[Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency].

Objective: To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency. Methods: This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively. Results: The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 µmol/L) was found in all patients, and decreased to 20-70 µmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders. Conclusions: Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers.

Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine ß-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an E. coli Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.

Exogenous methionine contributes to reversing the resistance of Streptococcus suis to macrolides.

Streptococcus suis (S. suis) has been increasingly recognized as a porcine zoonotic pathogen that threatens the health of both pigs and humans. Multidrug-resistant Streptococcus suis is becoming increasingly prevalent, and novel strategies to treat bacterial infections caused by these organisms are desperately needed. In the present study, an untargeted metabolomics analysis showed that the significant decrease in methionine content and the methionine biosynthetic pathway were significantly affected by the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis in drug-resistant S. suis. The addition of L-methionine restored the bactericidal activity of macrolides, doxycycline, and ciprofloxacin on S. suis in vivo and in vitro. Further studies showed that the exogenous addition of methionine affects methionine metabolism by reducing S-adenosylmethionine synthetase activity and the contents of S-adenosylmethionine, S-adenosyl homocysteine, and S-ribose homocysteine. Methionine can decrease the total methylation level and methylesterase activity in multidrug resistant S. suis. The drug transport proteins and efflux pump genes were significantly downregulated in S. suis by exogenous L-methionine. Moreover, the exogenous addition of methionine can reduce the survival of S. suis by affecting oxidative stress and metal starvation in bacteria. Thus, L-methionine may influence the development of resistance in S. suis through methyl metabolism and metal starvation. This study provides a new perspective on the mitigation of drug resistance in S. suis.IMPORTANCEBacterial antibiotic resistance has become a severe threat to human and animal health. Increasing the efficacy of existing antibiotics is a promising strategy against antibiotic resistance. Here, we report that L-methionine enhances the efficacy of macrolides, doxycycline, and ciprofloxacin antibiotics in killing Streptococcus suis, including multidrug-resistant pathogens. We investigated the mechanism of action of exogenous methionine supplementation in restoring macrolides in Streptococcus suis and the role of the methionine cycle pathway on methylation levels, efflux pump genes, oxidative stress, and metal starvation in Streptococcus suis. It provides a theoretical basis for the rational use of macrolides in clinical practice and also identifies a possible target for restoring drug resistance in Streptococcus suis.

Variation of homocysteine levels in rheumatoid arthritis patients: relationship to inflammation, cardiovascular risk factors, and methotrexate.

BACKGROUND: The aim of this study was to evaluate the variation of homocysteine (Hcy) levels in patients with rheumatoid arthritis (RA) and to analyze the relationship to inflammatory parameters, cardiovascular risk, and methotrexate (MTX). METHODS: This cross-sectional study assessed disease activity and treatment in RA patients. The European League Against Rheumatism (EULAR) 2015 HeartSCORE was performed for cardiovascular (CV) risk estimation and levels of plasma Hcy, serum folate concentrations, vitamin B12, and erythrocyte sedimentation rate (ESR) were measured. RESULTS: A total of 103 participants with mean age 53 ± 10 years and mean disease duration 10.55 ± 7.34 years were included. Patients were treated with MTX in 69.9% of cases and corticosteroid in 80.5% of cases. Of all patients, 13% had a cardiovascular inheritance, 25% were hypertensive, and 18% had diabetes. The EULAR 2015 HeartSCORE was high and very high (≥5%) in 35% of cases. Mean Hcy level was 12.54 ± 4.2 µmol/L [6.89-32.92] and hyperhomocysteinemia was noted in 20.4% of patients. Analytic study demonstrated that hyperhomocysteinemia was associated with male gender (p = 0.01), MTX use (p = 0.01), smoking (p = 0.008), renal failure (p = 0.04), and high disease activity (p = 0.05), but there was no association with the HeartSCORE (p = 0.23). Hcy level was negatively correlated with folate (p = 0.009) and vitamin B12 level (p = 0.02) and positively with age (p = 0.01), C­reactive protein (CRP; p = 0.05), and Simplified Disease Activity Index (SDAI; p = 0.03). In multivariate logistic regression analysis, current MTX use, levels of vitamin B12 and creatine, and Clinical Disease Activity Index (CDAI) appeared to be independent factors associated with hyperhomocysteinemia. CONCLUSION: MTX use, CDAI, and the levels of vitamin B12 and creatine are independent factors associated with hyperhomocysteinemia.

