

    Fibrinogen solutions were irradiated with UVC (254 nm) to inactivate contaminating viruses. In order to protect fibrinogen during UVC irradiation, 0.5 mM rutin was added prior to UVC exposure and subsequently removed during processing. Viral kill by 0.1 J/cm2 UVC resulted in the following inactivation values (log 10): non-lipid-enveloped viruses: Parvo > or = 5.5; encephalomyocarditis virus > or = 6.5; hepatitis A virus > or = 6.5: lipid-enveloped viruses: human immunodeficiency virus > or = 5.7; vesicular stomatitis virus > or = 5.7. Fibrinogen irradiated with 0.5 mM rutin did not significantly differ from unirradiated material in terms of clot time and breaking strength. In the absence of rutin, UVC irradiation of fibrinogen at similar fluence led to loss of solubility, increased clot time and the cleavage of fibrino-peptides that reacted with dinitrophenyl hydrazine as a test for ketonic carbonyl groups. High-performance liquid chromatography and mass spectrometry data showed that rutin exposed to UVC formed numerous breakdown, oxidation and combinational products. Experiments with 3H-rutin showed that after UVC irradiation, subsequent processing by a C18 resin and alcohol precipitation removed > 99% rutin, representing < 10 ppm rutin in the final fibrinogen preparations. Residual 3H-rutin was not covalently bonded to the fibrinogen. Immunochemical studies with rabbit antisera to UVC irradiated (with rutin) fibrinogen showed the absence of neoimmungens. By all measures, rutin prevents fibrinogen degradation during virucidal UVC irradiation.

  15. Nanostructuring of PEG-fibrinogen polymeric scaffolds.

    PubMed

    Frisman, Ilya; Seliktar, Dror; Bianco-Peled, Havazelet

    2010-07-01

    Recent studies have shown that nanostructuring of scaffolds for tissue engineering has a major impact on their interactions with cells. The current investigation focuses on nanostructuring of a biocompatible, biosynthetic polymeric hydrogel scaffold made from crosslinked poly(ethylene glycol)-fibrinogen conjugates. Nanostructuring was achieved by the addition of the block copolymer Pluronic F127, which self-assembles into nanometric micelles at certain concentrations and temperatures. Cryo-transmission electron microscopy experiments detected F127 micelles, both embedded within PEGylated fibrinogen hydrogels and in solution. The density of the F127 micelles, as well as their ordering, increased with increasing block copolymer concentration. The mechanical properties of the nanostructured hydrogels were investigated using stress-sweep rheological testing. These tests revealed a correlation between the block copolymer concentration and the storage modulus of the composite hydrogels. In vitro cellular assays confirmed that the increased modulus of the hydrogels did not limit the ability of the cells to form extensions and become spindled within the three-dimensional (3-D) hydrogel culture environment. Thus, altering the nanostructure of the hydrogel may be used as a strategy to control cellular behavior in 3-D through changes in mechanical properties of the environment.

  16. [Molecular biology of haemostasis: fibrinogen, factor XIII].

    PubMed

    Meyer, M

    2004-05-01

    Genetic defects of fibrinogen are caused by a broad spectrum of mutations in one of the three structural genes FGA, FGB and FGG. They result in complete or partial lack of plasma fibrinogen (a- or hypofibrinogenaemia) or in structural abnormalities affecting protein function (dysfibrinogenaemia). In contrast to afibrinogenaemia mainly caused by nonsense, frameshift, and splice site mutations resulting in substantially truncated polypeptide chains (mainly Aalpha), in hypo- and dysfibrinogenaemias missense mutations lead to the exchange of single amino acids as dominating underlying defect. In the cases with quantitative disorders, bleeding with various degrees of severity is generally observed. Dysfibrinogenaemia is associated with both bleeding or thrombosis or even a combination of haemorrhagic and thromboembolic symptoms. About one half of the dysfibrinogenaemic cases is clinically asymptomatic. The plasmatic factor XIII (FXIII) is a heterotetramer composed of two A and two B subunits encoded by two different genes. FXIII deficiency is associated with bleeding, wound dehiscence and recurrent spontaneous abortions. The most frequent form is caused by defects in the A subunit with a broad spectrum of underlying mutations. Defects of the B subunit are very rare and were molecularly elucidated in only a few cases.

  17. Effect of Vitamin B12 supplementation on serum homocysteine in patients undergoing hemodialysis: A randomized controlled trial.

    PubMed

    Tayebi, Ali; Biniaz, Vajihe; Savari, Samira; Ebadi, Abbas; Shermeh, Mahdi Sadeghi; Einollahi, Behzad; Rahimi, Abolfazl

    2016-03-01

    Clinical studies have shown that hyper-homocysteinemia is a potent independent risk factor for cardiovascular diseases, and many different methods have been investigated for lowering it in hemodialysis (HD) patients. Our study investigated the effect of Vitamin B 12 supplementation on serum homocysteine levels in these patients. This randomized trial was conducted on 140 HD patients. They were randomly distributed by lottery method into two groups: intervention and control. In the intervention group, 100 μg/mL of Vitamin B 12 was intravenously injected two times a week, for eight weeks. No intervention was performed in the control group. Serum levels of homocysteine, hemoglobin (Hb), and hematocrit (Hct) were measured at the beginning and again after eight weeks (2 months) of treatment. About 91% of the patients had hyperhomocysteinemia (serum homocysteine >15 μmol/L). The median baseline levels of serum homocysteine in the intervention and control groups were 31.9 and 26.9 μmol/L, respectively (P = 0.1). After eight weeks, the median homocysteine level reduced significantly in the Vitamin B 12 group to 22.2 versus 28.4 μmol/L in control group (P = 0.006). The mean Hb and Hct also changed significantly during our study (12.3 vs. 11.4 g/dL; P = 0.003 and 37.9 vs. 35.3%; P = 0.02, respectively). Our results demonstrated the existence of a statistical negative relationship between Vitamin B 12 and serum levels of homocysteine. Detailed investigations with larger sample sizes and longer-term use of Vitamin B 12 are recommended.

  18. Comparison of the effect of homocysteine in the reduced form, its thiolactone and protein homocysteinylation on hemostatic properties of plasma.

    PubMed

    Malinowska, Joanna; Nowak, Paweł; Olas, Beata

    2011-03-01

    Mechanisms involved in the relationship between hyperhomocysteinemia and hemostatic process are still unclear. In the literature there are few papers describing studies on the effects of homocysteine (Hcys) on proteins that participate in blood coagulation and fibrinolysis in human. The aim of our study was to establish and compare the influence of a reduced form of Hcys (at final doses of 0.01 - 1 mM) and the most reactive form of Hcys - its cyclic thioester, homocysteine thiolactone (HTL, 0.1 - 1 μM) on the clot formation (using whole human plasma and purified fibrinogen) and the fibrin lysis. Moreover, the aim of our study was to explain the effect of plasma protein modifications (S- and N-homocysteinylation) on selected parameters of hemostasis. We observed that HTL, like its precursor, a reduced form of Hcys stimulated polymerization of fibrinogen, but this process was not dose-dependent. In the presence of HTL (at the lowest tested concentration - 0.1μM) the increase was about 55%. Our present results also demonstrated that Hcys in the reduced form (0.01 - 1 mM) and HTL at lower doses than Hcys (0.1 - 1 μM) reduced the fibrin lysis in whole human plasma. Our results reported that HTL, like the reduced form of Hcys (at concentrations corresponding to concentrations in plasma during hyperhomocysteinemia) induced modifications of hemostatic plasma proteins, and the consequence of these modifications may be alteration in protein structure associated with changes of hemostatic functions.

  19. The role of fibrinogen and haemostatic assessment in postpartum haemorrhage: preparations for a randomised controlled trial.

    PubMed

    Wikkelsø, Anne Juul

    2015-04-01

    Pregnancy is a state of hypercoagulobility that might be an evolutionary way of protecting parturients from exsanguination following child birth. Observational studies suggest an association between a low level of fibrinogen (coagulation factor I) at the start of postpartum haemorrhage (PPH) and subsequent severity of bleeding. Fibrinogen concentrate may be prescribed to correct acquired hypofibrinogenaemia, but evidence is lacking regarding the treatment efficacy. This thesis assesses the current evidence for the use of fibrinogen concentrate and haemostatic assessment in bleeding patients with special attention to the obstetrical population. It includes five papers: In Paper I the benefits or harms of fibrinogen concentrate in bleeding patients in general was evaluated using a systematic Cochrane review methodology with metaanalysis of all published randomized controlled trials (RCTs). Six trials with high risk of bias were included (248 patients). Fibrinogen appeared to reduce the need of allogenic transfusions by 53%. However, the included trials were conducted only in an elective surgical setting with a population of mainly cardiac surgical patients. Paper II was also a systematic review based on Cochrane methodology evaluating the use of viscoelastic haemostatic assays to guide haemostatic transfusion in bleeding patients. Nine RCTs (776 patients) with high risk of bias were included primarily in elective cardiac surgical patients and none were specific for the obstetric subpopulation. Viscoelastic haemostatic assay guided transfusion algorithm reduced blood loss and the proportion of patients exposed to fresh frozen plasma (FFP) or platelets. In both studies, we were unable to make firm conclusion on our primary outcome, "all cause mortality" due to lack of adequate data. Paper III was based on two national Danish registries evaluating the predictability of postpartum blood transfusion. Prediction was found difficult. However, retained placental parts seemed

  20. Preparation of CuO/ZnO nanocomposite and its application as a cysteine/homocysteine colorimetric and fluorescence detector.

    PubMed

    Šimšíková, Michaela; Čechal, Jan; Zorkovská, Anna; Antalík, Marián; Šikola, Tomáš

    2014-11-01

    Cysteine and homocysteine play a crucial role in many biological functions but abnormal levels of these amino acids may lead to various forms of pathogenesis. Therefore, selective and easy-to-use methods for the detection of cysteine and homocysteine are essential for the early diagnosis of developing diseases. In this paper we report on a rapid, straightforward and highly selective method for the detection of cysteine (Cys) and homocysteine (Hcy) which uses a CuO/ZnO nanocomposite as a dual colorimetric and fluorometric assay. The presence of Cys and Hcy in a solution of these nanorods (NRs) induces a change in its color from light blue to dark grey which is visible to the naked eye. This is accompanied by a blue shift in the absorption spectra from 725 nm to 650 nm and a decrease in the intensity of CuO/ZnO nanocomposite emission. These changes are ascribed to the reduction of Cu(II) to Cu(0), and the oxidation of cysteine (homocysteine) and subsequent formation of the disulfide bond. This novel assay method does not respond to any other amino-acid which is present in living organisms; therefore the selective determination of cysteine (homocysteine) with a lower analyte limit of 40 μM (4.8 μg mL(-1)) can be carried out in aqueous solutions without the need for any sophisticated instrumentation, fluorophore molecules or complicated procedures.

  1. The fibrous form of intracellular inclusion bodies in recombinant variant fibrinogen-producing cells is specific to the hepatic fibrinogen storage disease-inducible variant fibrinogen.

    PubMed

    Arai, Shinpei; Ogiwara, Naoko; Mukai, Saki; Takezawa, Yuka; Sugano, Mitsutoshi; Honda, Takayuki; Okumura, Nobuo

    2017-02-04

    Fibrinogen storage disease (FSD) is a rare disorder that is characterized by the accumulation of fibrinogen in hepatocytes and induces liver injury. Six mutations in the γC domain (γG284R, γT314P, γD316N, the deletion of γG346-Q350, γG366S, and γR375W) have been identified for FSD. Our group previously established γ375W fibrinogen-producing Chinese hamster ovary (CHO) cells and observed aberrant large granular and fibrous forms of intracellular inclusion bodies. The aim of this study was to investigate whether fibrous intracellular inclusion bodies are specific to FSD-inducible variant fibrinogen. Thirteen expression vectors encoding the variant γ-chain were stably or transiently transfected into CHO cells expressing normal fibrinogen Aα- and Bβ-chains or HuH-7 cells, which were then immunofluorescently stained. Six CHO and HuH-7 cell lines that transiently produced FSD-inducible variant fibrinogen presented the fibrous (3.2-22.7 and 2.1-24.5%, respectively) and large granular (5.4-25.5 and 7.7-23.9%) forms of intracellular inclusion bodies. Seven CHO and HuH-7 cell lines that transiently produced FSD-non-inducible variant fibrinogen only exhibit the large granular form. These results demonstrate that transiently transfected variant fibrinogen-producing CHO cells and inclusion bodies of the fibrous form may be useful in non-invasive screening for FSD risk factors for FSD before its onset.

  2. Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease.

    PubMed

    Pacana, Tommy; Cazanave, Sophie; Verdianelli, Aurora; Patel, Vaishali; Min, Hae-Ki; Mirshahi, Faridoddin; Quinlivan, Eoin; Sanyal, Arun J

    2015-01-01

    Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA

  3. Dietary glycemic index, but not glycemic load, is positively associated with serum homocysteine concentration in free-living young Japanese women.

    PubMed

    Murakami, Kentaro; Sasaki, Satoshi; Uenishi, Kazuhiro

    2014-01-01

    It has been suggested that diets which enhance diurnal insulin secretion, such as a high glycemic index (GI) and glycemic load (GL) diet, can be expected to increase homocysteine levels. We investigated the hypothesis that dietary GI and GL are positively associated with serum homocysteine concentration in a group of free-living young Japanese women. This preliminary cross-sectional study included 1050 female Japanese dietetic students aged 18 to 22 years. Dietary intake was assessed using a validated, self-administered, comprehensive diet history questionnaire. Fasting blood samples were collected and serum homocysteine concentrations were measured. Adjustment was made for survey year, region, municipality level, current smoking, current alcohol consumption, dietary supplement use, physical activity, body mass index, energy intake, and intakes of B vitamins (folate, vitamin B6, vitamin B12, and riboflavin). After adjustment for nondietary confounding factors, both dietary GI and GL were positively associated with homocysteine concentration (both P for trend=.001). The positive association between dietary GI and homocysteine concentration remained after further adjustment for intakes of B vitamins. Mean (95% confidence interval) values of serum homocysteine concentration for each quintile of dietary GI were 6.9 (6.7-7.2), 7.1 (6.8-7.3), 7.0 (6.7-7.2), 7.4 (7.2-7.7), and 7.3 (7.0-7.6) μmol/L, respectively (P for trend = .04). Conversely, there was no association between dietary GL and homocysteine concentration after further adjustment for intakes of B vitamins (P for trend = .40). To conclude, in a group of free-living young Japanese women, dietary GI, but not GL, was independently and positively associated with serum homocysteine concentration.

  4. Turkish propolis supresses MCF-7 cell death induced by homocysteine.

    PubMed

    Tartik, Musa; Darendelioglu, Ekrem; Aykutoglu, Gurkan; Baydas, Giyasettin

    2016-08-01

    Elevated plasma homocysteine (Hcy) level is a most important risk factor for various vascular diseases including coronary, cerebral and peripheral arterial and venous thrombosis. Propolis is produced by honeybee from various oils, pollens and wax materials. Therefore, it has various biological properties including antioxidant, antitumor and antimicrobial activities. This study investigated the effects of propolis and Hcy on apoptosis in cancer cells. According to our findings, Hcy induced apoptosis in human breast adenocarcinoma (MCF-7) cells by regulating numerous genes and proteins involved in the apoptotic signal transduction pathway. In contrast, treatment with propolis inhibited caspase- 3 and -9 induced by Hcy in MCF-7 cells. It can be concluded that Hcy may augment the activity of anticancer agents that induce excessive reactive oxygen species (ROS) generation and apoptosis in their target cells. In contrast to the previous studies herein we found that propolis in low doses protected cancer cells inhibiting cellular apoptosis mediated by intracellular ROS-dependent mitochondrial pathway.

  5. [Determination of homocysteine by tandem mass spectrometry with chemical ionization].

    PubMed

    Miroshnichenko, I I; Platova, A I; Safarova, T P; Iakovleva, O B

    2014-01-01

    Homocysteine (Hcy) is an intermediate of methionine metabolism. High plasma Hcy concentrations are an independent risk factor for stroke, peripheral vascular disease, deep venous thrombosis, coronary disease, and cognitive deficiency. Apparently, it is a great importance to measure Hcy levels in human blood. A new method for the quantification of Hcy by means of reversed-phase LC/atmospheric pressure chemical ionization mass spectrometry has been developed. The MRM ion transition, m/z 136.0 ® 90.0 was used for Hcy quantification. The limit of detection was 0.4 mM, quantification was performed from 1 mM to 40 mM with coefficient of determination of R2=0,997. The method was applied successfully to Hcy determination in human blood.

  6. The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients.

    PubMed

    Dietrich-Muszalska, Anna; Malinowska, Joanna; Olas, Beata; Głowacki, Rafal; Bald, Edward; Wachowicz, Barbara; Rabe-Jabłońska, Jolanta

    2012-05-01

    The mechanisms of oxidative stress in schizophrenic patients are not fully understood. In the present study, we investigated the effect of elevated level of homocysteine (Hcys) on some parameters of oxidative stress, namely thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation in plasma, the level of carbonyl groups in plasma proteins, as well as the amount of 3-nitrotyrosine in plasma proteins isolated from schizophrenic patients. Patients hospitalised in I and II Psychiatric Department of Medical University in Lodz, Poland were interviewed with special questionnaire (treatment, course of diseases, dyskinesis and other EPS). According to DSM-IV criteria all patients had diagnosis of paranoid type. They were treated with antipsychotic drugs (clozapine, risperidone, olanzapine). Mean time of schizophrenia duration was about 5 years. High-performance liquid chromatography was used to analyse the total level of homocysteine in plasma. Levels of carbonyl groups and 3-nitrotyrosine residues in plasma proteins were measured by ELISA and a competition ELISA, respectively. The lipid peroxidation in plasma was measured by the level of TBARS. Our results showed that in schizophrenic patients the amount of homocysteine in plasma was higher in comparison with the control group. We also observed a statistically increased level of biomarkers of oxidative/nitrative stress such as carbonyl groups or 3-nitrotyrosine in plasma proteins from schizophrenic patients. Moreover, our experiments indicate that the correlation between the increased amount of homocysteine and the oxidative stress exists. Considering the data presented in this study, we suggest that the elevated Hcys in schizophrenic patients may stimulate the oxidative stress.

  7. Hereditary renal amyloidosis with a novel variant fibrinogen.

    PubMed Central

    Uemichi, T; Liepnieks, J J; Benson, M D

    1994-01-01

    Two families with hereditary renal amyloidosis were found to have a novel mutation in the fibrinogen A alpha chain gene. This form of amyloidosis is an autosomal dominant condition characterized by proteinuria, hypertension, and subsequent azotemia. DNAs of patients with amyloidosis were screened for a polymorphism in fibrinogen A alpha chain gene by single-strand conformation polymorphism analysis, and affected individuals from two kindreds were found to have a mutation. Both of these kindreds are American of Irish descent presenting with non-neuropathic, nephropathic amyloidosis in the fifth to the seventh decade of life. DNA sequencing showed a point mutation in the fibrinogen A alpha chain gene that is responsible for substitution of valine for glutamic acid at position 526. By restriction fragment length polymorphism analysis, 7 affected individuals and 14 asymptomatic individuals in these two kindreds were positive for the fibrinogen A alpha chain Val 526 gene. Fibrinogen was isolated from plasma of a heterozygous gene carrier and shown to contain approximately 50% variant fibrinogen. Discovery of this new mutation confirms the association between fibrinogen A alpha chain variant and hereditary renal amyloidosis and establishes a new biochemical subtype of amyloidosis. Images PMID:8113408

  8. Ultrastructural and biochemical analysis of fibrinogen receptors on activated thrombocytes

    SciTech Connect

    O'Toole, E.T.

    1989-01-01

    The present studies have been concerned with the role of fibrinogen and its receptor, GP IIb/IIIa, during the activation and early aggregation of pigeon thrombocytes. Thrombocytes were surface labeled with {sup 125}I then separated on SDS-PAGE. Analysis by gel autoradiography revealed major bands at MW 145 kd and 98 kd, which corresponded to human GPIIb and GPIIIa. Immunologic similarity of the pigeon and human receptor components was established by dot blot analysis using polyclonal antibodies directed against human GPIIb and GPIIIa. Pigeon fibrinogen, isolated by plasma precipitation with PEG-1000 and purified over Sepharose 4B, was used to study receptor-ligand interaction. Separation of pigeon fibrinogen on SDS-PAGE resulted in three peptides having apparent MW of 62kd, 55kd, and 47kd which are comparable to human fibrinogen. Further similarity of human and pigeon fibrinogen was verified by immonodiffusion against an antibody specific for the human protein. The role of fibrinogen and its receptor in thrombocyte function was established by turbidimetric aggregation using thrombin as an agonist under conditions requiring Ca++ and fibrinogen.

  9. Antibody functionalized graphene biosensor for label-free electrochemical immunosensing of fibrinogen, an indicator of trauma induced coagulopathy.

    PubMed

    Saleem, Waqas; Salinas, Carlos; Watkins, Brian; Garvey, Gavin; Sharma, Anjal C; Ghosh, Ritwik

    2016-12-15

    An antibody, specific to fibrinogen, has been covalently attached to graphene and deposited onto screen printed electrodes using a chitosan hydrogel binder to prepare an inexpensive electrochemical fibrinogen biosensor. Fourier Transform Infrared (FT-IR) spectroscopy has been utilized to confirm the presence of the antibody on the graphene scaffold. Electrochemical Impedance Spectroscopy (EIS) has been utilized to demonstrate that the biosensor responds in a selective manner to fibrinogen in aqueous media even in the presence of plasminogen, a potentially interfering molecule in the coagulopathy cascade. Furthermore, the biosensor was shown to reliably sense fibrinogen in the presence of high background serum albumin levels. Finally, we demonstrated detection of clinically relevant fibrinogen concentrations (938-44,542μg/dL) from human serum and human whole blood samples using this biosensor. This biosensor can potentially be used in a point-of-care device to detect the onset of coagulopathy and monitor response following therapeutic intervention in trauma patients. Thus this biosensor may improve the clinical management of patients with trauma-induced coagulopathy.

  10. Specific potassium ion interactions facilitate homocysteine binding to betaine-homocysteine S-methyltransferase.

    PubMed

    Mládková, Jana; Hladílková, Jana; Diamond, Carrie E; Tryon, Katherine; Yamada, Kazuhiro; Garrow, Timothy A; Jungwirth, Pavel; Koutmos, Markos; Jiráček, Jiří

    2014-10-01

    Betaine-homocysteine S-methyltransferase (BHMT) is a zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. This reaction supports S-adenosylmethionine biosynthesis, which is required for hundreds of methylation reactions in humans. Herein we report that BHMT is activated by potassium ions with an apparent K(M) for K⁺ of about 100 µM. The presence of potassium ions lowers the apparent K(M) of the enzyme for homocysteine, but it does not affect the apparent K(M) for betaine or the apparent k(cat) for either substrate. We employed molecular dynamics (MD) simulations to theoretically predict and protein crystallography to experimentally localize the binding site(s) for potassium ion(s). Simulations predicted that K⁺ ion would interact with residues Asp26 and/or Glu159. Our crystal structure of BHMT bound to homocysteine confirms these sites of interaction and reveals further contacts between K⁺ ion and BHMT residues Gly27, Gln72, Gln247, and Gly298. The potassium binding residues in BHMT partially overlap with the previously identified DGG (Asp26-Gly27-Gly28) fingerprint in the Pfam 02574 group of methyltransferases. Subsequent biochemical characterization of several site-specific BHMT mutants confirmed the results obtained by the MD simulations and crystallographic data. Together, the data herein indicate that the role of potassium ions in BHMT is structural and that potassium ion facilitates the specific binding of homocysteine to the active site of the enzyme.

  11. LINE-1 DNA methylation is inversely correlated with cord plasma homocysteine in man: a preliminary study.

    PubMed

    Fryer, Anthony A; Nafee, Tamer M; Ismail, Khaled M K; Carroll, William D; Emes, Richard D; Farrell, William E

    2009-08-16

    Folic acid supplementation during pregnancy has known beneficial effects. It reduces risk of neural tube defects and low birth weight. Folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. However, most data on the effects of folate on the epigenome is derived from animal or in vitro models. We examined the relationship between cord blood methylation and maternal folic acid intake, cord blood folate and homocysteine using data from 24 pregnant women. Genome-wide methylation was determined by the level of methylation of LINE-1 repeats using Pyrosequencing. We show that cord plasma homocysteine (p = 0.001, r = -0.688), but not serum folate or maternal folic acid intake, is inverse correlated with LINE-1 methylation. This remained significant after correction for potential confounders (p = 0.004). These data indicate that levels of folate-associated intermediates in cord blood during late pregnancy have significant consequences for the fetal epigenome.

  12. Risk of authoritarianism: fibrinogen-transmitted hepatitis C in Japan.

    PubMed

    Yasunaga, Hideo

    2007-12-15

    In 1977, the US Food and Drug Administration revoked all licences for fibrinogen concentrate because of the risk for hepatitis infection and suspected lack of effectiveness. However, in Japan, fibrinogen concentrate was used routinely for treatment of obstetric bleeding until 1988. Even in 1997, academic texts by Japanese authorities in obstetrics still recommended that obstetricians use the product. An estimated 10 000 cases of hepatitis C infection are attributable to use of fibrinogen in Japan and are a result of authoritarianism that hindered effective policy changes. Scientists have a duty to refine repeatedly the quality of their evidence, and policymakers need to adjust existing policies continually to accord with the latest scientific evidence.

  13. Effects of oral contraceptives, or lanosterol, on ADP-induced aggregation and binding of /sup 125/I-fibrinogen to rat platelets

    SciTech Connect

    McGregor, L.; Toor, B.; McGregor, J.L.; Renaud, S.; Clemetson, K.J.

    1984-03-01

    The aggregation to ADP and the binding of /sup 125/I-fibrinogen to platelets from rats treated with oral contraceptives or normal platelets treated in vitro with lanosterol were compared to their respective controls. Both types of platelets showed a significant increase in ADP-induced aggregation and in binding of fibrinogen, indicating that the effect of oral contraceptives could be partly due to increased levels of lanosterol in platelet membrane.

  14. [Fibrinogen and pentoxifylline. Results of a French cooperative exploratory study of stage II arteritis].

    PubMed

    Soria, J; Lancrenon, S; Chassoux, G

    1989-01-01

    A collaborative exploratory study was undertaken by 139 private angiologists in 427 out-patients with PVD stage II treated for 90 days with Pentoxifylline 1 200 mg per day. In 306 patients (71,6%) the fibrinogen level was decreased by 0,21 g/l in mean (p less than 0.01). This significant decrease is correlated to the global improvement (p less than 0.01) and is within the magnitude of difference that is associated between vascular death and comparative groups in recent epidemiologic studies. In 121 patients (28, 4%) of the non responders in whom the claudication was not improved or was even worsened, no change in the fibrinogen level was seen.

  15. Acidosis and Coagulopathy: The Differential Effects on Fibrinogen Synthesis and Breakdown in Pigs

    DTIC Science & Technology

    2007-11-01

    were mea- sured using the Dimension Clinical Chemistry System (Dade Behring, Newark, DE). PT, aPTT, fibrinogen concentration, and D-dimer levels were...concentrations and coagulation parameters at each time point were made using Bonferroni multiple comparisons test relative to baseline. Statistical...and the end of the study. There were no changes in any parameters in the control group during the study. In the acid group, PT and aPTT were

  16. /sup 111/In-platelet and /sup 125/I-fibrinogen deposition in the lungs in experimental acute pancreatitis

    SciTech Connect

    Goulbourne, I.A.; Watson, H.; Davies, G.C.

    1987-12-01

    An experimental model of acute pancreatitis in rats has been used to study intrapulmonary /sup 125/I-fibrinogen and /sup 111/In-platelet deposition. Pancreatitis caused a significant increase in wet lung weight compared to normal, and this could be abolished by heparin or aspirin pretreatment. /sup 125/I-fibrinogen was deposited in the lungs of animals to a significantly greater degree than in controls (P less than 0.01). /sup 125/I-fibrinogen deposition was reduced to control levels by pretreatment with aspirin or heparin (P less than 0.05). The uptake of radiolabeled platelets was greater in pancreatitis than in controls (P less than 0.001). Pancreatitis appears to be responsible for platelet entrapment in the lungs. Platelet uptake was reduced by heparin treatment but unaffected by aspirin therapy.

  17. Hypofibrinogenemia and the α-Fibrinogen Thr312Ala Polymorphism may be Risk Factors for Early Pregnancy Loss.

    PubMed

    Kamimoto, Yuki; Wada, Hideo; Ikejiri, Makoto; Nakatani, Kaname; Sugiyama, Takashi; Osato, Kazuhiro; Murabayashi, Nao; Habe, Koji; Mizutani, Hitoshi; Matsumoto, Takeshi; Ohishi, Kohshi; Ikeda, Tomoaki

    2017-01-01

    We analyzed a cohort of 36 females with pregnancy loss. In addition to 11 patients with antiphospholipid antibody syndrome and 2 patients with congenital antithrombin (AT) or protein C deficiency, we identified 5 patients with low fibrinogen levels (median 110 mg/dL) prior to 10 weeks of gestation. Four of these 5 patients underwent a fibrinogen gene analysis, and all 4 were found to be heterozygotes for the α-fibrinogen (FGA) Thr321Ala polymorphism. One female without hypofibrinogenemia with a history of 8 pregnancy losses was found to be homozygous for the same polymorphism, and she also showed hypercoagulability without thrombosis. In conclusion, there was a relatively high frequency of pregnancy loss in the setting of hypofibrinogenemia and/or the FGA Thr312Ala polymorphism, and this may be an important risk factor for pregnancy loss and a hypercoagulable state in later pregnancy.

  18. Impact of homocysteine-thiolactone on plasma fibrin networks.

    PubMed

    Genoud, Valeria; Lauricella, Ana María; Kordich, Lucía C; Quintana, Irene

    2014-11-01

    Epidemiologic studies have shown that hyperhomocysteinemia is an independent risk factor for vascular disease. Homocysteine (Hcy) circulates as different species, mostly protein bound, and approximately 1% as its reduced form and the cyclic thioester homocysteine-thiolactone (HTL). Despite the level of plasma thiolactone being markedly low, detrimental effects are related to its high reactivity. HTL reacts with proteins by acylation of free basic amino groups; in particular, the epsilon-amino group of lysine residues forms adducts and induces structural and functional changes in plasma proteins. In order to assess the effects of HTL on plasma fibrin networks, a pool of normal plasma incubated with HTL (100, 500 and 1,000 μmol/L, respectively) was evaluated by global coagulation tests and fibrin formation kinetic assays, and the resulting fibrin was observed by scanning electron microscopy. HTL significantly prolonged global coagulation tests in a concentration-dependent manner with respect to control, and increases were up to 14.5%. Fibrin formation kinetic parameters displayed statistically significant differences between HTL-treated plasma and control in a concentration-dependent way, showing higher lag phase and lower maximum reaction velocity and final network optical density. Electron microscopy analysis of HTL plasma networks revealed a compact architecture, with more branches and shorter fibers than control. We can conclude that HTL induced a slower coagulation process, rendering more tightly packed fibrin clots. Since these features of the networks have been related to impaired fibrinolysis, the N-homocysteinylation reactions would be involved in the prothrombotic effects associated to hyperhomocysteinemia.

  19. Status of B-vitamins and homocysteine in diabetic retinopathy: association with vitamin-B12 deficiency and hyperhomocysteinemia.

    PubMed

    Satyanarayana, Alleboena; Balakrishna, Nagalla; Pitla, Sujatha; Reddy, Paduru Yadagiri; Mudili, Sivaprasad; Lopamudra, Pratti; Suryanarayana, Palla; Viswanath, Kalluru; Ayyagari, Radha; Reddy, Geereddy Bhanuprakash

    2011-01-01

    Diabetic retinopathy (DR) is a common cause of blindness. Although many studies have indicated an association between homocysteine and DR, the results so far have been equivocal. Amongst the many determinants of homocysteine, B-vitamin status was shown to be a major confounding factor, yet very little is known about its relationship to DR. In the present study, we, therefore, investigated the status of B-vitamins and homocysteine in DR. A cross-sectional case-control study was conducted with 100 normal control (CN) subjects and 300 subjects with type-2 diabetes (T2D). Of the 300 subjects with T2D, 200 had retinopathy (DR) and 100 did not (DNR). After a complete ophthalmic examination including fundus fluorescein angiography, the clinical profile and the blood levels of all B-vitamins and homocysteine were analyzed. While mean plasma homocysteine levels were found to be higher in T2D patients compared with CN subjects, homocysteine levels were particularly high in the DR group. There were no group differences in the blood levels of vitamins B1 and B2. Although the plasma vitamin-B6 and folic acid levels were significantly lower in the DNR and DR groups compared with the CN group, there were no significant differences between the diabetes groups. Interestingly, plasma vitamin-B12 levels were found to be significantly lower in the diabetes groups compared with the CN group; further, the levels were significantly lower in the DR group compared with the DNR group. Higher homocysteine levels were significantly associated with lower vitamin-B12 and folic acid but not with other B-vitamins. Additionally, hyperhomocysteinemia and vitamin-B12 deficiency did not seem to be related to subjects' age, body mass index, or duration of diabetes. These results thus suggest a possible association between vitamin-B12 deficiency and hyperhomocysteinemia in DR. Further, the data indicate that vitamin-B12 deficiency could be an independent risk factor for DR.

  20. Fibrinogen facilitates the anti-tumor effect of nonnative endostatin

    PubMed Central

    Tang, Huadong; Fu, Yan; Lei, Qingxin; Han, Qing; Ploplis, Victoria A.; Castellino, Francis J.; Li, Ling; Luo, Yongzhang

    2009-01-01

    Endostatin is a potent inhibitor of tumor angiogenesis. Interestingly, nonnative endostatin also exhibits an anti-tumor effect, which remains a mystery so far. Here we show that intravenous injection of nonnative endostatin results in tumor inhibition effect. Soluble and active endostatin is isolated from human blood after the addition of nonnative endostatin in vitro. By fractionation of the whole blood, we surprisingly identify fibrinogen specifically binding to and inhibiting the aggregation of nonnative endostatin. Moreover, the anti-tumor activity of nonnative endostatin is substantially impaired in fibrinogen-deficient mice. Our studies demonstrate that fibrinogen facilitates the anti-tumor effect of nonnative endostatin, which also provides new insights into the novel physiological function of fibrinogen. PMID:19167351

  1. Human fibrinogen adsorption on positively charged latex particles.

    PubMed

    Zeliszewska, Paulina; Bratek-Skicki, Anna; Adamczyk, Zbigniew; Cieśla, Michał

    2014-09-23

    Fibrinogen (Fb) adsorption on positively charged latex particles (average diameter of 800 nm) was studied using the microelectrophoretic and the concentration depletion methods based on AFM imaging. Monolayers on latex were adsorbed from diluted bulk solutions at pH 7.4 and an ionic strength in the range of 10(-3) to 0.15 M where fibrinogen molecules exhibited an average negative charge. The electrophoretic mobility of the latex after controlled fibrinogen adsorption was systematically measured. A monotonic decrease in the electrophoretic mobility of fibrinogen-covered latex was observed for all ionic strengths. The results of these experiments were interpreted according to the three-dimensional electrokinetic model. It was also determined using the concentration depletion method that fibrinogen adsorption was irreversible and the maximum coverage was equal to 0.6 mg m(-2) for ionic strength 10(-3) M and 1.3 mg m(-2) for ionic strength 0.15 M. The increase of the maximum coverage was confirmed by theoretical modeling based on the random sequential adsorption approach. Paradoxically, the maximum coverage of fibrinogen on positively charged latex particles was more than two times lower than the maximum coverage obtained for negative latex particles (3.2 mg m(-2)) at pH 7.4 and ionic strength of 0.15 M. This was interpreted as a result of the side-on adsorption of fibrinogen molecules with their negatively charged core attached to the positively charged latex surface. The stability and acid base properties of fibrinogen monolayers on latex were also determined in pH cycling experiments where it was observed that there were no irreversible conformational changes in the fibrinogen monolayers. Additionally, the zeta potential of monolayers was more positive than the zeta potential of fibrinogen in the bulk, which proves a heterogeneous charge distribution. These experimental data reveal a new, side-on adsorption mechanism of fibrinogen on positively charged surfaces and

  2. The effects of hydrogen peroxide promoted by homocysteine and inherited catalase deficiency on human hypocatalasemic patients.

    PubMed

    Góth, László; Vitai, Márta

    2003-10-15

    Elevated plasma homocysteine can generate oxygen free radicals and hydrogen peroxide. The enzyme catalase is involved in the protection against hydrogen peroxide. We examined the effect of oxidative stress promoted by homocysteine on erythrocyte metabolism (blood hemoglobin, MCV, folate, B12, serum LDH, LDH isoenzymes, haptoglobin) in the oxidative stress sensitive Hungarian patients with inherited catalase deficiency. The plasma homocysteine (HPLC method, Bio-Rad), folate, B12 (capture binding assay, Abbott), blood hemoglobin concentrations, blood catalase activity (spectrophotometric assay of hydrogen peroxide), and MCV values were determined in 7 hypocatalasemic families including hypocatalasemic (male:12, female:18) patients and their results were compared to those of the normocatalasemic (male:17 female: 12) family members. We found decreased (p <.036) folate (ng/ml) concentrations (male hypocatalasemic 5.44 +/- 2.81 vs. normocatalasemic 7.56 +/- 1.97, female 5.01 +/- 1.93 vs. 6.61 +/- 1.91), blood hemoglobin (p <.010, male:140.2 +/- 11.0 vs. 153.6 +/- 11.6 g/l, female: 128.4 +/- 10.9 vs. 139.6 +/- 9.2 g/l). Increased levels of MCV (p <.001) were detected in hypocatalasemic patients (male: 98.6 +/- 3.4 vs. 90.1 +/- 7.5 fl, female: 95.9 +/- 3.9 vs. 90.1 +/- 2.5 fl), plasma homocysteine (p <.049, male: 9.72 +/- 3.61 vs. 7.36 +/- 2.10 umol/l, female: 9.06 +/- 3.10 vs. 6.84 +/- 2.50 umol/l) and not significant (p >.401) plasma B12 (male: 336 +/- 108 vs. 307 +/- 76 pg/ml, female: 373 +/- 180 vs. 342 +/- 75 pg/ml). The serum markers of hemolysis (LDH, LDH isoenzymes, haptoglobin) did not show significant (p >.228) signs of oxidative erythrocyte damage. We report firstly on increased plasma homocysteine concentrations in inherited catalase deficiency. The increased plasma homocysteine and inherited catalase deficiency together could promote oxidative stress via hydrogen peroxide. The patients with inherited catalase deficiency are more sensitive to oxidative stress

  3. Homocysteine and Raynaud's phenomenon: a review.

    PubMed

    Lazzerini, Pietro Enea; Capecchi, Pier Leopoldo; Bisogno, Stefania; Cozzalupi, Mauro; Rossi, Pier Carlo; Pasini, Franco Laghi

    2010-01-01

    Raynaud's phenomenon, categorized as primary and secondary when occurring isolated or in association with an underlying disease, respectively, is a paroxysmal and recurrent acral ischemia resulting from an abnormal arterial vasospastic response to cold or emotional stress. The key issue in the pathogenesis of Raynaud's phenomenon is presumed to be a dysregulation in the mechanisms of vascular motility resulting in an imbalance between vasodilatation and vasoconstriction. Homocysteine, a non-protein forming sulphured amino acid proposed as an independent risk factor for atherothrombosis in the general population, clearly demonstrated to produce vascular damage through mechanisms also including endothelial injury and modifications in circulating mediators of vasomotion. The rationale for homocysteine involvement in the pathogenesis of Raynaud's phenomenon led some authors to investigate the possible association between mild hyperhomocysteinemia and such a vascular disturbance, particularly in the course of connective tissue disease. Here we review data regarding this putative association and the supposed mechanisms involved, also discussing the emblematic case of a patient with new-onset severe Raynaud's phenomenon and markedly elevated homocysteinemia.