Characteristics and prognosis analysis of bilateral sudden sensorineural hearing loss: A retrospective case-control study.

OBJECTIVES: To evaluate the clinical characteristics and prognostic factors of simultaneous and sequential bilateral sudden sensorineural hearing loss (Si-BSSNHL and Se-BSSNHL, respectively). DESIGN: Retrospective case-control study. SETTING: A single tertiary referral centre. PARTICIPANTS: Patients diagnosed with unilateral sudden sensorineural hearing loss (USSNHL), Si-BSSNHL, or Se-BSSNHL between September 2018 and November 2019. MAIN OUTCOME MEASURES: Demographic and clinical characteristics, audiological features, laboratory results and hearing recovery were analysed for intergroup comparisons. Prognostic factors for BSSNHL were analysed using univariate and multivariate logistic analyses between the overall and no-recovery groups. RESULTS: Compared to the USSNHL group, a larger final pure-tone average (PTA) (H = 38.0 and 53.8, respectively, both adjusted p-value (p adj) <.05), lower hearing gain (H = -70.8 and - 74.6, respectively, both p adj <.001) and higher homocysteine levels (H = 46.8, 58.8, respectively, both p adj <.05) were observed in the Si-BSSNHL and Se-BSSNHL groups, while the rate of positive vestibular tests and proportion of tinnitus were lower in the Se-BSSNHL group (χ2  = 8.5 and 38.1, respectively, both p adj <0.05). The USSNHL group showed a significant difference in the degree of deafness and therapeutic outcome in the Se-BSSNHL and Si-BSSNHL groups, respectively (χ2  = 12.4, p adj <.05; χ2  = 13.6; p adj <.05). Hypertension (95% confidence interval, 1.014-28.623, p < .05) and onset days (95% confidence interval, 0.007-0.626, p < .05) were associated with the therapeutic effects of BSSNHL. CONCLUSIONS: Higher homocysteine levels in BSSNHL may implicate microvascular disorders as a causative factor of BSSNHL. Hypertension and onset days were associated with the prognosis of BSSNHL.

Risk factors and predictors for venous thromboembolism in people with ischemic stroke: A systematic review.

Identification of individuals with ischemic stroke at particularly high risk of venous thromboembolism (VTE) is crucial for targeted thromboprophylaxis. To guide clinical decision-making and development of risk prediction models, increased knowledge on risk factors and biomarkers is needed. Therefore, we set out to identify risk factors and predictors for VTE in people with ischemic stroke by conducting a systematic review of the literature. Medline and Embase were searched from January 1990 and onwards. Studies investigating demographic, clinical, and/or laboratory factors for stroke-related VTE were considered. Two reviewers screened all retrieved records, independently and in duplicate. Risk of bias assessments were guided by a structured framework (PROSPERO-ID: CRD42020176361). Of 4674 identified records, 26 studies were included. Twenty-six demographic, clinical, and laboratory factors associated with increased risk of stroke-related VTE after multivariable adjustments were identified. The following factors were reported by ≥2 studies: prior VTE, cancer, prestroke disability, leg weakness, increasing lesion volume of the brain infarct, infection, low Barthel Index, increasing length of hospital stay, biochemical indices of dehydration, as well as elevated levels of D-dimer, C-reactive protein, and homocysteine. The majority of the studies were of poor quality with moderate or high risk of bias. In conclusion, this systematic review informs on several potential risk factors and predictors for VTE in people with ischemic stroke. To improve risk stratification and guide development of risk prediction models, further confirmation is needed because there were few high-quality studies on each factor.