  4. Fibrinogen Recovery in Two Methods of Cryoprecipitate Preparation

    DTIC Science & Technology

    1989-08-01

    volume of isoagglutinins and absence of red blood cells, cryoprecipitate can be transfused without regard for the ABO group or Rh type of the...intervention and support. Treatment for these patients is replacement therapy, supplying fibrinogen through transfusion . The first treatment for...represents the transfusable product. Conversely, loss refers to the fibrinogen or factor VIII that is "lost" into the supernatant plasma and therefore not

  5. Homocysteine homeostasis in the rat is maintained by compensatory changes in cystathionine β-synthase, betaine-homocysteine methyltransferase, and phosphatidylethanolamine N-methyltransferase gene transcription occurring in response to maternal protein and folic acid intake during pregnancy and fat intake after weaning.

    PubMed

    Chmurzynska, Agata; Malinowska, Anna M

    2011-07-01

    The reactions of the methionine/homocysteine pathway are mediated by several enzymes, including phosphatidylethanolamine N-methyltransferase, cystathionine β-synthase, and betaine-homocysteine methyltransferase. Homocysteine homeostasis is regulated by these enzymes. We hypothesized here that the protein and folic acid content in the maternal diet affects methionine/homocysteine metabolism in the progeny. To test this hypothesis, pregnant rats were fed a diet with normal protein and normal folic acid levels (a modified casein-based AIN-93G diet), a protein-restricted and normal folic acid diet, a protein-restricted and folic acid-supplemented diet, or a normal protein and folic acid-supplemented diet. The progeny were fed either the modified AIN-93G diet or a high-fat lard-based diet. Progeny were analyzed for expression of the phosphatidylethanolamine N-methyltransferase, cystathionine β-synthase, and betaine-homocysteine methyltransferase genes in the liver and for serum homocysteine concentration. Interactions between prenatal and postnatal nutrition were also determined. The progeny of the dams fed the diets supplemented with folic acid showed decreased expression of all 3 genes (P < .001). An interaction effect between the protein and folic acid content in the maternal diet contributed to this down-regulation (P < .001), and the postweaning diet modified these effects. Serum homocysteine concentrations were approximately 15% higher in the male rats (P < .01), but neither prenatal nutrition nor the postweaning diet affected it significantly. We conclude that maternal diet during gestation has an important effect on the transcription level of these 3 genes, but changes in gene expression were not associated with significant changes in progeny homocysteine concentrations.

  6. A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma

    PubMed Central

    Xuan, Yang; Li, Xiao-Hong; Hu, Zhong-Qian; Teng, Zhi-Mei; Hu, Dao-Jun

    2016-01-01

    Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12–6.38; P = 2.7 × 10−2). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs). PMID:27126524

  7. Novel Aalpha chain truncation (fibrinogen Perth) resulting in low expression and impaired fibrinogen polymerization.

    PubMed

    Homer, V M; Mullin, J L; Brennan, S O; Barr, A; George, P M

    2003-06-01

    A young woman with a history of menorrhagia and easy bruising presented with a functional fibrinogen concentration of 1.8 mg mL(-1), a gravimetric concentration of 3.3 mg mL(-1) and a prolonged thrombin clotting time of 32 s. Both reverse phase analysis and reducing SDS-PAGE revealed a normal profile of Aalpha, Bbeta, and gamma chains. However, non-reducing gels revealed a broadened 340-kDa band, while the 305-kDa band was normal, suggesting a C-terminal truncation of the Aalpha chain. DNA sequencing of all exons and intron boundaries revealed a single heterozygous cytosine deletion at nucleotide 4841 of the Aalpha gene predicting a frameshift and the incorporation of 23 new residues (LMKLPSSTLPQLEKHSQVSSHLC) before termination after residue 517. In agreement with a predicted mass decrease of 9953 Da, the measured mass of the Aalpha(Perth) chain was 56 242 Da, while that of the normal Aalpha(A) chain was 66 189 Da. Tryptic mapping of isolated Aalpha chains revealed a new [M + 2H] ion at 607 m z(-1), corresponding to the predicted penultimate peptide LPSSTLPQLEK. The variant chain was poorly incorporated into plasma fibrinogen at a ratio of Aalpha(Perth)/Aalpha(A) of 0.15 : 1, suggesting the Aalpha(Perth) chain might be out-competed by normal chains during molecular assembly in the hepatocyte. Despite the low expression, polymerization curves showed a decreased V(max) and final turbidity, suggesting the fibrinogen Perth clots are composed of thinner fibers. However, the fibrinolytic rate was very similar to that of the control.

  8. Lowering homocysteine and modifying nutritional status with folic acid and vitamin B(12) in Indian patients of vascular disease.

    PubMed

    Bhargava, Seema; Ali, Arif; Bhargava, Eishaan Kamta; Manocha, Anjali; Kankra, Mamta; Das, Sabari; Mohan Srivastava, Lalit

    2012-05-01

    Hyperhomocysteinemia is more commonly associated with vascular disease in Indians than in the western populations. It is caused by genetic polymorphisms or dietary deficiencies of the B vitamins. We attempted to identify the association of hyperhomocysteinemia with vitamin B(12) and folate in Indian patients of vascular disease. Homocysteine, vitamin B(12) and folate levels were estimated in 100 controls and 100 patients of vascular disease. Homocysteine estimation was repeated in 73 patients on different vitamin supplements for 6 months. Homocysteine exhibited a significant negative correlation with B(12) only in cerebrovascular disease and peripheral vascular diseasepatients, and with folate in coronary artery disease and cerebrovascular disease patients as well as controls. Single daily dose of folate was as effective as a combination of folate and cobalamin in reducing plasma homocysteine concentrations. Low levels of B(12) contribute to the higher incidence of cerebrovascular disease and peripheral vascular disease, and low folate levels account for higher prevalence of hyperhomocysteinemia in coronary artery disease and cerebrovascular disease. Moreover, irrespective of the cause of hyperhomocysteinemia, folate is known to ameliorate it. Hence, large-scale corrective measures like food fortification or dietary supplementation with folate might benefit the Indian population and reduce the incidence and morbidity of vascular disease.

  9. Homocysteine injures vascular endothelial cells by inhibiting mitochondrial activity

    PubMed Central

    Yang, Fengyong; Qi, Xiujing; Gao, Zheng; Yang, Xingju; Zheng, Xingfeng; Duan, Chonghao; Zheng, Jian

    2016-01-01

    The aim of the present study was to investigate the role of homocysteine (Hcy) in the pathogenesis of pulmonary embolism (PE) and the associated molecular mechanisms in human umbilical vein endothelial cells (HUVECs). Hcy contents were detected with high-performance liquid chromatography. Apoptosis was detected by flow cytometry using Annexin-V staining. Cytochrome c oxidase (COX) activity was assessed with an enzyme activity assay, and the expression levels of COX 17 were determined by western blot analysis. Intracellular reactive oxygen species levels were measured using a microplate reader with a fluorescence probe. The results demonstrated that, compared with the control group, the serum Hcy levels were significantly elevated in the PE group, suggesting that Hcy may be an indicator for PE. Following treatment with Hcy, the apoptosis rate was markedly elevated in HUVECs. Moreover, Hcy decreased COX activity and downregulated the expression of COX 17 in HUVECs. Furthermore, Hcy increased the ROS levels in these endothelial cells. However, all the above-mentioned physiopathological changes induced by Hcy in HUVECs could be restored by folic acid. In conclusion, the results of the present study demonstrated that Hcy inhibited COX activity, downregulated COX 17 expression, increased intracellular ROS levels and enhanced apoptosis in endothelial cells. PMID:27698720

  10. Chemical constituents of ambient particulate air pollution and biomarkers of inflammation, coagulation and homocysteine in healthy adults: A prospective panel study

    PubMed Central

    2012-01-01

    Background Ambient air pollution has been associated with activation of systemic inflammation and hypercoagulability and increased plasma homocysteine, but the chemical constituents behind the association are not well understood. We examined the relations of various chemical constituents of fine particles (PM2.5) and biomarkers of inflammation, coagulation and homocysteine in the context of traffic-related air pollution. Methods A panel of 40 healthy college students underwent biweekly blood collection for 12 times before and after their relocation from a suburban campus to an urban campus with changing air pollution contents in Beijing. Blood samples were measured for circulatory biomarkers of high-sensitivity C reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), fibrinogen, plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator (t-PA), von Willebrand factor (vWF), soluble platelet selectin (sP-selectin), and total homocysteine (tHcy). Various air pollutants were measured in a central air-monitoring station in each campus and 32 PM2.5 chemical constituents were determined in the laboratory. We used three different mixed-effects models (single-constituent model, constituent-PM2.5 joint model and constituent residual model) controlling for potential confounders to estimate the effects of PM2.5 chemical constituents on circulatory biomarkers. Results We found consistent positive associations between the following biomarkers and PM2.5 chemical constituents across different models: TNF-α with secondary organic carbon, chloride, zinc, molybdenum and stannum; fibrinogen with magnesium, iron, titanium, cobalt and cadmium; PAI-1 with titanium, cobalt and manganese; t-PA with cadmium and selenium; vWF with aluminum. We also found consistent inverse associations of vWF with nitrate, chloride and sodium, and sP-selectin with manganese. Two positive associations of zinc with TNF-α and of cobalt with fibrinogen, and two inverse

  11. Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation.

    PubMed

    Asselta, Rosanna; Robusto, Michela; Platé, Manuela; Santoro, Cristina; Peyvandi, Flora; Duga, Stefano

    2015-07-01

    Fibrinogen is a hexameric glycoprotein consisting of two sets of three polypeptides (the Aα, Bβ, and γ chains, encoded by the three genes FGA, FGB, and FGG). It is involved in the final phase of the coagulation process, being the precursor of the fibrin monomers necessary for the formation of the hemostatic plug. Rare inherited fibrinogen disorders can manifest as quantitative deficiencies, qualitative defects, or both. In particular, dysfibrinogenemia and hypo-dysfibrinogenemia are characterized by reduced functional activity associated with normal or reduced antigen levels, and are usually determined by heterozygous mutations affecting any of the three fibrinogen genes. In this study, we investigated the genetic basis of dys- and hypo-dysfibrinogenemia in seven unrelated patients. Mutational screening disclosed six different variants, two of which novel (FGB-p.Asp185Asn and FGG-p.Asn230Lys). The molecular characterization of the FGG-p.Asn230Lys mutation, performed by transient expression experiments of the recombinant mutant protein, demonstrated that it induces an almost complete impairment in fibrinogen secretion, according to a molecular mechanism often associated with quantitative fibrinogen disorders. Conversely, the FGB-p.Asp185Asn variant was demonstrated to be a gain-of-glycosylation mutation leading to a hyperglycosylation of the Bβ chain, not affecting fibrinogen assembly and secretion. To our knowledge, this is the second gain-of-glycosylation mutation involving the FGB gene.

  12. Organotypic tissue culture investigation of homocysteine thiolactone cardiotoxic effect.

    PubMed

    Lopatina, Ekaterina V; Kipenko, A V; Penniyaynen, V A; Pasatetskaya, N A; Djuric, D; Krylov, B V

    2015-06-01

    Homocysteine thiolactone was demonstrated to inhibit the growth of 10-12-day-old chicken embryo cardiac tissue explants at 7 × 10⁻⁹ -1 × 10⁻³ M concentrations in a dose-dependent manner. The maximal cardiotoxic effect of homocysteine thiolactone was detected at 1 × 10⁻³ M, which corresponds to severe hyperhomocysteinemia. The results of experiments on culturing of cardiac tissue explants in the medium containing homocysteine thiolactone (1 × 10⁻³ M) and ouabain at concentrations regulating the signal-transducing (1 × 10⁻¹⁰ M) and pumping (1 × 10⁻⁸ M) functions of Na⁺,K⁺ -ATPase indicate that the cardiotoxic effect of homocysteine thiolactone is supposed to result from inhibition of the Na⁺,K⁺ -ATPase pumping function.

  13. Homocysteine-lowering therapy: a role in stroke prevention?

    PubMed

    Spence, J David

    2007-09-01

    On the basis of the results of several recent clinical trials, many researchers have concluded that vitamin therapy designed to lower total homocysteine concentrations is not effective in reducing the risk of cardiovascular events. However, whereas almost all myocardial infarctions are due to plaque rupture, stroke has many more pathophysiological mechanisms, and thrombosis-which is increased by raised total homocysteine concentrations-has an important role in many of these processes. Thus, stroke and myocardial infarction could respond differently to vitamin therapy. A detailed assessment of the results of the recent HOPE-2 trial and a reanalysis of the VISP trial restricted to patients capable of responding to vitamin therapy suggest that higher doses of vitamin B12 and perhaps new approaches to lowering total homocysteine besides routine vitamin therapy with folate, vitamin B6, and vitamin B12 could reduce the risk of stroke. Thus, therapy to lower homocysteine could still help to prevent stroke, if not other vascular outcomes.

  14. Activation of transsulfuration pathway by salvianolic acid a treatment: a homocysteine-lowering approach with beneficial effects on redox homeostasis in high-fat diet-induced hyperlipidemic rats

    PubMed Central

    2013-01-01

    Background Elevated homocysteine is a cardiovascular risk factor in hyperlipidemia. Transsulfuration pathway provides an endogenous pathway for homocysteine conversion to antioxidant glutathione (GSH). Salvianolic acid A (Sal A) contains two molecules of caffeic acid and one molecule of danshensu that is capable of enhancing homocysteine transsulfuration, which led to the hypothesis that Sal A has activatory effect on transsulfuration pathway and this effect may have beneficial effects on both homocysteine and redox status in hyperlipidemia. Methods and results To test this hypothesis, we developed a rat model of hyperlipidemia induced by high-fat diet for 16 weeks, during which rats were treated with 1 mg/kg salvianolic acid A (Sal A) for the final 4 weeks. Activities of key enzymes and metabolite profiling in the transsulfuration pathway revealed that hyperlipidemia led to elevated plasma homocysteine levels after 16-week dietary treatment, which was associated with reduced activities of homocysteine transsulfuration enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). The impaired transsulfuration pathway prevented homocysteine transsulfuration to cysteine, resulting in cysteine deficiency and subsequent reduction in GSH pool size. The redox status was altered in the setting of hyperlipidemia as indicated by GSH/GSSG ratio. Sal A treatment increased hepatic CBS and CSE activities, which was associated with reduced accumulation in circulating homocysteine levels and attenuated decline in hepatic cysteine content in hyperlipidemic rats. Sal A also led to an increase in GSH pool size, which subsequently caused a restored GSH/GSSG ratio. The activatory effect of Sal A on CBS was also observed in normal rats and in in vitro experiment. Conclusion Our results suggest that activation of transsulfuration pathway by Sal A is a promising homocysteine-lowering approach that has beneficial effects on redox homeostasis in hyperlipidemic settings

  15. Randomised clinical trial of an intensive intervention in the primary care setting of patients with high plasma fibrinogen in the primary prevention of cardiovascular disease

    PubMed Central

    2012-01-01

    Background We have studied the possible effects of an intensive lifestyle change program on plasma fibrinogen levels, in patients with no cardiovascular disease, with elevated levels of fibrinogen, normal cholesterol levels, and a moderate estimated risk of coronary heart disease (CHD) and we have also analysed whether the effect on fibrinogen is independent of the effect on lipids. Results This clinical trial was controlled, unblinded and randomized, with parallel groups, done in 13 Basic Health Areas (BHA) in l'Hospitalet de Llobregat (Barcelona) and Barcelona city. The study included 436 patients, aged between 35 and 75 years, with no cardiovascular disease, elevated levels of fibrinogen (> 300 mg/dl), cholesterol < 250 mg/dl, 218 of whom received a more intensive intervention consisting of advice on lifestyle and treatment. The follow-up frequency of the intervention group was every 2 months. The other 218 patients followed their standard care in the BHAs. Fibrinogen, plasma cholesterol and other clinical biochemistry parameters were assessed. The evaluation of the baseline characteristics of the patients showed that both groups were homogenous. Obesity and hypertension were the most prevalent risk factors. After 24 months of the study, statistically significant changes were seen between the adjusted means of the two groups, for the following parameters: fibrinogen, plasma cholesterol, systolic and diastolic blood pressure and body mass index. Conclusion Intensive intervention to achieve lifestyle changes has shown to be effective in reducing some of the estimated CHD factors. However, the effect of intensive intervention on plasma fibrinogen levels did not correlate with the variations in cholesterol. Trial Registration ClinicalTrials.gov: NCT01089530 PMID:22381072

  16. Biochemical and molecular characterization of the homocysteine S-methyltransferase from broccoli (Brassica oleracea var. italica).

    PubMed

    Lyi, Sangbom M; Zhou, Xin; Kochian, Leon V; Li, Li

    2007-04-01

    Plants are known for their unique ability to synthesize methionine from S-methylmethionine (SMM) and homocysteine using the enzyme SMM: homocysteine S-methyltransferase (HMT) in the SMM cycle. Two cDNAs exhibiting HMT activity were cloned from broccoli and functionally expressed in E. coli. One cDNA, that encodes an enzyme with high substrate specificity for homocysteine, was designated as BoHMT1. The other cDNA was the BoSMT gene that we previously characterized and encodes a selenocysteine methyltransferase (Lyi, S.M., Heller, L.I., Rutzke, M., Welch, R.M., Kochian, L.V., Li, L., 2005. Molecular and biochemical characterization of the selenocysteine Se-methyltransferase gene and Se-methylselenocysteine synthesis in broccoli. Plant Physiol. 138, 409-420). Both exist as single gene sequences in the broccoli genome. While BoSMT expression was extremely low or undetectable in broccoli plants unless the plants were exposed to selenium, the BoHMT1 mRNA accumulated in most tissues of the plant except older leaves. In contrast to BoSMT whose expression was dramatically upregulated by treating plants with selenate, the transcript levels of BoHMT1 were not markedly affected in plants exposed to selenium. BoHMT1 expression responded significantly to changes in plant sulfur status. However, its expression was not dramatically affected in plants treated with methionine, SMM, homocysteine, or the heavy metal, cadmium. The differences in the substrate specificity and gene expression in response to changes in plant sulfur and selenium status between BoHMT1 and BoSMT suggest that the enzymes encoded by these two genes play distinct roles in sulfur and selenium metabolism in broccoli.

  17. Predictive Role of Intraoperative Plasma Fibrinogen for Postoperative Portal Venous Flow in Living Donor Liver Transplantation.

    PubMed

    Chae, Min Suk; Park, Chul Soo; Oh, Su A; Hong, Sang Hyun

    2017-02-14

    BACKGROUND Previous studies have reported poor graft regeneration after living donor liver transplantation (LDLT) due to inappropriate portal venous flow (PVF). In this study, we investigated the perioperative factors affecting postoperative PVF after LDLT. MATERIAL AND METHODS The perioperative data of 366 LDLT patients were retrospectively reviewed. The average PVF on postoperative days 1, 3, and 5 was measured and dichotomized at a cut-off value for patient survival of 1,477 mL/min. Perioperative variables, including coagulation profiles, were compared between high and low postoperative PVF groups. The factors potentially significant (p<0.1) for a low postoperative PVF were evaluated in a univariate analysis, followed by the development of a predictive model for a low postoperative PVF. RESULTS A low post-LDLT PVF was determined in 113 patients (30.9%). The univariate analysis identified systemic hypertension, LDLT duration, average mean blood pressure, and insulin administration as the significantly related factors. Other significant factors were a plasma fibrinogen, at the anhepatic phase and 1 h after graft reperfusion, as well as the platelet count at the anhepatic phase. After multivariate adjustment, plasma fibrinogen 1 h after graft reperfusion against a recipient background of systemic hypertension was independently associated with a low mean postoperative PVF. CONCLUSIONS A low mean PVF during the early post-LDLT period was independently related to the plasma fibrinogen level 1 h after graft reperfusion, and to a history of systemic hypertension. Thus, the practice of aggressive supplementation of plasma fibrinogen during the immediate post-reperfusion period merits serious consideration.

  18. Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism.

    PubMed

    Kamat, Pradip K; Mallonee, Carissa J; George, Akash K; Tyagi, Suresh C; Tyagi, Neetu

    2016-12-01

    Alcohol is the most socially accepted addictive drug. Alcohol consumption is associated with some health problems such as neurological, cognitive, behavioral deficits, cancer, heart, and liver disease. Mechanisms of alcohol-induced toxicity are presently not yet clear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with amino acid homocysteine (Hcy), which has been linked with brain neurotoxicity. Elevated Hcy impairs with various physiological mechanisms in the body, especially metabolic pathways. Hcy metabolism is predominantly controlled by epigenetic regulation such as DNA methylation, histone modifications, and acetylation. An alteration in these processes leads to epigenetic modification. Therefore, in this review, we summarize the role of Hcy metabolism abnormalities in alcohol-induced toxicity with epigenetic adaptation and their influences on cerebrovascular pathology.

  19. Folic acid and vitamin B(12) supplementation lowers plasma homocysteine but has no effect on serum bone turnover markers in elderly women: a randomized, double-blind, placebo-controlled trial.

    PubMed

    Keser, Irena; Ilich, Jasminka Z; Vrkić, Nada; Giljević, Zlatko; Colić Barić, Irena

    2013-03-01

    An elevated homocysteine level is a newly recognized risk factor for osteoporosis. Older individuals may have elevated homocysteine levels due to inadequate folate intake and/or lower absorption of vitamin B(12). The aim of this study was to determine whether there is an impact of folic acid and vitamin B(12) supplementation on homocysteine levels and, subsequently, on bone turnover markers in older women with mildly to moderately elevated homocysteine levels. It is hypothesized that supplementation with folic acid and vitamin B(12) will improve homocysteine levels and, in turn, positively modify bone turnover markers in this population. This randomized, double-blind, placebo-controlled trial included 31 women (65 to 93 years) with homocysteine levels greater than 10 μmol/L. Participants were randomly assigned to receive either a daily folic acid (800 μg) and vitamin B(12) (1000 μg) (n = 17) or a matching placebo (n = 14) for 4 months. The results showed significantly lower homocysteine concentrations in the vitamin group compared to the placebo group (10.6 vs 18.5 μmol/L, P = .007). No significant difference in serum alkaline phosphatase or C-terminal cross-linking telopeptide of type I collagen was found between the vitamin and placebo groups before or after supplementation. The use of folic acid and vitamin B(12) as a dietary supplement to improve homocysteine levels could be beneficial for older women, but additional research must be conducted in a larger population and for a longer period to determine if there is an impact of supplementation on bone turnover markers or other indicators of bone health.

  20. Insulin counter-regulatory factors, fibrinogen and C-reactive protein during olanzapine administration: effects of the antidiabetic metformin.

    PubMed

    Baptista, Trino; Sandia, Ignacio; Lacruz, Anny; Rangel, Nairy; de Mendoza, Soaira; Beaulieu, Serge; Contreras, Quilianio; Galeazzi, Tatiana; Vargas, Doritza

    2007-03-01

    In this study, the Authors assessed some insulin counter-regulatory factors, fibrinogen and C-reactive protein after olanzapine administration, and the effect of metformin on these variables, 37 patients with chronic schizophrenia were given olanzapine (10 mg/day for 14 weeks). Nineteen patients received metformin (850-2550 mg/day) and 18 received placebo in a randomized, double-blind protocol. The following variables were quantified before and after olanzapine: cortisol, leptin, tumor necrosis factor-alpha, glucagon, growth hormone, fibrinogen and C-reactive protein. Results were correlated with the changes in body weight and the insulin resistance index. We have reported elsewhere that metformin did not prevent olanzapine-induced weight gain, and the insulin resistance index significantly decreased after metformin and placebo; Baptista T, et al. Can J Psychiatry 2006; 51: 192-196. Cortisol, tumor necrosis factor-alpha and fibrinogen levels significantly decreased in both groups. Glucagon significantly increased after metformin (P=0.03). Leptin tended to increase after placebo (P=0.1) and displayed a small nonsignificant reduction after metformin. The C-reactive protein did not change significantly in any group. Contrarily to most published studies, olanzapine was associated with decreased insulin resistance. Decrements in cortisol, fibrinogen and tumor necrosis factor-alpha levels point to an improvement in the metabolic profile. The trend for leptin to increase after placebo, but not after metformin in spite of similar weight gain suggests a beneficial effect of this antidiabetic agent.

  1. Comparison of isotope dilution mass spectrometry methods for the determination of total homocysteine in plasma and serum.

    PubMed

    Satterfield, Mary B; Sniegoski, Lorna T; Welch, Michael J; Nelson, Bryant C; Pfeiffer, Christine M

    2003-09-01

    Two independent methods have been critically evaluated and applied to the measurement of total homocysteine in serum and plasma: solid-phase anion extraction (SPAE) gas chromatography/mass spectrometry (GC/MS) and protein precipitation liquid chromatography/tandem mass spectrometry (LC/MS/MS). In addition, analysis of samples prepared by SPAE was accomplished by liquid chromatography/mass spectrometry (LC/MS) and LC/MS/MS. These methods have been used to determine total homocysteine levels in several existing serum-based Standard Reference Materials (SRMs) from the National Institute of Standards and Technology and in patient plasma samples provided by the Centers for Disease Control and Prevention. The precision of the homocysteine measurements in serum and plasma was critically evaluated, and method comparisons were carried out using Bland-Altman plots and bias analysis. On the basis of the excellent precision and close agreement of the mass spectrometric (MS) methods, the MS-based methods will be used for certification of a serum-based SRM for homocysteine and folates.

  2. Aronia melanocarpa as a protector against nitration of fibrinogen.

    PubMed

    Bijak, Michał; Saluk, Joanna; Antosik, Adam; Ponczek, Michał B; Żbikowska, Halina M; Borowiecka, Marta; Nowak, Paweł

    2013-04-01

    Fibrinogen (Fg) also known as coagulation factor I represents about 4% of the total human plasma proteins. The main function of Fg is its involvement in last phase of blood coagulation cascade, when thrombin-induced conversion of dissolved plasma fibrinogen into an insoluble fibrin clot occurs. The reaction of fibrinogen with peroxynitrite causes both structural modifications and changes of the biological properties of this plasma glycoprotein. Recently, there is an increased interest in the screening of natural products present in fruits, vegetables and herbs for their possible antioxidative activities. Therefore, the aim of our study was to estimate the effect of extract from berries of Aronia melanocarpa against nitrative and oxidative damage induced by peroxynitrite. The extract from A. melanocarpa (0.5-50 μg/ml) added to Fg 10 min before peroxynitrite (100 μM) significantly inhibited both the formation of the high molecular weight protein aggregates and nitration of Fg molecule. The extract also abolished peroxynitrite-induced inhibition of fibrinogen polymerization (by 95% at 50 μg/ml). The obtained results indicate that natural extract from berries of A. melanocarpa has protective effects against peroxynitrite-induced nitrative damage of plasma fibrinogen, and therefore may contribute in the prevention of peroxynitrite-related cardiovascular or inflammatory diseases.

  3. Fibrin(ogen) mediates acute inflammatory responses to biomaterials

    PubMed Central

    1993-01-01

    Although "biocompatible" polymeric elastomers are generally nontoxic, nonimmunogenic, and chemically inert, implants made of these materials may trigger acute and chronic inflammatory responses. Early interactions between implants and inflammatory cells are probably mediated by a layer of host proteins on the material surface. To evaluate the importance of this protein layer, we studied acute inflammatory responses of mice to samples of polyester terephthalate film (PET) that were implanted intraperitoneally for short periods. Material preincubated with albumin is "passivated," accumulating very few adherent neutrophils or macrophages, whereas uncoated or plasma- coated PET attracts large numbers of phagocytes. Neither IgG adsorption nor surface complement activation is necessary for this acute inflammation; phagocyte accumulation on uncoated implants is normal in hypogammaglobulinemic mice and in severely hypocomplementemic mice. Rather, spontaneous adsorption of fibrinogen appears to be critical: (a) PET coated with serum or hypofibrinogenemic plasma attracts as few phagocytes as does albumin-coated material; (b) in contrast, PET preincubated with serum or hypofibrinogenemic plasma containing physiologic amounts of fibrinogen elicits "normal" phagocyte recruitment; (c) most importantly, hypofibrinogenemic mice do not mount an inflammatory response to implanted PET unless the material is coated with fibrinogen or the animals are injected with fibrinogen before implantation. Thus, spontaneous adsorption of fibrinogen appears to initiate the acute inflammatory response to an implanted polymer, suggesting an interesting nexus between two major iatrogenic effects of biomaterials: clotting and inflammation. PMID:8245787

  4. Vitamin B-6 Supplementation Could Mediate Antioxidant Capacity by Reducing Plasma Homocysteine Concentration in Patients with Hepatocellular Carcinoma after Tumor Resection.

    PubMed

    Cheng, Shao-Bin; Lin, Ping-Ting; Liu, Hsiao-Tien; Peng, Yi-Shan; Huang, Shih-Chien; Huang, Yi-Chia

    2016-01-01

    Vitamin B-6 has a strong antioxidative effect. It would be useful to determine whether vitamin B-6 supplementation had effects on antioxidant capacities in patients with hepatocellular carcinoma (HCC) who had recently undergone tumor resection. Thirty-three HCC patients were randomly assigned to either the placebo (n = 16) group or the vitamin B-6 50 mg/d (n = 17) group for 12 weeks. Plasma pyridoxal 5'-phosphate, homocysteine, indicators of oxidative stress, and antioxidant capacities were measured. Plasma homocysteine in the vitamin B-6 group was significantly decreased at week 12, while the level of trolox equivalent antioxidant capacity (TEAC) was significantly increased at the end of the intervention period. Vitamin B-6 supplementation had a significant reducing effect on the change of plasma homocysteine (β = -2.4, p = 0.02) but not on the change of TEAC level after adjusting for potential confounders. The change of plasma homocysteine was significantly associated with the change of TEAC after adjusting for potential confounders (β = -162.0, p = 0.03). Vitamin B-6 supplementation seemed to mediate antioxidant capacity via reducing plasma homocysteine rather than having a direct antioxidative effect in HCC patients who had recently undergone tumor resection. The clinical trial number is NCT01964001, ClinicalTrials.gov.

  5. Bioactivation mechanism of cytotoxic homocysteine S-conjugates.

    PubMed

    Lash, L H; Elfarra, A A; Rakiewicz-Nemeth, D; Anders, M W

    1990-02-01

    S-(1,2-Dichlorovinyl)-L-homocysteine is a much more potent nephrotoxin than the corresponding cysteine S-conjugate S-(1,2-dichlorovinyl)-L-cysteine (A. A. Elfarra, L. H. Lash, and M. W. Anders (1986) Proc. Natl. Acad. Sci. USA 83, 2667-2671). The objective of the present experiments was to test the hypothesis that the increased toxicity of homocysteine S-conjugates may be associated with the formation of the reactive metabolite 2-oxo-3-butenoic acid, which may arise via a nonenzymatic retro-Michael elimination reaction from the 2-oxo acid metabolites of homocysteine S-conjugates. S-(2-Benzothiazolyl)-L-homocysteine, which was a substrate for purified bovine kidney cysteine conjugate beta-lyase (glutamine transaminase K) and whose metabolism was dependent on the presence of a 2-oxo acid, was cytotoxic in isolated rat kidney cells and was toxic to rat renal mitochondria, whereas the cysteine S-conjugate S-(2-benzothiazolyl)-L-cysteine had little effect. L-Methionine sulfoximine, L-canavanine, and the Michael acceptor methyl vinyl ketone were cytotoxic. The 2-hydroxy acid analogs of S-(1,2-dichlorovinyl)-L-homocysteine and 2-oxo-3-butenoic acid, S-(1,2-dichlorovinyl)-2-hydroxy-4-mercaptobutanoic acid and 2-hydroxy-3-butenoic acid, respectively, which are expected to be metabolized by rat renal L-2-hydroxy (L-amino) acid oxidase to yield 2-oxo-3-butenoic acid, were also cytotoxic. To obtain evidence for the formation of 2-oxo-3-butenoic acid as a product of the metabolism of L-homocysteine S-conjugates and analogs, trapping experiments were conducted. S-(2-Benzothiazolyl)-L-homocysteine, S-(1,2-dichlorovinyl)-L-homocysteine, L-methionine sulfoximine, and L-canavanine were converted by snake venom L-amino acid oxidase to 2-oxo-3-butenoic acid, which was trapped by the nucleophile methanethiol to yield 4-methylthio-2-oxobutanoic acid; the trapped product was derivatized with 2,4-dinitrophenylhydrazine and was identified by its electronic absorption spectrum and by high

  6. The interactions of fibrinogen and dextrans with erythrocytes

    PubMed Central

    Rampling, M.; Sirs, John A.

    1972-01-01

    1. The rate of packing of erythrocytes in whole blood, under a centrifugal field of 200 g, has been studied using an automatic recording centrifuge. 2. Reduction of the supernatant fibrinogen concentration, by repeatedly washing the cells, lowers the rate of packing and reduces the cell flexibility. 3. Resuspending the cells in their own plasma or in isotonic solutions containing fibrinogen restores their flexibility. 4. Rouleaux formation has been shown to have no effect on the rate of packing by comparison of blood diluted with plasma, isotonic NaCl or Ringer—Locke solutions. While the degree of rouleaux formation varied with the diluent used, the rate of packing and packed cell haematocrit were the same, for the same dilution. 5. Both formalin and dextran altered the degree of rouleaux formation and reduced erythrocyte flexibility. Dextran was found to act indirectly on the erythrocyte flexibility by reducing the plasma fibrinogen concentration. PMID:5046146

  7. Homocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen free radicals.

    PubMed Central

    Wang, G; O, K

    2001-01-01

    Homocysteinaemia is an independent risk factor for atherosclerosis. The development of atherosclerosis involves monocyte chemoattractant protein 1 (MCP-1)-mediated monocyte recruitment to the lesion site. The action of MCP-1 is mostly via its interaction with MCP-1 receptor (CCR2), which is the major receptor for MCP-1 on the surface of monocytes. The objective of the present study was to investigate the effect of homocysteine on CCR2 expression in human THP-1 monocytes. Cells were incubated with various concentrations of homocysteine for 6, 12, 24 and 48 h. The expression of CCR2 mRNA was determined by nuclease protection assay and the CCR2 protein was measured by Western immunoblotting analysis. The binding of MCP-1 to CCR2 as a functional receptor on the monocyte surface was determined by flow cytometry. Homocysteine (0.05-0.2 mM) significantly enhanced the expression of CCR2 mRNA (129-209% of the control) and CCR2 protein (up to 183% of control) in these cells after 24 h of incubation. Stimulation of CCR2 expression was associated with a parallel increase in the binding activity of CCR2 (129-191% of control) as well as an enhanced chemotactic response of homocysteine-treated monocytes. Further investigation revealed that the levels of superoxide were significantly elevated in cells incubated with homocysteine for 12-48 h. The addition of superoxide dismutase, a scavenger of superoxide, to the culture medium abolished the stimulatory effect of homocysteine on CCR2 expression as well as the binding activity of the receptor. The stimulatory effect of homocysteine on the expression of CCR2 mRNA and the levels of CCR2 protein was also observed in human peripheral blood monocytes. In conclusion, the present study has clearly demonstrated that homocysteine stimulates CCR2 expression in monocytes, leading to an enhanced binding activity and chemotatic response. Homocysteine-induced superoxide formation might serve as one of the underlying mechanisms for this effect

  8. Relation of C-reactive protein, fibrinogen, and cardiorespiratory fitness to risk of systemic hypertension in men.

    PubMed

    Jae, Sae Young; Kurl, Sudhir; Laukkanen, Jari A; Lee, Chong-Do; Choi, Yoon-Ho; Fernhall, Bo; Franklin, Barry A

    2015-06-15

    We investigated the relation between inflammation and incident hypertension, independent of obesity, and tested the associations of cardiorespiratory fitness (fitness) and indexes of inflammation for the development of hypertension in 2,475 normotensive men. Inflammatory markers were C-reactive protein (CRP) and fibrinogen. Fitness was directly measured by peak oxygen uptake during sign/symptom-limited treadmill exercise testing to volitional fatigue; 266 men (10.7%) developed hypertension during an average of 4 years follow-up. After adjusting for potential confounding variables, the relative risk (RR) and 95% confidence interval (CI) for incident hypertension in those in the upper tertile versus lower tertile were 1.55 (95% CI 1.15 to 2.09) for CRP and 1.51 (95% CI 1.10 to 2.06) for fibrinogen. Although the association between fibrinogen and incident hypertension persisted after adjusting for body mass index (p = 0.049), the relation between CRP and incident hypertension was no longer statistically significant (p = 0.08). Fit men had a 27% decreased (RR 0.73, 95% CI 0.56 to 0.94) risk of incident hypertension compared with unfit men in a multivariable adjusted model. In the joint analysis, unfit men with upper CRP had 1.81 times (95% CI 1.21 to 2.70) and unfit men with upper fibrinogen had 2.03 times (95% CI 1.33 to 3.12) greater risks of incident hypertension compared with fit men with low CRP and fibrinogen, respectively. However, these risks did not significantly increase in fit men with upper CRP (RR 1.12, 95% CI 0.76 to 1.63) and fibrinogen (RR 1.26, 95% CI 0.86 to 1.85) groups. In conclusion, these results suggest that heightened levels of fibrinogen, but not CRP, are associated with incident hypertension, independent of body weight, and that high fitness attenuates the risk of incident hypertension across upper levels of inflammatory markers in men.

  9. Derivation and Validation of Homocysteine Score in U.S. Men and Women123

    PubMed Central

    Jung, Seungyoun; Je, Youjin; Giovannucci, Edward L; Rosner, Bernard; Ogino, Shuji; Cho, Eunyoung

    2015-01-01

    Background: One-carbon metabolism, which is crucial in DNA synthesis and genomic stability, is an interrelated network of biochemical reactions involved in several dietary and lifestyle factors. The development of the homocysteine score using these factors may be useful to reflect the status of one-carbon metabolism in large epidemiologic studies without biologic samples to measure homocysteine directly. Objective: The aim of this study was to develop an homocysteine score that reflects one-carbon metabolism better than individual dietary or lifestyle factors. Methods: We divided 2023 participants with measured plasma total homocysteine data in the Nurses’ Health Study and the Health Professionals Follow-Up Study into training (n = 1619) and testing (n = 404) subsets. Using multivariable linear regression, we selected lifestyle determinants of plasma homocysteine in the training set and derived the homocysteine score weighted by the β coefficient for each predictor. The validation of the homocysteine score was assessed using the plasma homocysteine in the independent samples of the training set. Results: In the training set, smoking, multivitamin use, and caffeine, alcohol, and dietary and supplemental folate intake were significant independent determinants of plasma homocysteine in multivariable linear regression (P ≤ 0.01) and were included in the derivation of the homocysteine score. The Pearson correlation of the homocysteine score with plasma homocysteine was 0.30 in the testing subset (P < 0.001). The homocysteine score was positively associated with the plasma homocysteine concentration in the testing subset and in an independent population of women; the mean difference of plasma homocysteine concentration between the extreme quintiles of homocysteine score ranged from 0.83 μmol/L to 1.52 μmol/L. Population misclassification either from the lowest quintile of plasma homocysteine into the highest quintile of the homocysteine score or from the highest

  10. Correlation of Homocysteine Metabolic Enzymes Gene Polymorphism and Mild Cognitive Impairment in the Xinjiang Uygur Population

    PubMed Central

    Luo, Mei; Ji, Huihui; Zhou, Xiaohui; Liang, Jie; Zou, Ting

    2015-01-01

    Background The aim of this study was to investigate the genetic polymorphisms in the homocysteine (HCY) metabolic enzymes in the Xinjiang Uygur population who have mild cognitive impairment (MCI). Material/Methods Based on the epidemiological investigation, 129 cases of diagnosed Uygur MCI patients and a matched control group with 131 cases were enrolled for analyzing the association between the polymorphisms in the HCY metabolism related genes (C677T, A1298C, and G1968A polymorphisms in MTHFR, as well as the A2756G polymorphism in MS) and MCI by using the SNaPshot method. We then determined the homocysteine level in patients. Results In Xinjiang Uygur subjects, the A1298C polymorphisms in MTHFR and the A2756G polymorphisms in the MS gene in the MCI group were different from those in the control group. However, the C677T and G1968A polymorphisms in the MTHFR gene in MCI patients were not different from those in the control group. Multivariate logistic regression showed that, in addition to the well-known risk factors, such as low education level, high cholesterol level, high level of low-density lipoprotein, and high homocysteine levels, the A>G mutation in the MS gene at the rs1805087 locus was another independent risk factor for MCI in the Uyghur MCI population. The risk of MCI in G allele carriers was 2.265 times higher than that in matched control individuals (95% CI: 1.205~4.256, P<0.05). Conclusions The genetic polymorphism of HCY metabolizing enzymes is correlated to the occurrence of MCI in the Xinjiang Uygur population. The A2756G polymorphism in the MS gene could be an independent risk factor for MCI in the Xinjiang Uygur population. PMID:25625218

  11. Involvement of homocysteine, homocysteine thiolactone, and paraoxonase type 1 (PON-1) in the etiology of defective human sperm function.