[Clinical characteristics and CBS gene analysis of 13 cases with classic homocystinuria].

Objective: To analyze the clinical features and CBS gene variants of 13 patients with classic homocystinuria, and the strategies of individual treatment and prevention were explored. Methods: The general information, clinical manifestations, laboratory tests, cranial images, CBS gene variants, diagnosis and therapeutic strategies of 13 patients with classic homocystinuria admitted to the Department of Pediatrics of Children's Hospital Affiliated to Zhengzhou University and Peking University First Hospital from November 2013 to June 2021 were analyzed retrospectively. Results: There were 13 patients diagnosed at the age of 10 days to 14 years, 6 were male and 7 were female. There were 3 patients detected by newborn screening and received treatment at the asymptomatic stage. There were 10 patients clinically diagnosed at the age of 5 to 14 years. Their symptoms appeared at age of 1 to 6 years. The major clinical manifestations were marfanoid features, lens dislocation and (or) myopia, developmental delay, osteoporosis, and cardiovascular diseases. Brain magnetic resonance imaging showed asymmetric infarcts in 4 patients and hypomyelination in 1 case. Increased blood methionine, plasma total homocysteine and urinary total homocysteine with normal urinary methylmalonic acid were found in 13 patients. The biochemical features were consistent with classic homocystinuria. Totally 18 variants were identified in CBS gene of 13 patients, 10 variants were novel and 8 were reported. only 1 patient was partially responsive to vitamin B6 treatment, while 12 cases were non-responsive. They were mainly treated with low methionine diet and betaine supplement. Three vitamin B6 non-responsive cases received liver transplantation at age of 3, 8 and 8 years, respectively. Their blood methionine and total homocysteine returned to normal within a week after liver transplantation. One patient died. Prenatal diagnosis was performed for a fetus when the mother was pregnant again. Two pathogenic CBS gene variants were identified from the amniocytes as same as the proband. Conclusions: The clinical manifestations of classic homocystinuria are complex and variable. Blood amino acid analysis, serum or urine total homocysteine assay and gene analysis are critical for its diagnosis. There were 10 novel CBS gene varients were identified expanding the CBS gene varient spectrum. Liver transplantation is an effective treatment. Prenatal diagnosis is important to prevent classic homocysteinuria.

Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1ß, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk. METHODS: Serum levels of interleukin-1ß, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels ≥135 mg/dL and <500 mg/dL who were randomly allocated to treatment with either 4 grams daily of icosapent ethyl or mineral oil used as a comparator. RESULTS: At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1ß (all P values <0.001), with similar changes at 24 months. In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months. As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized low-density lipoprotein cholesterol, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for high-sensitivity C-reactive protein, and 48.7% for interleukin-1ß (all P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was -1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator. CONCLUSIONS: Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01492361.

Homocysteine, Thioretinaco Ozonide, and Oxidative Phosphorylation in Cancer and Aging: A Proposed Clinical Trial Protocol.