    PubMed

    Aitken, R J; Flanagan, H M; Connaughton, H; Whiting, S; Hedges, A; Baker, M A

    2016-03-01

    This study reports, for the first time, the significant (p ≤ 0.01) accumulation of homocysteine residues in low density, defective sperm suspensions isolated from patients attending an infertility clinic. This overabundance of homocysteine was not related to a deficiency in folate availability but may have been a reflection of the oxidative stress that characterizes such defective sperm populations. Direct addition of the homocysteine cyclic congener, homocysteine thiolactone, to human spermatozoa resulted in the rapid induction of mitochondrial reactive oxygen species (ROS) generation (p < 0.001), the stimulation of lipid peroxidation (p < 0.01), the promotion of tyrosine phosphorylation (p < 0.001), and the suppression of sperm motility (p < 0.001) in the absence of any significant impact on DNA integrity. The parent homocysteine molecule was less active and took 24 h to stimulate mitochondrial ROS production possibly because of the need to convert this compound to the corresponding thiolactone before it could exert a measureable biological effect. Thiolactone was also effective in suppressing the carboxymethylation of key proteins in the sperm tail, which are thought to be involved in the regulation of sperm movement. The major enzyme responsible for removing thiolactone from proteins, paraoxonase (PON-1), was shown to be a major target for alkylation by lipid aldehydes, such as 4-hydroxynonenal, generated as a consequence of oxidative stress. Exposure of human spermatozoa to such aldehydes resulted in a dose-dependent accumulation of homocysteine in spermatozoa (p < 0.03). These results suggest that one of the consequences of oxidative stress in mammalian spermatozoa is the inhibition of PON-1, which then enhances the availability of homocysteine thiolactone to interact with the epsilon-amino group of lysine residues on sperm proteins, triggering a raft of significant biological changes in these cells that ultimately compromise sperm function.

  12. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CA...

  13. Chemical biology of homocysteine thiolactone and related metabolites.

    PubMed

    Jakubowski, Hieronim; Głowacki, Rafał

    2011-01-01

    Protein-related homocysteine (Hcy) metabolism produces Hcy-thiolactone, N-Hcy-protein, and N epsilon-homocysteinyl-lysine (N epsilon-Hcy-Lys). Hcy-thiolactone is generated in an error-editing reaction in protein biosynthesis when Hcy is erroneously selected in place of methionine by methionyl-tRNA synthetase. Hcy-thiolactone, an intramolecular thioester, is chemically reactive and forms isopeptide bonds with protein lysine residues in a process called N-homocysteinylation, which impairs or alters the protein's biological function. The resulting protein damage is exacerbated by a thiyl radical-mediated oxidation. N-Hcy-proteins undergo structural changes leading to aggregation and amyloid formation. These structural changes generate proteins, which are toxic and which induce an autoimmune response. Proteolytic degradation of N-Hcy-proteins generates N epsilon-Hcy-Lys. Levels of Hcy-thiolactone, N-Hcy-protein, and N epsilon-Hcy-Lys increase under pathological conditions in humans and mice and have been linked to cardiovascular and brain disorders. This chapter reviews fundamental biological chemistry of Hcy-thiolactone, N-Hcy-protein, and N epsilon-Hcy-Lys and discusses their clinical significance.

  14. Homocysteine as a Pathological Biomarker for Bone Disease.

    PubMed

    Behera, Jyotirmaya; Bala, Jyoti; Nuru, Mohammed; Tyagi, Suresh C; Tyagi, Neetu

    2016-11-18

    In the last few decades, perturbation in methyl-group and homocysteine (Hcy) balance have emerged as independent risk factors in a number of pathological conditions including neurodegenerative disease, cardiovascular dysfunction, cancer development, autoimmune disease and kidney disease. Recent studies report Hcy to be a newly recognized risk factor for osteoporosis. Elevated Hcy levels are known to modulate osteoclastgenesis by causing detrimental effects on bone via oxidative stress induced metalloproteinase-mediated extracellular matrix degradation and decrease in bone blood flow. Evidence from previous studies also suggests that the decreased chondrocytes mediated bone mineralization in chick limb-bud mesenchymal cells and during the gestational period of ossification in rat model. However, Hcy imbalance and its role in bone loss, regression in vascular invasion, and osteoporosis, are not clearly understood. More investigations are required to explore the complex interplay between Hcy imbalance and onset of bone disease progression. This article reviews the current body of knowledge on regulation of Hcy mediated oxidative stress and its role in bone remodeling, vascular blood flow and progression of bone disease. This article is protected by copyright. All rights reserved.

  15. Influence of a constant magnetic field on the fibrinogen-fibrin system. [in blood coagulation process

    NASA Technical Reports Server (NTRS)

    Matskevichene, V. B.; Platonova, A. T.

    1974-01-01

    The effect of a constant magnetic field with a strength of 2500 oersteds on the fibrinogen-fibrin system was studied in the organism of healthy rabbits with exposure times of 1 and 5 hours. The results obtained indicate disruptions in the stage of conversion of fibrinogen to fibrin and an increase in the amount of fibrinogen.

  16. A novel role for the fibrinogen Asn-Gly-Arg (NGR) motif in platelet function.

    PubMed

    Moriarty, Róisín; McManus, Ciara A; Lambert, Matthew; Tilley, Thea; Devocelle, Marc; Brennan, Marian; Kerrigan, Steven W; Cox, Dermot

    2015-02-01

    The integrin αIIbβ3 on resting platelets can bind to immobilised fibrinogen resulting in platelet spreading and activation but requires activation to bind to soluble fibrinogen. αIIbβ3 is known to interact with the general integrin-recognition motif RGD (arginine-glycine-aspartate) as well as the fibrinogen-specific γ-chain dodecapeptide; however, it is not known how fibrinogen binding triggers platelet activation. NGR (asparagine-glycine-arginine) is another integrin-recognition sequence present in fibrinogen and this study aims to determine if it plays a role in the interaction between fibrinogen and αIIbβ3. NGR-containing peptides inhibited resting platelet adhesion to fibrinogen with an IC50 of 175 µM but failed to inhibit the adhesion of activated platelets to fibrinogen (IC50> 500 µM). Resting platelet adhesion to mutant fibrinogens lacking the NGR sequences was reduced compared to normal fibrinogen under both static and shear conditions (200 s⁻¹). However, pre-activated platelets were able to fully spread on all types of fibrinogen. Thus, the NGR motif in fibrinogen is the site that is primarily responsible for the interaction with resting αIIbβ3 and is responsible for triggering platelet activation.

  17. Origin of the nonadhesive properties of fibrinogen matrices probed by force spectroscopy.

    PubMed

    Yermolenko, Ivan S; Fuhrmann, Alexander; Magonov, Sergei N; Lishko, Valeryi K; Oshkadyerov, Stanislav P; Ros, Robert; Ugarova, Tatiana P

    2010-11-16

    The deposition of a multilayered fibrinogen matrix on various surfaces results in a dramatic reduction of integrin-mediated cell adhesion and outside-in signaling in platelets and leukocytes. The conversion of a highly adhesive, low-density fibrinogen substrate to the nonadhesive high-density fibrinogen matrix occurs within a very narrow range of fibrinogen coating concentrations. The molecular events responsible for this transition are not well understood. Herein, single-cell and molecular force spectroscopy were used to determine the early steps in the formation of nonadhesive fibrinogen substrates. We show that the adsorption of fibrinogen in the form of a molecular bilayer coincides with a several-fold reduction in the adhesion forces generated between the AFM tip and the substrate as well as between a cell and the substrate. The subsequent deposition of new layers at higher coating concentrations of fibrinogen results in a small additional decrease in adhesion forces. The poorly adhesive fibrinogen bilayer is more extensible under an applied tensile force than is the surface-bound fibrinogen monolayer. Following chemical cross-linking, the stabilized bilayer displays the mechanical and adhesive properties characteristic of a more adhesive fibrinogen monolayer. We propose that a greater compliance of the bi- and multilayer fibrinogen matrices has its origin in the interaction between the molecules forming the adjacent layers. Understanding the mechanical properties of nonadhesive fibrinogen matrices should be of importance in the therapeutic control of pathological thrombosis and in biomaterials science.

  18. Homocysteine, iron and cardiovascular disease: a hypothesis.

    PubMed

    Baggott, Joseph E; Tamura, Tsunenobu

    2015-02-06

    Elevated circulating total homocysteine (tHcy) concentrations (hyperhomocysteinemia) have been regarded as an independent risk factor for cardiovascular disease (CVD). However, several large clinical trials to correct hyperhomocysteinemia using B-vitamin supplements (particularly folic acid) have largely failed to reduce the risk of CVD. There is no doubt that a large segment of patients with CVD have hyperhomocysteinemia; therefore, it is reasonable to postulate that circulating tHcy concentrations are in part a surrogate marker for another, yet-to-be-identified risk factor(s) for CVD. We found that iron catalyzes the formation of Hcy from methionine, S-adenosylhomocysteine and cystathionine. Based on these findings, we propose that an elevated amount of non-protein-bound iron (free Fe) increases circulating tHcy. Free Fe catalyzes the formation of oxygen free radicals, and oxidized low-density lipoprotein is a well-established risk factor for vascular damage. In this review, we discuss our findings on iron-catalyzed formation of Hcy from thioethers as well as recent findings by other investigators on this issue. Collectively, these support our hypothesis that circulating tHcy is in part a surrogate marker for free Fe, which is one of the independent risk factors for CVD.

  19. Homocysteine induces inflammatory transcriptional signaling in monocytes.

    PubMed

    Meng, Shu; Ciment, Stephen; Jan, Michael; Tran, Tran; Pham, Hung; Cueto, Ramon; Yang, Xiao-Feng; Wang, Hong

    2013-01-01

    Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. Here, we studied transcriptional regulation in homocysteine (Hcy)-induced gene expression in monocytes (MC). We identified 11 Hcy-induced genes, 17 anti-inflammatory cytokine interleukin 10-induced, 8 pro-inflammatory cytokine interferon gamma (IFN gamma)-induced and 8 pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha)-induced genes through literature search. Binding frequency of 36 transcription factors (TFs) implicated in inflammation and MC differentiation were analyzed within core promoter regions of identified genes, and classified into 3 classes based on the significant binding frequency to the promoter of Hcy-induced genes. Class 1 TFs exert high significant binding frequency in Hcy-induced genes. Class 2 and 3 TFs have low and no significant binding frequency, respectively. Class 1 TF binding occurrence in Hcy-induced genes is similar to that in IFN gamma -induced genes, but not that in TNF alpha -induced. We conclude that Hcy is a pro-inflammatory amino acid and induces inflammatory transcriptional signal pathways mediated by class 1 TF. We term class 1 TF as putative Hcy-responsive TFs.

  20. Homocysteine induces inflammatory transcriptional signaling in monocytes

    PubMed Central

    Meng, Shu; Ciment, Stephen; Jan, Michael; Tran, Tran; Pham, Hung; Cueto, Ramón; Yang, Xiao-Feng; Wang, Hong

    2013-01-01

    Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. This study is to investigate transcriptional mechanism underlying homocysteine (Hcy)-induced and monocytes (MC)-derived inflammatory response. We identified 11 Hcy-induced genes, 17 anti-inflammatory cytokine interleukin 10-induced, 8 pro-inflammatory cytokine interferon γ (IFNγ)-induced and 8 pro-inflammatory cytokine tumor necrosis factor α (TNFα)-induced genes through literature search. Binding frequency of 36 transcription factors (TFs) implicated in inflammation and MC differentiation were analyzed within core promoter regions of identified genes, and classified into 3 classes based on the significant binding frequency to the promoter of Hcy-induced genes. Class 1 TFs exert high significant binding frequency in Hcy-induced genes. Class 2 and 3 TFs have low and no significant binding frequency, respectively. Class 1 TF binding occurrence in Hcy-induced genes is similar to that in IFNγ-induced genes, but not that in TNFα-induced. We conclude that Hcy is a pro-inflammatory amino acid and induces inflammatory transcriptional signal pathways mediated by class 1 TF. We term class 1 TF, which includes heat shock factor, MC enhancer factor-2, nuclear factor of activated T-cells, nuclear factor kappa light chain enhancer of activated B cells and Krueppel-like factor 4, as putative Hcy-responsive TFs. PMID:23276953

  1. Natural variability of in vitro adherence to fibrinogen and fibronectin does not correlate with in vivo infectivity of Staphylococcus aureus.

    PubMed

    Ythier, Mathilde; Entenza, Jose M; Bille, Jacques; Vandenesch, François; Bes, Michèle; Moreillon, Philippe; Sakwinska, Olga

    2010-04-01

    Adherence to fibrinogen and fibronectin plays a crucial role in Staphylococcus aureus experimental endocarditis. Previous genetic studies have shown that infection and carriage isolates do not systematically differ in their virulence-related genes, including genes conferring adherence, such as clfA and fnbA. We set out to determine the range of adherence phenotypes in carriage isolates of S. aureus, to compare the adherence of these isolates to the adherence of infection isolates, and to determine the relationship between adherence and infectivity in a rat model of experimental endocarditis. A total of 133 healthy carriage isolates were screened for in vitro adherence to fibrinogen and fibronectin, and 30 isolates were randomly chosen for further investigation. These 30 isolates were compared to 30 infective endocarditis isolates and 30 blood culture isolates. The infectivities of the carriage isolates, which displayed either extremely low or high adherence to fibrinogen and fibronectin, were tested using a rat model of experimental endocarditis. The levels of adherence to both fibrinogen and fibronectin were very similar for isolates from healthy carriers and members of the two groups of infection isolates. All three groups of isolates showed a wide range of adherence to fibrinogen and fibronectin. Moreover, the carriage isolates that showed minimal adherence and the carriage isolates that showed strong adherence had the same infectivity in experimental endocarditis. Adherence was proven to be important for pathogenesis in experimental endocarditis, but even the least adherent carriage strains had the ability to induce infection. We discuss the roles of differential gene expression, human host factors, and gene redundancy in resolving this apparent paradox.

  2. Fibrinogen Binding Sites P336 and Y338 of Clumping Factor A Are Crucial for Staphylococcus aureus Virulence

    PubMed Central

    Josefsson, Elisabet; Higgins, Judy; Foster, Timothy J.; Tarkowski, Andrej

    2008-01-01

    We have earlier shown that clumping factor A (ClfA), a fibrinogen binding surface protein of Staphylococcus aureus, is an important virulence factor in septic arthritis. When two amino acids in the ClfA molecule, P336 and Y338, were changed to serine and alanine, respectively, the fibrinogen binding property was lost. ClfAP336Y338 mutants have been constructed in two virulent S. aureus strains Newman and LS-1. The aim of this study was to analyze if these two amino acids which are vital for the fibrinogen binding of ClfA are of importance for the ability of S. aureus to generate disease. Septic arthritis or sepsis were induced in mice by intravenous inoculation of bacteria. The clfAP336Y338 mutant induced significantly less arthritis than the wild type strain, both with respect to severity and frequency. The mutant infected mice developed also a much milder systemic inflammation, measured as lower mortality, weight loss, bacterial growth in kidneys and lower IL-6 levels. The data were verified with a second mutant where clfAP336 and Y338 were changed to alanine and serine respectively. When sepsis was induced by a larger bacterial inoculum, the clfAP336Y338 mutants induced significantly less septic death. Importantly, immunization with the recombinant A domain of ClfAP336SY338A mutant but not with recombinant ClfA, protected against septic death. Our data strongly suggest that the fibrinogen binding activity of ClfA is crucial for the ability of S. aureus to provoke disease manifestations, and that the vaccine potential of recombinant ClfA is improved by removing its ability to bind fibrinogen. PMID:18493318

  3. Practical application of /sup 125/I-fibrinogen leg scanning

    SciTech Connect

    Hull, R.D.; Hirsh, J.

    1981-07-01

    The diagnosis of venous thrombosis by radioiodine-labeled fibrinogen scanning depends upon the incorporation of circulating labeled fibrinogen into a developing or established thrombus which is then detected by measuring the increase of overlying surface radioactivity with an isotope detector. The scanning procedure is simple and rapid, and one technician can screen 15 to 20 patients daily. A single intravenous injection of 100 ..mu..Ci of /sup 125/I-fibrinogen enables scanning to be performed for approximately 7 days. leg scanning has been a valuable research tool and is also useful for the clinical management of patients with venous thrombosis. Its limitations are its insensitivity to iliac vein thrombosis and relative insensitivity to thrombi in the upper thigh, and when used diagnostically in patients with clinically suspected venous thrombosis there is a delay of up to 2 days before a positive result is obtained. For these reasons leg scanning should not be used alone in patients with clinically suspected venous thrombosis. The practical indications for using /sup 125/I-fibrinogen leg scanning are (1) for diagnosis of clinically suspected venous thrombosis when used in combination with impedance plethysmography; (2) detection of acute venous thrombosis in patients with chronic venous insufficiency; (3) screening patients who develop calf vein thrombosis when there is contraindication to anticoagulant therapy; and (4) screening certain high-risk patients and patient groups in whom the prophylaxis is either contraindicated or ineffective.

  4. Fibrinogen and red blood cells in venous thrombosis.

    PubMed

    Aleman, Maria M; Walton, Bethany L; Byrnes, James R; Wolberg, Alisa S

    2014-05-01

    Deep vein thrombosis and pulmonary embolism, collectively termed venous thromboembolism (VTE), affect over 1 million Americans each year. VTE is triggered by inflammation and blood stasis leading to the formation of thrombi rich in fibrin and red blood cells (RBCs). However, little is known about mechanisms regulating fibrin and RBC incorporation into venous thrombi, or how these components mediate thrombus size or resolution. Both elevated circulating fibrinogen (hyperfibrinogenemia) and abnormal fibrin(ogen) structure and function, including increased fibrin network density and resistance to fibrinolysis, have been observed in plasmas from patients with VTE. Abnormalities in RBC number and/or function have also been associated with VTE risk. RBC contributions to VTE are thought to stem from their effects on blood viscosity and margination of platelets to the vessel wall. More recent studies suggest RBCs also express phosphatidylserine, support thrombin generation, and decrease fibrinolysis. RBC interactions with fibrin(ogen) and cells, including platelets and endothelial cells, may also promote thrombus formation. The contributions of fibrin(ogen) and RBCs to the pathophysiology of VTE warrants further investigation.

  5. The mechanical properties of individual, electrospun fibrinogen fibers

    PubMed Central

    Carlisle, Christine R.; Coulais, Corentin; Namboothiry, Manoj; Carroll, David L.; Hantgan, Roy R.; Guthold, Martin

    2010-01-01

    We used a combined atomic force microscopic (AFM)/fluorescence microscopic technique to study the mechanical properties of individual, electrospun fibrinogen fibers in aqueous buffer. Fibers (average diameter 208 nm) were suspended over 12 μm-wide grooves in a striated, transparent substrate. The AFM, situated above the sample, was used to laterally stretch the fibers and to measure the applied force. The fluorescence microscope, situated below the sample, was used to visualize the stretching process. The fibers could be stretched to 2.3 times their original length before breaking; the breaking stress was 22 × 106 Pa. We collected incremental stress–strain curves to determine the viscoelastic behavior of these fibers. The total stretch modulus was 17.5 × 106 Pa and the relaxed elastic modulus was 7.2 × 106 Pa. When held at constant strain, electrospun fibrinogen fibers showed a fast and slow stress relaxation time of 3 and 55 s. Our fibers were spun from the typically used 90% 1,1,1,3,3,3-hexafluoro-2-propanol (90-HFP) electrospinning solution and re-suspended in aqueous buffer. Circular dichroism spectra indicate that α-helical content of fibrinogen is ~70% higher in 90-HFP than in aqueous solution. These data are needed to understand the mechanical behavior of electrospun fibrinogen structures. Our technique is also applicable to study other nanoscopic fibers. PMID:19058845

  6. Evaluation of Fibrinogen Self-assembly: Role of its αC Region

    PubMed Central

    Koo, Jaseung; Rafailovich, Miriam H.; Medved, Leonid; Tsurupa, Galina; Kudryk, Bohdan J.; Liu, Ying; Galanakis, Dennis K.

    2010-01-01

    SUMMARY Background Exposure of cryptic, functional sites on fibrinogen upon its adsorption to hydrophobic surfaces of biomaterials have been linked to inflammatory response and fibrosis. Such adsorption also induces ordered fibrinogen aggregation which is poorly understood. Objective To investigate hydrophobic surface-induced fibrinogen aggregation. Methods: Contact and lateral force scanning probe microscopy, yielding topography, image dimensions, and fiber elastic modulus measurements were used along with transmission and scanning electron microscopy. Fibrinogen aggregation was induced under non-enzymatic conditions by adsorption on a trioctyl-surface monolayer (trioctylmethylamine) grafted onto silica clay plates. Results A more than one molecule thick coating was generated by adsorption on the plate from 100–200 μg/ml fibrinogen solutions, and three-dimensional networks formed from 4 mg/ml fibrinogen incubated with uncoated or fibrinogen-coated plates. Fibrils appeared laterally assembled into branching and overlapping fibers whose heights from surface ranged from ~3 to 740 nm. The elastic modulus of fibrinogen fibers was 1.55 MPa. No fibrils formed when fibrinogen lacking αC-domains was used as coating or was incubated with intact fibrinogen-coated plates, or when the latter plates were sequentially incubated with anti-Aα529–539 mAb and intact fibrinogen. When an anti-Aα241–476 mAb was used instead, fine, long fibers formed. Similarly, sequential incubations of fibrinogen-coated plates with recombinant αC-domain (Aα392–610 fragment) or αC-connector (Aα221–372 fragment) and fibrinogen resulted in distinctly fine fiber networks. Conclusions Adsorption-induced fibrinogen self-assembly is initiated by a more than one molecule-thick surface layer and eventuates in three-dimensional networks whose formation requires fibrinogen with intact αC-domains. PMID:20880206

  7. Purification of fibrinogen and virus removal using preparative electrophoresis.

    PubMed

    Gilbert, A; Evtushenko, M; Nair, H

    2001-01-01

    The Gradiflow is a novel, scalable preparative electrophoresis technique that uses the dual characteristics of size and charge to isolate target macro- and micromolecules from complex biological solutions. It does this with high resolution and in rapid time. The mild buffers are used to assist in retaining biological activity of the isolated protein. Gradiflow technology employs a sandwich of three polyacrylamide membranes configured to allow passage of macromolecules ranging in size from 10 kDa to 1,500 kDa. Fibrinogen was isolated from cryoprecipitate 1 using a single phase process. This separation was achieved within three hours with yields of 85%. Purified fibrinogen was then characterized using biophysical characterization of fibrin clot structure and compared with clots derived from a commercially available product and human plasma. Significantly, clots developed from Gradiflow fibrinogen had characteristics closer to human plasma. Viral removal characteristics of the Gradiflow were investigated by spiking the source material (cryoprecipitate 1) with canine parvovirus and testing for its presence in the isolated fibrinogen using PCR. Parvo removal was found to be greater than 4 logs and was achieved during the purification process. The Gradiflow offers the advantage of large-scale separation of macromolecules and provides a new approach to fibrinogen separation that is quite distinct from other present-day technologies. The technology is capable of isolating protein with high purity, recovery, and functionality in combination with the removal of viruses during the purification. Furthermore, it is capable of integrating into present production systems, significantly improving yield and functionality of target molecules.

  8. Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease.

    PubMed

    Puls, Florian; Goldschmidt, Imeke; Bantel, Heike; Agne, Clemens; Bröcker, Verena; Dämmrich, Maximilian; Lehmann, Ulrich; Berrang, Jens; Pfister, Eva-Doreen; Kreipe, Hans Heinrich; Baumann, Ulrich

    2013-09-01

    Fibrinogen storage disease (FSD) is a rare autosomal-dominant hereditary disorder characterized by hypofibrinogenemia and accumulation of fibrinogen aggregates within the hepatocellular endoplasmatic reticulum (ER). Some FSD patients present with elevated amino-transferases and fibrosis/cirrhosis similar to alpha-1-antitrypsin deficiency (ATD), also an ER storage disease. Pharmacological stimulation of autophagy has been shown to mediate clearance of protein aggregates and halt progression of liver fibrosis in in vivo models of ATD. Our aim was to evaluate the presence of autophagy and a possible response to autophagy-enhancing therapy in patients with FSD. Hepatic fibrosis was assessed by transient elastography in 2 newly identified FSD families with fibrinogen Aguadilla and Brescia mutations, encompassing 8 affected members. Available liver biopsies were assessed for autophagy. Two patients, who had had elevated alanine amino-transaminase levels (2-5 above upper limit of normal), were treated with the autophagy enhancer carbamazepine (CBZ). Transient elastography did not show evidence of significant fibrosis in any affected family members. Quantitative electron microscopy of one patient showed a 5.15-fold increase of late stage autophagocytic vacuoles compared to control livers. CBZ at low anticonvulsive treatment levels led to rapid normalization of alanine-aminotransferase and decrease of caspase-cleaved and uncleaved cytokeratin-18 fragments (M30 and M65). These effects reversed after discontinuation of treatment. Response to CBZ may be mediated by pharmacologically enhanced autophagy resulting in reduction of aggregate-related toxicity in FSD. These results suggest clinical applicability of pharmacological stimulation of autophagy in FSD, but potentially also in other related disorders.

  9. Plasma total homocysteine status of vegetarians compared with omnivores: a systematic review and meta-analysis.

    PubMed

    Obersby, Derek; Chappell, David C; Dunnett, Andrew; Tsiami, Amalia A

    2013-03-14

    There is strong evidence indicating that elevated plasma total homocysteine (tHcy) levels are a major independent biomarker and/or a contributor to chronic conditions, such as CVD. A deficiency of vitamin B₁₂ can elevate homocysteine. Vegetarians are a group of the population who are potentially at greater risk of vitamin B₁₂ deficiency than omnivores. This is the first systematic review and meta-analysis to appraise a range of studies that compared the homocysteine and vitamin B₁₂ levels of vegetarians and omnivores. The search methods employed identified 443 entries, from which, by screening using set inclusion and exclusion criteria, six eligible cohort case studies and eleven cross-sectional studies from 1999 to 2010 were revealed, which compared concentrations of plasma tHcy and serum vitamin B₁₂ of omnivores, lactovegetarians or lacto-ovovegetarians and vegans. Of the identified seventeen studies (3230 participants), only two studies reported that vegan concentrations of plasma tHcy and serum vitamin B₁₂ did not differ from omnivores. The present study confirmed that an inverse relationship exists between plasma tHcy and serum vitamin B₁₂, from which it can be concluded that the usual dietary source of vitamin B₁₂ is animal products and those who choose to omit or restrict these products are destined to become vitamin B₁₂ deficient. At present, the available supplement, which is usually used for fortification of food, is the unreliable cyanocobalamin. A well-designed study is needed to investigate a reliable and suitable supplement to normalise the elevated plasma tHcy of a high majority of vegetarians. This would fill the gaps in the present nutritional scientific knowledge.

  10. Transient Decrease in Circulatory Testosterone and Homocysteine Precedes the Development of Metabolic Syndrome Features in Fructose-Fed Sprague Dawley Rats

    PubMed Central

    Sakamuri, Anil; Pitla, Sujatha; Putcha, Uday Kumar; Jayapal, Sugeedha; Pothana, Sailaja; Vadakattu, Sai Santosh

    2016-01-01

    Background. Increased fructose consumption is linked to the development of metabolic syndrome (MS). Here we investigated the time course of development of MS features in high-fructose-fed Sprague Dawley rats along with circulatory testosterone and homocysteine levels. Methods. Rats were divided into control and experimental groups and fed with diets containing 54.5% starch and fructose, respectively, for 4, 12, and 24 weeks. Plasma testosterone and homocysteine levels were measured along with insulin, glucose, and lipids. Body composition, insulin resistance, and hepatic lipids were measured. Results. Increase in hepatic triglyceride content was first observed in metabolic disturbance followed by hypertriglyceridemia and systemic insulin resistance in fructose-fed rats. Hepatic lipids were increased in time-dependent manner by fructose-feeding starting from 4 weeks, but circulatory triglyceride levels were increased after 12 weeks. Fasting insulin and Homeostatis Model Assessment of Insulin Resistance (HOMA-IR) were increased after 12 weeks of fructose-feeding. Decreased visceral adiposity, circulatory testosterone, and homocysteine levels were observed after 4 weeks of fructose-feeding, which were normalized at 12 and 24 weeks. Conclusions. We conclude that transient decrease in circulatory testosterone and homocysteine levels and increased hepatic triglyceride content are the earliest metabolic disturbances that preceded hypertriglyceridemia and insulin resistance in fructose-fed SD rats. PMID:27818793

  11. Location of peptide fragments in the fibrinogen molecule by immunoelectron microscopy.

    PubMed Central

    Telford, J N; Nagy, J A; Hatcher, P A; Scheraga, H A

    1980-01-01

    Antibodies to the disulfide knot fragment of bovine fibrinogen have been used to locate the site of this fragment within the intact fibrinogen molecule. The antibodies were isolated from rabbit antifibrinogen antisera by affinity chromatography. Electron micrographs of reaction mixtures of bovine fibrinogen and antibodies against the disulfide knot fragment showed pairs of fibrinogen molecules crosslinked by antibody molecules as well as higher order antibody-fibrinogen complexes. From an electron microscopic investigation of the crosslinked material, we conclude that the disulfide knot lies within the central nodule of the trinodular fibrinogen molecule. Antibodies to fragment H were used in the same manner to locate this fragment within the outer nodules of the human fibrinogen molecule. Images PMID:6769127

  12. Long‐term effect of Helicobacter pylori eradication on plasma homocysteine in elderly patients with cobalamin deficiency

    PubMed Central

    Marino, Marília Campos Abreu; de Oliveira, Celso Affonso; Rocha, Andreia Maria Camargos; Rocha, Gifone Aguiar; Clementino, Nelma Cristina Diogo; Antunes, Leonardo França; Oliveira, Ricardo Araújo; Martins, Almir Sousa; Del Puerto, Helen Lima; D'Almeida, Vânia; Galdieri, Luciano; Pedroso, Ênio Roberto Pietra; Cabral, Mônica Maria Demas Álvares; Nogueira, Ana Margarida Miguel Ferreira; Queiroz, Dulciene Maria Magalhães

    2007-01-01

    Background Helicobacter pylori gastritis may lead to impairment of the production of pepsinogen and acid, which are essential to cobalamin absorption. In turn, cobalamin deficiency leads to hyperhomocysteinaemia, a risk factor for cardio and cerebrovascular diseases. Aim To evaluate the effect of H pylori eradication on plasma homocysteine levels in elderly patients. Patients Sixty‐two H pylori‐positive elderly patients with cobalamin deficiency were prospectively studied. Methods Homocysteine and cobalamin concentrations were determined before, 6 and 12 months after H pylori eradication. Results Corpus atrophy was observed in a few patients; otherwise, in most of them, the degree of corpus gastritis was moderate to severe. The initial homocysteine mean (SD) levels decreased from 41.0 (27.1) to 21.6 (10.1) μmol/l at the 6 month follow‐up (p<0.001) and to 13.1 (3.8) μmol/l 12 months after H pylori eradication (p<0.001). Conversely, initial cobalamin mean levels increased from 145.5 (48.7) pmol/l to 209.8 (87.1) pmol/l and to 271.2 (140.8) pmol/l, 6 and 12 months after treatment, respectively (p<0.001 for both). Although the erythrocyte mean corpuscular volume was within reference intervals, it decreased significantly 6 (p = 0.002) and 12 (p<0.001) months after treatment. Conclusions The results of the current study demonstrated that the eradication of H pylori in elderly patients with cobalamin deficiency is followed by increasing of cobalamin and decreasing of homocysteine blood levels. PMID:17005765

  13. Time-dependent association between platelet-bound fibrinogen and the Triton X-100 insoluble cytoskeleton

    SciTech Connect

    Peerschke, E.I. )

    1991-02-01

    Previous studies indicated a correlation between the formation of EDTA-resistant (irreversible) platelet-fibrinogen interactions and platelet cytoskeleton formation. The present study explored the direct association of membrane-bound fibrinogen with the Triton X-100 insoluble cytoskeleton of aspirin-treated, gel-filtered platelets, activated but not aggregated with 20 mumol/L adenosine diphosphate (ADP) or 150 mU/mL human thrombin (THR) when bound fibrinogen had become resistant to dissociation by EDTA. Conversion of exogenous 125I-fibrinogen to fibrin was prevented by adding Gly-Pro-Arg and neutralizing THR with hirudin before initiating binding studies. After 60 minutes at 22 degrees C, the cytoskeleton of ADP-treated platelets contained 20% +/- 12% (mean +/- SD, n = 14) of membrane-bound 125I-fibrinogen, representing 10% to 50% of EDTA-resistant fibrinogen binding. The THR-activated cytoskeleton contained 45% +/- 15% of platelet bound fibrinogen, comprising 80% to 100% of EDTA-resistant fibrinogen binding. 125I-fibrinogen was not recovered with platelet cytoskeletons if binding was inhibited by the RGDS peptide, excess unlabeled fibrinogen, or disruption of the glycoprotein (GP) IIb-IIIa complex by EDTA-treatment. Both development of EDTA-resistant fibrinogen binding and fibrinogen association with the cytoskeleton were time dependent and reached maxima 45 to 60 minutes after fibrinogen binding to stimulated platelets. Although a larger cytoskeleton formed after platelet stimulation with thrombin as compared with ADP, no change in cytoskeleton composition was noted with development of EDTA-resistant fibrinogen binding.

  14. Specific cell components of Bacteroides gingivalis mediate binding and degradation of human fibrinogen.

    PubMed Central

    Lantz, M S; Allen, R D; Vail, T A; Switalski, L M; Hook, M

    1991-01-01

    Bacteroides (Porphyromonas) gingivalis, which has been implicated as an etiologic agent in human periodontal diseases, has been shown to bind and degrade human fibrinogen. B. gingivalis strains bind fibrinogen reversibly and with high affinity and bind to a specific region of the fibrinogen molecule that appears to be located between the D and E domains (M. S. Lantz, R. D. Allen, P. Bounelis, L. M. Switalski, and M. Hook, J. Bacteriol. 172:716-726, 1990). We now report that human fibrinogen is bound and then degraded by specific B. gingivalis components that appear to be localized at the cell surface. Fibrinogen binding to bacterial cells occurred at 4, 22, and 37 degrees C. A functional fibrinogen-binding component (Mr, 150,000) was identified when sodium dodecyl sulfate-solubilized bacteria were fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, and probed with 125I-fibrinogen. Fibrinogen degradation did not occur at 4 degrees C but did occur at 22 and 37 degrees C. When bacteria and iodinated fibrinogen were incubated at 37 degrees C, two major fibrinogen fragments (Mr, 97,000 and 50,000) accumulated in incubation mixture supernatant fractions. Two major fibrinogen-degrading components (Mr, 120,000 and 150,000) have been identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in substrate-containing gels. Fibrinogen degradation by the Mr-120,000 and -150,000 proteases was enhanced by reducing agents, completely inhibited by N-alpha-p-tosyl-L-lysyl chloromethyl ketone, and partially inhibited by n-ethyl maleimide, suggesting that these enzymes are thiol-dependent proteases with trypsinlike substrate specificity. The fibrinogen-binding component could be separated from the fibrinogen-degrading components by selective solubilization of bacteria in sodium deoxycholate. Images PMID:1987144

  15. Alpha-methyl-homocysteine thiolactone protects lung of BALB/c mice irradiated with 6 Gy

    NASA Astrophysics Data System (ADS)

    Lubec, G.; Foltinova, J.; Leplawy, T.; Mallinger, R.; Tichatschek, E.; Getoff, N.

    1996-06-01

    The radiation protective activity of intraperitoneally administered alpha-methyl-homocysteine thiolactone (α-MHCTL; 100 mg/kg body weight) in female BALB/c mice and such treated with cysteine treated (100 mg/kg body weight), using unirradiated and placebo treated irradiated mice were tested as controls. 6 Gy whole body irradiated was applied and after a period of three weeks the animals were sacrificed and lungs were taken for morphometry and the determination of o-tyrosine. Septal areas were highest in the irradiated, placebo treated mice (68.67 + 9.82% septal area to total area)and lowest in the α-MHCTL treated irradiated mice (55.67 +11.29%), significant at the p < 0.05 level. Morphometric data were accompanied by highest levels of o-tyrosine, a reliable parameter for OH-attack, in the irradiated, placebo treated group with 1.87 + 0.40 μM/g lung tissue and 0.32 + 0.13 gmM/g lung tissue in the αMHCTL treated group; the statistical difference was significant. Significant radiation protection in the mammalian system at the morphological and biochemical level were found. The potent effect could be explained by the influence of alpha-alkylation in homocysteine thiolactone (HCTL) which renders amino acids unmetabolizeable, nontoxic, increases lipophilicity and therefore improving permeability through membranes. The present report confirms morphological data on the radiation protective activity of this interesting thiol compound.

  16. Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle.

    PubMed

    Pérez-Miguelsanz, Juliana; Vallecillo, Néstor; Garrido, Francisco; Reytor, Edel; Pérez-Sala, Dolores; Pajares, María A

    2017-03-10

    The paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT), an enzyme that exerts a dual function in maintenance of methionine levels and osmoregulation, as a new component of the nuclear branch of the cycle. In most tissues, low expression of Bhmt coincides with a preferential nuclear localization of the protein. Conversely, the liver, with very high Bhmt expression levels, presents a main cytoplasmic localization. Nuclear BHMT is an active homotetramer in normal liver, although the total enzyme activity in this fraction is markedly lower than in the cytosol. N-terminal basic residues play a role in cytoplasmic retention and the ratio of glutathione species regulates nucleocytoplasmic distribution. The oxidative stress associated with D-galactosamine (Gal) or buthionine sulfoximine (BSO) treatments induces BHMT nuclear translocation, an effect that is prevented by administration of N-acetylcysteine (NAC) and glutathione ethyl ester (EGSH), respectively. Unexpectedly, the hepatic nuclear accumulation induced by Gal associates with reduced nuclear BHMT activity and a trend towards increased protein homocysteinylation. Overall, our results support the involvement of BHMT in nuclear homocysteine remethylation, although moonlighting roles unrelated to its enzymatic activity in this compartment cannot be excluded.

  17. Serum homocysteine in pre-eclampsia and eclampsia.

    PubMed

    Hoque, Md Mozammel; Bulbul, Tania; Mahal, Monzarin; Islam, Nur-A-Farzana; Ferdausi, Munira

    2008-04-01

    Pre-eclampsia and eclampsia are common obstetrical problem causing adverse effects on pregnancy outcome. Large bodies of evidences suggest that hyperhomocysteinemia is a causal factor of pre-eclampsia/eclampsia. This study designed to explore the association between hyperhomocysteinemia and pre-eclampsia/eclampsia, the knowledge of which expected to be used for prevention of pre-eclampsia and eclampsia. In a case-control study serum homocysteine was measured in 136 controls (healthy pregnant), 84 pre-eclamptic and 120 eclamptic pregnant women. Serum homocysteine in patients with pre-eclampsia (9.54 +/- 3.21 micromol/L) and eclampsia (10.57 +/- 3.39 micromol/L) found to be significantly increased compared to controls (6.86 +/- 2.47 micromol/L) (p < 0.001). Between pre-eclampsia and eclampsia, homocysteine found to be raised more in eclampsia compared to pre-eclampsia (p < 0.03). In conclusion, hyperhomocysteinemia is associated with pre-eclampsia as well as eclampsia, but in eclampsia the severity of homocysteine elevation is more compared to that in pre-eclampsia.

  18. Protective effects of dibenzocyclooctadiene lignans from Schisandra chinensis against beta-amyloid and homocysteine neurotoxicity in PC12 cells.

    PubMed

    Song, Ju-Xian; Lin, Xiang; Wong, Ricky Ngok-Shun; Sze, Stephen Cho-Wing; Tong, Yao; Shaw, Pang-Chui; Zhang, Yan-Bo

    2011-03-01

    Aggregated beta-amyloid (Aβ) and elevated plasma levels of homocysteine have been implicated as critical factors in the pathogenesis of Alzheimer's disease. The neuroprotective effects and possible mechanism of four structurally similar dibenzocyclooctadiene lignans (namely schisandrin, schisantherin A, schisandrin B and schisandrin C) isolated from the fruit of Schisandra chinensis (Turcz.) Baill. (Schisandraceae) against Aβ₂₅₋₃₅ and homocysteine toxicity in PC12 cells was studied. Exposure of PC12 cells to 0.5 µm Aβ₂₅₋₃₅ caused significant cell death, increased the number of apoptotic cells, elevated reactive oxygen species, increased the levels of the pro-apoptotic protein Bax and caspase-3 activation. All these effects induced by Aβ₂₅₋₃₅ were markedly reversed by schisandrin B and schisandrin C pretreatment, while schisandrin and schisantherin A had no obvious effects. Meanwhile, schisandrin B and schisandrin C reversed homocysteine-induced cytotoxicity. The results indicated that schisandrin B and schisandrin C protected PC12 cells against Aβ toxicity by attenuating ROS production and modulating the apoptotic signal pathway through Bax and caspase-3. Further structure-activity analysis of Schisandra lignans and evaluations of their neuroprotective effects using AD animal models are warranted.

  19. [Prognostic value of serum homocysteine levels in elderly hospitalized patients].

    PubMed

    Hernández-Betancor, Iván; Martín-Ponce, Esther; Martínez-Riera, Antonio; Viña-Rodríguez, Juan José; González-Reimers, Emilio; de la Vega-Prieto, María José; Santolaria, Francisco

    2015-06-01

    Antecedentes y objetivos: el aumento de la homocisteína se relaciona con la enfermedad vascular y un incremento de la mortalidad. La disminución de la homocisteína se asocia también con un peor pronóstico en enfermos en hemodiálisis; sin embargo, esta relación no ha sido bien estudiada en otro tipo de pacientes. El objetivo del estudio fue analizar el valor pronóstico de los niveles de homocisteína en enfermos ancianos pluripatológicos ingresados en un servicio general de medicina interna Pacientes y métodos: estudiamos a 239 pacientes (121 mujeres y 118 varones; edad media: 78 años) en los que determinamos la homocisteína sérica y la relacionamos con los factores de riesgo vascular, enfermedad vascular: cardiopatía isquémica, ACV isquémico y arteriopatía periférica, estado de nutrición, creatinina, albúmina, ácido fólico y vitamina B12. Resultados: la mortalidad durante el ingreso de los enfermos con homocisteína menor de 9 mol/l fue del 33%, del 9% cuando estaba entre 9 y 20 mol/l y del 17% si era superior a 20 mol/l. La disminución de la homocisteína se relacionó con mayor comorbilidad, pérdida de peso y disminución de la albúmina. A largo plazo, el aumento de la homocisteína se relacionó con mayor mortalidad, especialmente en los pacientes con enfermedad vascular. Conclusión: en los pacientes ancianos pluripatológicos tanto la disminución como el aumento de la homocisteína se asocian con una mayor mortalidad.

  20. Fibrinogen nitrotyrosination after ischemic stroke impairs thrombolysis and promotes neuronal death.

    PubMed

    Ill-Raga, Gerard; Palomer, Ernest; Ramos-Fernández, Eva; Guix, Francesc X; Bosch-Morató, Mònica; Guivernau, Biuse; Tajes, Marta; Valls-Comamala, Victòria; Jiménez-Conde, Jordi; Ois, Angel; Pérez-Asensio, Fernando; Reyes-Navarro, Mario; Caballo, Carolina; Gil-Gómez, Gabriel; Lopez-Vilchez, Irene; Galan, Ana M; Alameda, Francesc; Escolar, Gines; Opazo, Carlos; Planas, Anna M; Roquer, Jaume; Valverde, Miguel A; Muñoz, Francisco J

    2015-03-01

    Ischemic stroke is an acute vascular event that compromises neuronal viability, and identification of the pathophysiological mechanisms is critical for its correct management. Ischemia produces increased nitric oxide synthesis to recover blood flow but also induces a free radical burst. Nitric oxide and superoxide anion react to generate peroxynitrite that nitrates tyrosines. We found that fibrinogen nitrotyrosination was detected in plasma after the initiation of ischemic stroke in human patients. Electron microscopy and protein intrinsic fluorescence showed that in vitro nitrotyrosination of fibrinogen affected its structure. Thromboelastography showed that initially fibrinogen nitrotyrosination retarded clot formation but later made the clot more resistant to fibrinolysis. This result was independent of any effect on thrombin production. Immunofluorescence analysis of affected human brain areas also showed that both fibrinogen and nitrotyrosinated fibrinogen spread into the brain parenchyma after ischemic stroke. Therefore, we assayed the toxicity of fibrinogen and nitrotyrosinated fibrinogen in a human neuroblastoma cell line. For that purpose we measured the activity of caspase-3, a key enzyme in the apoptotic pathway, and cell survival. We found that nitrotyrosinated fibrinogen induced higher activation of caspase 3. Accordingly, cell survival assays showed a more neurotoxic effect of nitrotyrosinated fibrinogen at all concentrations tested. In summary, nitrotyrosinated fibrinogen would be of pathophysiological interest in ischemic stroke due to both its impact on hemostasis - it impairs thrombolysis, the main target in stroke treatments - and its neurotoxicity that would contribute to the death of the brain tissue surrounding the infarcted area.

  1. Novel superhydrophilic poly(l-lactic acid-co-ε-caprolactone)/fibrinogen electrospun patch for rat abdominal wall reconstruction.

    PubMed

    Liu, Zhang; Li, Shaojie; Su, Ling; Sun, Kang; Wu, Xujun; Wu, Feng; Huang, Weihong; Yang, Li; Tang, Jianxiong; He, Hongbing

    2015-08-01

    A novel superhydrophilic hybrid scaffold was created by electrospinning a mixture of poly(l-lactic acid-co-ε-caprolactone) and formulated fibrinogen. The hybrid scaffolds possess the combined benefits of each individual component, such as moderate mechanical strength and excellent biocompatibility. In vitro studies also revealed that endothelial cells seeded on the hybrid scaffolds achieved a relatively high level of cell attachment after three days of culture and a significant increase in the proliferation rate after seven days of culture, compared with pure fibrinogen or poly(l-lactic acid-co-ε-caprolactone) scaffolds. A comparative study of hybrid and pure poly(l-lactic acid-co-ε-caprolactone) patches was performed in an abdominal wall defect model in rats. In both groups, implants degraded by six months, but muscle reconstruction was only observed in the hybrid patch group.

  2. Methionine, homocysteine, one carbon metabolism and fetal growth.

    PubMed

    Kalhan, Satish C; Marczewski, Susan E

    2012-06-01

    Methionine and folate are the key components of one carbon metabolism, providing the methyl groups for numerous methyl transferase reactions via the ubiquitous methyl donor, s-adenosyl methionine. Methionine metabolism is responsive to nutrient intake, is regulated by several hormones and requires a number of vitamins (B12, pyridoxine, riboflavin) as co-factors. The critical relationship between perturbations in the mother's methionine metabolism and its impact on fetal growth and development is now becoming evident. The relation of folate intake to fetal teratogenesis has been known for some time. Studies in human pregnancy show a continuous decrease in plasma homocysteine, and an increase in plasma choline concentrations with advancing gestation. A higher rate of transsulfuration of methionine in early gestation and of transmethylation in the 3rd trimester was seen in healthy pregnant women. How these processes are impacted by nutritional, hormonal and other influences in human pregnancy and their effect on fetal growth has not been examined. Isocaloric protein restriction in pregnant rats, resulted in fetal growth restriction and metabolic reprogramming. Isocaloric protein restriction in the non-pregnant rat, resulted in differential expression of a number of genes in the liver, a 50% increase in whole body serine biosynthesis and high rate of transmethylation, suggesting high methylation demands. These responses were associated with a significant decrease in intracellular taurine levels in the liver suggesting a role of cellular osmolarity in the observed metabolic responses. These unique changes in methionine and one carbon metabolism in response to physiological, nutritional and hormonal influences make these processes critical for cellular and organ function and growth.

  3. Plasma homocysteine is elevated in COPD patients and is related to COPD severity

    PubMed Central

    Seemungal, Terence AR; Lun, Johanna Cho Fook; Davis, Gershwin; Neblett, Carlos; Chinyepi, Nkhabe; Dookhan, Christina; Drakes, Samantha; Mandeville, Elizabeth; Nana, Fatima; Setlhake, Seatshogeng; King, Celia Poon; PintoPereira, Lexley; Delisle, Jerome; Wilkinson, Thomas MA; Wedzicha, Jagwiga A

    2007-01-01

    Background: Although recent studies have found that total plasma homocysteine (tHCY) and chronic obstructive pulmonary disease (COPD) are both risk factors for cardiac disease, there have been few studies of plasma homocysteine levels in COPD patients. We tested the hypothesis that total plasma homocysteine (tHCY) would be elevated in patients diagnosed with COPD compared with controls. Methods: We studied 29 COPD outpatients and 25 asymptomatic subjects (controls) over age 55 years with measurement of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), St. Georges Respiratory Questionnaire (SGRQ) score, tHCY and serum C-reactive protein (sCRP). Results: There was no difference between controls vs. COPD patients in mean age or gender but mean (SD) FEV1 was 2.25 (0.77) vs 1.43 (0.60) L; FEV1% predicted 76.1 (17.2) vs 49.1 (16.3) p < 0.001 in both cases. Median (IQR) tHCY was 8.22 (6.63, 9.55) in controls vs 10.96 (7.56, 13.60) micromol/l for COPD, p = 0.006 and sCRP 0.89 (0.47, 2.55) vs 2.05 (0.86, 6.19) mg/l, p = 0.023. tHCY(log) was also higher in (r, p) smokers (0.448, 0.001), patients with low FEV1% (−0.397, 0.003), males (0.475, <0.001), but high SGRQ Total score (0.289, 0.034), and high sCRP (0.316, 0.038). tHCY(log) was independently related to (regression coefficient, p) sCRP(log) (0.087, 0.024), male gender (0.345, <0.001) and presence of COPD (0.194, 0.031). Median (IQR) tHCY GOLD Stage I and II 8.05 (7.28, 11.04), GOLD Stage III and IV: 11.83(9.30, 18.30); p = 0.023. Conclusions: Plasma homocysteine is significantly elevated in COPD patients relative to age and sex-matched controls and is related to serum CRP and COPD severity. PMID:18229569

  4. Fibrinogen Concentrate in Dilutional Coagulopathy: a Dose Study in Pigs

    DTIC Science & Technology

    2014-01-01

    measurements, animals underwent a 60% normovolemic hemodilution (HD) with 6% hydroxyethyl starch (HES) 130/0.4 (Voluven, Fresenius Co., Bad Homburg...improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo...clinically relevant overestimation of fibrinogen concentration in plasma diluted with hydroxyethyl starch . Clin Appl Thromb Hemost 2010;16:461-71. 28

  5. PRIMING EFFECT OF HOMOCYSTEINE ON INDUCIBLE VASCULAR CELL ADHESION MOLECULE-1 EXPRESSION IN ENDOTHELIAL CELLS

    PubMed Central

    Séguin, Chantal; Abid, Md. Ruhul; Spokes, Katherine C.; Schoots, Ivo G; Brkovic, Alexandre; Sirois, Martin G.; Aird, William C.

    2017-01-01

    Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis, as well as for arterial and venous thrombosis. However, the mechanisms through which elevated circulating levels of homocysteine cause vascular injury and promote thrombosis remain unclear. Here, we tested the hypothesis that homocysteine (Hcy) sensitizes endothelial cells to the effect of inflammatory mediators. Human umbilical vein endothelial cells (HUVEC) were incubated with Hcy 1.0 mM for varying time points, and then treated in the absence or presence of 1.5 U/ml thrombin or 10 ng/ml lipopolysaccharide (LPS). Hcy alone had no effect on the expression of vascular cell adhesion molecule (VCAM)-1. However, Hcy enhanced thrombin- and LPS-mediated induction of VCAM-1 mRNA and protein levels. Consistent with these results, pretreatment of HUVEC with Hcy resulted in a two-fold increase in LSP-mediated induction of leukocyte adhesion. The latter effect was significantly inhibited by anti-VCAM-1 antibodies. Together, these findings suggest that Hcy sensitizes HUVEC to the effect of inflammatory mediators thrombin and LPS, at least in part through VCAM-1 expression and function. PMID:18406566

  6. Role of asymmetric dimethylarginine in homocysteine-induced apoptosis of vascular smooth muscle cells.

    PubMed

    Yuan, Qiong; Jiang, De-Jian; Chen, Qing-Quan; Wang, Shan; Xin, Hong-Ya; Deng, Han-Wu; Li, Yuan-Jian

    2007-05-18

    Homocysteine (Hcy) could induce apoptosis of vascular smooth muscle cells (VSMC). Asymmetric dimethylarginine (ADMA) has been thought as a novel risk factor for cardiovascular diseases. We hypothesized that ADMA mediates homocysteine-induced apoptosis of VSMC. In this experiment the level of ADMA in the medium measured by high-performance liquid chromatography (HPLC) was elevated when the apoptosis of T/G HA-VSMC was induced by Hcy which was detected by Hoechst33342 staining or flow cytometry (FCM) with Annecin V+Propidium Iodide (PI). Exogenous ADMA induced the apoptosis of VSMC. At the same time, ADMA elevated the level of intracellular reactive oxidative species (ROS) determined by fluorescent ROS detection kit. The activation of JNK and p38MAPK contributed to ADMA-induced apoptosis of VSMC. The present results suggest that endogenous ADMA is involved in apoptosis of VSMC induced by Hcy, and the effects of ADMA is related to elevation of intracellular ROS and activation of JNK/p38MAPK signaling pathways.

  7. Fibrinogen adsorption and host tissue responses to plasma functionalized surfaces.

    PubMed

    Tang, L; Wu, Y; Timmons, R B

    1998-10-01

    The physical and chemical characteristics of material surfaces are thought to play important roles in biomaterial-mediated tissue responses. To understand the importance of discrete biomaterial chemical characteristics in modifying host tissue responses, we constructed surfaces bearing different functional groups using radio frequency glow discharge plasma polymerization. Surfaces evaluated included those having high concentrations of -OH, -NH2, -CF3, and siloxyl groups. These surfaces and polyethylene terephthalate controls were used to assess the importance of particular physicochemical characteristics in surface:protein:cell interactions both in vitro and in vivo. The results obtained show that surface functionalities do significantly affect both the adsorption and "denaturation" of adsorbed fibrinogen (which is an important mediator of inflammatory responses to biomaterial implants). In addition, these surfaces provoke different degrees of acute inflammatory responses. Interestingly, the amounts of "denatured" fibrinogen that spontaneously accumulate on the individual surfaces correlate closely with the extent of biomaterial-mediated inflammation. These results suggest that surfaces that tend to "irreversibly" bind fibrinogen prompt greater acute inflammatory responses. Unexpectedly, all test surfaces except those bearing a siloxyl group engender relatively similar biomaterial-mediated fibrotic responses. Thus surface functionalities alone may not be sufficient to affect subsequent fibrotic responses.

  8. EXCESS FIBRINOGEN ADSORPTION TO MONOLAYERS OF MIXED LIPIDS

    PubMed Central

    Deshmukh, V.; Britt, D.W.; Hlady, V.

    2010-01-01

    Adsorption of fibrinogen to the monolayers of mixed lipids, dipalmitoyl phosphatidyl choline (DPPC) and eicosylamine (EA) was measured at a surface pressure of 20 mN/m by an in situ surface plasmon resonance technique. Pressure-area isotherms of DPPC+EA mixtures on water and buffer subphases indicated good lipid miscibility and some contraction of the monolayers at intermediate and higher surface pressures. Surface electric potential of the DPPC+EA monolayers showed excess values for intermediate DPPC:EA ratios. Fibrinogen adsorption and its adsorption rates from a dilute solution (0.03 mg/ml) were proportional to the fraction of EA in the monolayer indicating that protein binding was primarily driven by electrostatic interactions between positive EA charges in the monolayer and a net negative protein charge. At a higher protein concentration (0.06 mg/ml) both the fibrinogen adsorbed amount and its maximum adsorption rate showed excess values relative to the pure EA for 1:1, 2:1 and 3:1 DPPC+EA monolayers. This excess adsorption could be explained, in part, by the contraction of the monolayers with intermediate DPPC:EA ratios which resulted in an excess surface electric potential. PMID:20829000

  9. Fibrinogen, an endogenous ligand of Toll-like receptor 4, activates monocytes in pre-eclamptic patients.

    PubMed

    Al-ofi, Ebtisam; Coffelt, Seth B; Anumba, Dilly O

    2014-06-01

    Pre-eclampsia (PE) remains the leading cause of pregnancy-associated mortality and morbidity, urging the need for a better understanding of its aetiology and pathophysiological progression. A key characteristic of PE is a systemic, exaggerated, inflammatory condition involving abnormal cytokine levels in serum, altered immune cell phenotype and Th1/Th2-type immunological imbalance. However, it is unknown how this heightened inflammatory condition manifests. We previously reported increased expression of the lipopolysaccharide receptor, Toll-like receptor 4 (TLR4), on monocytes from PE patients compared with normotensive, pregnant patients (NP). This upregulation of TLR4 on PE monocytes was accompanied by a hyper-responsiveness to bacterial TLR4 ligands. To determine whether non-microbial, endogenous TLR4 ligands also activate monocytes from PE patients, we investigated the expression of host-derived TLR4 ligands and the response of monocytes to these endogenous ligands. Plasma levels of fibrinogen - but not fibronectin or heparan sulphate - were higher in PE patients than in NP. Exposure to fibrinogen was associated with significantly increased production of inflammatory cytokines by monocytes from PE patients. Interestingly, this effect was not observed with NP monocytes. Our findings suggest that the fibrinogen-TLR4 axis might play an important role in the atypical activation of monocytes observed in PE patients that may contribute to the exaggerated inflammatory condition.

  10. Detection of fibrinogen antigens with two latex techniques applied to urine concentrates

    PubMed Central

    Donati, Maria Benedetta; Semeraro, N.; Vermylen, J.

    1973-01-01

    Fibrinogen antigens were measured either with an agglutination inhibition method (using latex particles coated with fibrinogen; Diagen test) or with a direct agglutination technique (using latex particles coated with a mixture of anti-D and anti-E antibodies; Thrombo-Wellcotest). Both methods were compared with the tanned red cell haemagglutination inhibition immunoassay (TRCHII) during progressive degradation of fibrinogen with plasmin and using purified fibrinogen fragments or urine concentrates from chronic glomerulonephritis or transplanted patients. Due to the different sensitivity of the two latex techniques to fibrinogen and its plasmin derivatives, their combined use may be helpful to distinguish the nature of the fibrinogen-like material excreted in urine. PMID:4201501

  11. A Nomogram based on Inflammatory Factors C-Reactive Protein and Fibrinogen to Predict the Prognostic Value in Patients with Resected Non-Small Cell Lung Cancer

    PubMed Central

    Zeng, Qiuyao; Xue, Ning; Dai, Danian; Xing, Shan; He, Xia; Li, Shibing; Du, Yi; Huang, Chumei; Li, Linfang; Liu, Wanli

    2017-01-01

    Purpose: This study aimed to develop an effective nomogram for predicting survival in surgically treated non-small cell lung cancer patients. Methods: We retrospectively evaluated 856 NSCLC in this study. Cox regression analyses were performed to identify significant prognostic factors for developing a nomogram to predict overall survival (OS). The discriminative ability was assessed with the concordance index (C-index). Results: On multivariate analysis of the 856 cohort, independent factors for survival were CRP, fibrinogen, tumor status, nodal status, distant metastasis and clinical stage, which were entered into the nomogram. The C-index of the established nomogram 0.720 (95% CI: 0.671-0.769) was higher than that of the seventh edition TNM staging system 0.689 (95% CI: 0.668-0.709) for predicting OS (P < 0.05). Compared with patients with low CRP levels (< 8.6 g/L) and low fibrinogen levels (< 3.7 g/L), patients with high CRP and fibrinogen levels had shorter OS. Subgroup analyses revealed that the nomogram was a favorable prognostic parameter in stage I-IV NSCLC (P < 0.05). Conclusion: A nomogram integrating CRP and fibrinogen, which could be convenient and feasible to obtain from the serum preoperatively, may assist in risk stratification for individual patient with resected NSCLC.

  12. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials

    PubMed Central

    Holmes, Michael V; Newcombe, Paul; Hubacek, Jaroslav A; Sofat, Reecha; Ricketts, Sally L; Cooper, Jackie; Breteler, Monique MB; Bautista, Leonelo E; Sharma, Pankaj; Whittaker, John C; Smeeth, Liam; Fowkes, F Gerald R; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A; Singleton, Andrew B; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B; Rich, Stephen S; Matarin, Mar; Norman, Paul E; Flicker, Leon; Almeida, Osvaldo P; van Bockxmeer, Frank M; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J; Bobak, Martin; Sterne, Jonathan AC; Smith, George Davey; Talmud, Philippa J; van Duijn, Cornelia; Humphries, Steve E; Price, Jackie F; Ebrahim, Shah; Lawlor, Debbie A; Hankey, Graeme J; Meschia, James F; Sandhu, Manjinder S; Hingorani, Aroon D; Casas, Juan P

    2011-01-01

    folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. Interpretation In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. Funding Full funding sources listed at end of paper (see Acknowledgments). PMID:21803414

  13. Resolving two-dimensional kinetics of the integrin αIIbβ3-fibrinogen interactions using binding-unbinding correlation spectroscopy.

    PubMed

    Litvinov, Rustem I; Mekler, Andrey; Shuman, Henry; Bennett, Joel S; Barsegov, Valeri; Weisel, John W

    2012-10-12

    Using a combined experimental and theoretical approach named binding-unbinding correlation spectroscopy (BUCS), we describe the two-dimensional kinetics of interactions between fibrinogen and the integrin αIIbβ3, the ligand-receptor pair essential for platelet function during hemostasis and thrombosis. The methodology uses the optical trap to probe force-free association of individual surface-attached fibrinogen and αIIbβ3 molecules and forced dissociation of an αIIbβ3-fibrinogen complex. This novel approach combines force clamp measurements of bond lifetimes with the binding mode to quantify the dependence of the binding probability on the interaction time. We found that fibrinogen-reactive αIIbβ3 pre-exists in at least two states that differ in their zero force on-rates (k(on1) = 1.4 × 10(-4) and k(on2) = 2.3 × 10(-4) μm(2)/s), off-rates (k(off1) = 2.42 and k(off2) = 0.60 s(-1)), and dissociation constants (K(d)(1) = 1.7 × 10(4) and K(d)(2) = 2.6 × 10(3) μm(-2)). The integrin activator Mn(2+) changed the on-rates and affinities (K(d)(1) = 5 × 10(4) and K(d)(2) = 0.3 × 10(3) μm(-2)) but did not affect the off-rates. The strength of αIIbβ3-fibrinogen interactions was time-dependent due to a progressive increase in the fraction of the high affinity state of the αIIbβ3-fibrinogen complex characterized by a faster on-rate. Upon Mn(2+)-induced integrin activation, the force-dependent off-rates decrease while the complex undergoes a conformational transition from a lower to higher affinity state. The results obtained provide quantitative estimates of the two-dimensional kinetic rates for the low and high affinity αIIbβ3 and fibrinogen interactions at the single molecule level and offer direct evidence for the time- and force-dependent changes in αIIbβ3 conformation and ligand binding activity, underlying the dynamics of fibrinogen-mediated platelet adhesion and aggregation.

  14. Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy

    PubMed Central

    Mendiola, Andrew S.; Garza, Rolando; Cardona, Sandra M.; Mythen, Shannon A.; Lira, Sergio A.; Akassoglou, Katerina; Cardona, Astrid E.

    2017-01-01

    Fractalkine (FKN) is a chemokine expressed constitutively by healthy neurons and signals to microglia upon interaction with the FKN receptor, CX3CR1. Signaling between FKN and CX3CR1 transduces inhibitory signals that ameliorate microglial activation and proinflammatory cytokine release in neuroinflammatory conditions. The aim of this study is to determine the mechanisms associated with microglial activation and vascular leakage during diabetic retinopathy (DR) and under conditions of low-level endotoxemia, common in diabetic patients. Utilizing the Ins2Akita strain (Akita), a mouse model of type 1 diabetes, our results show that leakage of the blood-protein fibrin(ogen) into the retina occurs as a result of chronic (4 months) but not acute (1.5 months) hyperglycemia. Conversely, inducing endotoxin-mediated systemic inflammation during acute diabetes resulted in fibrinogen deposition in the retina, a phenotype that was exacerbated in mice lacking CX3CR1 signaling. Systemic inflammation in Cx3cr1−/− mice led to robust perivascular clustering of proliferating microglia in areas of fibrinogen extravasation, and induced IL-1β expression in microglia and astrocytes. Lastly, we determined a protective effect of modulating FKN/CX3CR1 signaling in the diabetic retina. We show that intravitreal (iv) administration of recombinant FKN into diabetic FKN-KO mice, reduced fibrinogen deposition and perivascular clustering of microglia in the retina during systemic inflammation. These data suggest that dysregulated microglial activation via loss of FKN/CX3CR1 signaling disrupts the vascular integrity in retina during systemic inflammation. PMID:28119571

  15. Formation and cell translocation of carbon nanotube-fibrinogen protein corona

    NASA Astrophysics Data System (ADS)

    Chen, Ran; Radic, Slaven; Choudhary, Poonam; Ledwell, Kimberley G.; Huang, George; Brown, Jared M.; Chun Ke, Pu

    2012-09-01

    The binding of plasma fibrinogen with both single-walled and multi-walled carbon nanotubes (SWNTs and MWNTs) has been examined. Specifically, our absorbance study indicated that MWNTs were coated with multi-layers of fibrinogen to render a "hard protein corona," while SWNTs were adsorbed with thin layers of the protein to precipitate out of the aqueous phase. In addition, static quenching as a result of energy transfer from fluorescently labeled fibrinogen to their nanotube substrates was revealed by Stern-Volmer analysis. When exposed to HT-29 cells, the nanotubes and fibrinogen could readily dissociate, possibly stemming from their differential affinities for the amphiphilic membrane bilayer.

  16. Redistribution of the fibrinogen receptor of human platelets after surface activation

    PubMed Central

    1984-01-01

    We investigated the whole cell distribution of the platelet membrane receptor for fibrinogen in surface-activated human platelets. Fibrinogen-labeled colloidal gold was used in conjunction with platelet whole mount preparations to visualize directly the fibrinogen receptor. Unstimulated platelets fail to bind fibrinogen, and binding was minimal in the stages of activation immediately following adhesion. The amount of fibrinogen bound per platelet increased rapidly during the shape changes associated with surface activation until 7,600 +/- 500 labels were present at saturation. Maximal binding of fibrinogen was followed by receptor redistribution. During the early stages of spreading, fibrinogen labels were uniformly distributed over the entire platelet surface, including pseudopodia, but the labels become progressively centralized as the spreading process continued. In well spread platelets, labels were found over the central regions, whereas peripheral areas were cleared of receptors. Receptor redistribution during spreading was accompanied by cytoskeletal reorganization such that a direct correlation was seen between the development of specific ultrastructural zones and the distribution of surface receptor sites suggesting a link between the surface receptors and the cytoskeleton. The association of fibrinogen receptors with contractile elements of the cytoskeleton, which permits coordinated receptor centralization, is important to the understanding of the role of fibrinogen in normal platelet aggregation and clot retraction. PMID:6088559

  17. Carotid intima-media thickness and plasma fibrinogen among subjects with metabolic syndrome: Isfahan cohort study, Iran

    PubMed Central

    Bayanfar, Zahra; Sadeghi, Masoumeh; Heidari, Ramin; Gharipour, Mojgan; Talaie, Mohammad; Sedaghat, Akram

    2014-01-01

    BACKGROUND The role of plasma fibrinogen, a key regulator of inflammation processes and increased carotid intima-media thickness (cIMT) to predict metabolic syndrome (MetS) is currently under investigation. We assessed differences in the indicators of cIMT and also plasma fibrinogen level between MetS and non-MetS subjects. We also assessed the role of these two parameters for independently relationship with MetS state. METHODS The subjects in this cross-sectional survey were population-based samples of 93 men and women aged ≥ 35 years and over who were selected from the Isfahan cohort study, Isfahan, Iran. Fibrinogen was measured by the clotting assay of Clauss. Ultrasound studies of the carotid artery were performed to measure cIMT. MetS defined based on the National Cholesterol Education Program’s Adult Treatment Panel III. RESULTS The mean level of plasma fibrinogen was not different in the two groups with and without MetS (240.10 ± 27.80 vs. 242.56 ± 35.82, P = 0.714), but the mean of cIMT was considerably higher in MetS group than in non-MetS group (0.85 ± 0.06 mm vs. 0.66 ± 0.09 mm, P < 0.001). Using a multivariable logistic regression model, high cIMT could effectively predict MetS state with the presence of different components of MetS (odds ratio = 17.544, 95% confidence interval = 2.151-142.860, P = 0.008). The optimal cutoff point of cIMT for discriminating these two clinical states was 0.6 mm yielding a sensitivity of 61.5% and a specificity of 59.6%. CONCLUSION Individuals with MetS demonstrated increased cIMT values compared with those without MetS. However, high plasma fibrinogen level may not be associated with MetS state. PMID:25477980

  18. [Socio-demographic, lifestyle, gynecological, and obstetric predictors of serum or plasma concentrations of homocysteine, folic acid, and vitamins B12 and B6 among low-income women in São Paulo, Brazil].

    PubMed

    Almeida, Lana Carneiro; Tomita, Luciana Yuki; D'Almeida, Vânia; Cardoso, Marly Augusto

    2008-03-01

    This study examined the socio-demographic, lifestyle, gynecological, and obstetric factors associated with serum or plasma concentrations of homocysteine, folic acid, and vitamins B12 and B6 among low-income women in São Paulo, Brazil. Serum concentrations of folic acid and vitamin B12 were measured by fluoroimmunoassay, while plasma vitamin B6 and homocysteine levels were measured by reversed-phase high performance liquid chromatography. Independent variables were initially selected by Pearson correlation or Kruskal-Wallis test (p < 0.20). Based on cut-off values, altered concentrations of homocysteine, folic acid, and vitamins B12 and B6 were found in 20%, 6%, 11%, and 67% of participants, respectively. Age was positively correlated with vitamin B6 and homocysteine plasma concentrations (p < 0.001). Body mass index was positively correlated with vitamin B6 plasma concentration (p < 0.001). Multiple linear regression models accounted for 10.2%, 5.8%, 14.4%, and 9.4% of folic acid, vitamins B12 and B6, and homocysteine plasma or serum concentrations, respectively. In this study, socio-demographic, lifestyle, gynecological, and obstetric variables showed important predictive value for serum or plasma levels of the biochemical indicators assessed.

  19. Fibrinogen, red blood cells, and factor XIII in venous thrombosis.

    PubMed

    Walton, B L; Byrnes, J R; Wolberg, A S

    2015-06-01

    Cardiovascular disease is the leading cause of death and disability worldwide. Among cardiovascular causes of death, venous thrombosis (VT) is ranked third most common in the world. Venous thrombi have high red blood cell and fibrin content; however, the pathophysiologic mechanisms that contribute to venous thrombus composition and stability are still poorly understood. This article reviews biological, biochemical, and biophysical contributions of fibrinogen, factor XIII, and red blood cells to VT, and new evidence suggesting interactions between these components mediate venous thrombus composition and size.

  20. Combined single cell AFM manipulation and TIRFM for probing the molecular stability of multilayer fibrinogen matrices

    PubMed Central

    Christenson, W.; Yermolenko, I.; Plochberger, B.; Camacho-Alanis, F.; Ros, A.; Ugarova, T.P.; Ros, R.

    2014-01-01

    Adsorption of fibrinogen on various surfaces produces a nanoscale multilayer matrix, which strongly reduces the adhesion of platelets and leukocytes with implications for hemostasis and blood compatibility of biomaterials. The nonadhesive properties of fibrinogen matrices are based on their extensibility, ensuing the inability to transduce strong mechanical forces via cellular integrins and resulting in weak intracellular signaling. In addition, reduced cell adhesion may arise from the weaker associations between fibrinogen molecules in the superficial layers of the matrix. Such reduced stability would allow integrins to pull fibrinogen molecules out of the matrix with comparable or smaller forces than required to break integrin–fibrinogen bonds. To examine this possibility, we developed a method based on the combination of total internal reflection fluorescence microscopy, single cell manipulation with an atomic force microscope and microcontact printing to study the transfer of fibrinogen molecules out of a matrix onto cells. We calculated the average fluorescence intensities per pixel for wild-type HEK 293 (HEK WT) and HEK 293 cells expressing leukocyte integrin Mac-1 (HEK Mac-1) before and after contact with multilayered matrices of fluorescently labeled fibrinogen. For contact times of 500 s, HEK Mac-1 cells show a median increase of 57% of the fluorescence intensity compared to 6% for HEKWT cells. The results suggest that the integrin Mac-1-fibrinogen interactions are stronger than the intermolecular fibrinogen interactions in the superficial layer of the matrix. The low mechanical stability of the multilayer fibrinogen surface may contribute to the reduced cell adhesive properties of fibrinogen-coated substrates. We anticipate that the described method can be applied to various cell types to examine their integrin-mediated adhesion to the extracellular matrices with a variable protein composition. PMID:24239757

  1. The influence of surface chemistry on adsorbed fibrinogen conformation, orientation, fiber formation and platelet adhesion.

    PubMed

    Zhang, Liudi; Casey, Brendan; Galanakis, Dennis K; Marmorat, Clement; Skoog, Shelby; Vorvolakos, Katherine; Simon, Marcia; Rafailovich, Miriam H

    2017-03-02

    Thrombosis is a clear risk when any foreign material is in contact with the bloodstream. Here we propose an immunohistological stain-based model for non-enzymatic clot formation that enables a facile screen for the thrombogenicity of blood-contacting materials. We exposed polymers with different surface chemistries to protease-free human fibrinogen. We observed that on hydrophilic surfaces, fibrinogen is adsorbed via αC regions, while the γ400-411 platelet-binding dodecapeptide on the D region becomes exposed, and fibrinogen fibers do not form. In contrast, fibrinogen is adsorbed on hydrophobic surfaces via the relatively hydrophobic D and E regions, exposing the αC regions while rendering the γ400-411 inaccessible. Fibrinogen adsorbed on hydrophobic surfaces is thus able to recruit other fibrinogen molecules through αC regions and polymerize into large fibrinogen fibers, similar to those formed in vivo in the presence of thrombin. Moreover, the γ400-411 is available only on the large fibers not elsewhere throughout the hydrophobic surface after fibrinogen fiber formation. When these surfaces were exposed to gel-sieved platelets or platelet rich plasma, a uniform monolayer of platelets, which appeared to be activated, was observed on the hydrophilic surfaces. In contrast, large agglomerates of platelets were clustered on fibers on the hydrophobic surfaces, resembling small nucleating thrombi. Endothelial cells were also able to adhere to the monomeric coating of fibrinogen on hydrophobic surfaces. These observations reveal that the extent and type of fibrinogen adsorption, as well as the propensity of adsorbed fibrinogen to bind platelets, may be modulated by careful selection of surface chemistry.

  2. The effects of homocysteine-related compounds on cardiac contractility, coronary flow, and oxidative stress markers in isolated rat heart.

    PubMed

    Zivkovic, Vladimir; Jakovljevic, Vladimir; Djordjevic, Dusica; Vuletic, Milena; Barudzic, Nevena; Djuric, Dragan

    2012-11-01

    Research on the effects of homocysteine on the vascular wall, especially in endothelial and smooth muscle cells, has indicated that increased homocysteine levels lead to cellular stress and cell damage. Considering the adverse effects of homocysteine on vascular function and the role of oxidative stress in these mechanisms, the aim of this study was to estimate the influence of different homocysteine isoforms on cardiac contractility, coronary flow, and oxidative stress markers in isolated rat heart. The hearts of male Wistar albino rats (n = 36, age 8 weeks, body mass 180-200 g), were excised and retrogradely perfused according to the Langendorff technique at a constant perfusion pressure (70 cmH(2)O) and administered with three isoforms of 10 μM homocysteine [DL-Hcy, DL-Hcy thiolactone-hydrochloride (TLHC) and L-Hcy TLHC). After the insertion and placement of the sensor in the left ventricle, the parameters of heart function: maximum rate of pressure development in the left ventricle (dP/dt max), minimum rate of pressure development in the left ventricle (dP/dt min), systolic left ventricular pressure (SLVP), diastolic left ventricular pressure (DLVP), mean blood pressure (MBP) and heart rate (HR)] were continuously registered. Flowmetry was used to evaluate the coronary flow. Markers of oxidative stress: index of lipid peroxidation measured as TBARS, nitric oxide measured through nitrites (NO(2)(-)), superoxide anion radical (O(2)(-)), and hydrogen peroxide (H(2)O(2)) in the coronary venous effluent were assessed spectrophotometrically. Our results showed that administration of Hcy compounds in concentration of 10 μM induced depression of cardiac contractility, manifested by a decrease in dp/dt max after administration of any Hcy compound, decrease in dp/dt min after administration of L-Hcy TLHC, decrease in SLVP after administration of DL-Hcy TLHC and DL-Hcy, and the drop in CF after administration of any Hcy compound. Regarding the effects of Hcy on

  3. Fibrinogen α-chain-derived peptide is upregulated in hippocampus of rats exposed to acute morphine injection and spontaneous alternation testing.

    PubMed

    Maki, Agatha E; Morris, Kenneth A; Catherman, Kasia; Chen, Xian; Hatcher, Nathan G; Gold, Paul E; Sweedler, Jonathan V

    2014-06-01

    Fibrinogen is a secreted glycoprotein that is synthesized in the liver, although recent in situ hybridization data support its expression in the brain. It is involved in blood clotting and is released in the brain upon injury. Here, we report changes in the extracellular levels of fibrinogen α-chain-derived peptides in the brain after injections of saline and morphine. More specifically, in order to assess hippocampus-related working memory, an approach pairing in vivo microdialysis with mass spectrometry was used to characterize extracellular peptide release from the hippocampus of rats in response to saline or morphine injection coupled with a spontaneous alternation task. Two fibrinopeptide A-related peptides derived from the fibrinogen α-chain-fibrinopeptide A (ADTGTTSEFIEAGGDIR) and a fibrinopeptide A-derived peptide (DTGTTSEFIEAGGDIR)-were shown to be consistently elevated in the hippocampal microdialysate. Fibrinopeptide A was significantly upregulated in rats exposed to morphine and spontaneous alternation testing compared with rats exposed to saline and spontaneous alternation testing (P < 0.001), morphine alone (P < 0.01), or saline alone (P < 0.01), respectively. The increase in fibrinopeptide A in rats subjected to morphine and a memory task suggests that a complex interaction between fibrinogen and morphine takes place in the hip