The objective of the proposed clinical interventional trial is to demonstrate the efficacy of a novel therapeutic strategy in subjects with cancer and hyperhomocysteinemia. Following discovery of abnormal homocysteine thiolactone metabolism in cultured malignant cells, thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone, and thioretinaco, the complex formed from cobalamin and thioretinamide, were demonstrated to have antineoplastic, anticarcinogenic, and anti-atherogenic properties in animal models. Retinol, ascorbate, and homocysteine thiolactone are necessary for biosynthesis of thioretinamide and thioretinaco by cystathionine synthase and for formation of thioretinaco ozonide from thioretinamide, cobalamin, and ozone. Thioretinaco ozonide is required for prevention of abnormal oxidative metabolism, aerobic glycolysis, suppressed immunity, and hyperhomocysteinemia in cancer.The pancreatic enzyme therapy of cancer promotes catabolism of proteins, nucleic acids, and glycosaminoglycans with excess homocysteinylated amino groups resulting from abnormal accumulation of homocysteine thiolactone in malignant cells. Dietary deficiencies of pyridoxal, folate, cobalamin, and nitriloside contribute to hyperhomocysteinemia in cancer, and in protein energy malnutrition. A deficiency of dietary sulfur amino acids downregulates cystathionine synthase, causing hyperhomocysteinemia.The organic sulfur compound diallyl trisulfide increases hydrogen sulfide production from homocysteine in animal models, inhibits Stat3 signaling in cancer stem cells, and produces apoptosis of malignant cells. The furanonaphthoquinone compound napabucasin inhibits Stat3 signaling and causes mitochondrial dysfunction, decreased oxidative phosphorylation, and apoptosis of malignant cells. The protocol of the proposed clinical trial in subjects with myelodysplasia consists of thioretinamide and cobalamin as precursors of thioretinaco ozonide, combined with pancreatic enzyme extracts, diallyl trisulfide, napabucasin, nutritional modification to minimize processed foods, vitamin supplements, essential amino acids, and beneficial dietary fats and proteins.

In vivo assessment of the effects of ginsenoside Rb1 on intimal hyperplasia in ApoE knockout mice.

OBJECTIVE: This study investigated the effects of ginsenoside Rb1 (Rb1) on injury-induced intimal hyperplasia in ApoE knock out (ApoE -/-) mice. We also examined the value of an ultrasound micro-image system in dynamic monitoring of lumen diameter and flow velocity. METHODS: After guide wire injury of the distal left common carotid artery (CCA), ApoE-/- mice were treated with intraperitoneal infusion of normal saline (NS), homocysteine (Hcy), ginsenoside Rb1 (Rb1), or Hcy+Rb1 for 4 wk. Bilateral CCA luminal diameters and flow velocities were measured with an ultrasound micro-image system before surgery and weekly afterwards. Following the final ultrasound, CCAs were harvested and analyzed for intima-medium thickness ratios. RESULTS: Progressive reduction in luminal diameters and increase in flow velocity of the injured left distal CCA segment were observed using ultrasound micro-imaging system in all groups compared with the relatively stable left proximal CCA and right CCA. The NS and Hcy groups had significantly higher degree of diameter reduction compared with the Rb1 and Rb1+Hcy groups. The ultrasound findings were consistent with histology analyses at 4 wk post-op. CONCLUSIONS: The study suggested that Rb1 attenuated the effects of Hcy on injured carotid arteries of ApoE -/- mice. The study also showed that ultrasound micro-image system was a reliable tool in monitoring luminal reduction after injury in a murine model. This study establishes a fundamental step of in vivo monitoring of the therapeutic effects of agents in a murine model without sacrificing the animals.

Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations.

In Europe, neuropsychiatric diseases currently make up approximately a third of the total burden of disease. In 2004, 27% of the overall population was affected by at least one of the most frequent neuropsychiatric diseases such as Alzheimer's dementia, Parkinson's disease, stroke or depression. The annual costs of care exceed those of cancer, cardiovascular conditions and diabetes. In order to delay the onset or course of neurodegenerative diseases, the available potential should be utilized. As well as improving quality of life of patients and relatives, this may reduce the great financial burden caused by neurodegenerative disorders. However, the availability of established drugs or therapeutic agents is very limited. This paper reviews the state of current knowledge as to how homocysteine metabolism is relevant for neurodegenerative and other neuropsychiatric diseases, with particular emphasis on the evidence for prophylactic and therapeutic strategies. In the European countries, many people do not take the recommended daily minimum amount of folate and vitamin B12. Deficiency of these vitamins and secondary changes in the concentrations of associated metabolites, such as methylmalonic acid and homocysteine, may contribute to the onset and progression of neuropsychiatric diseases. This paper reviews the evidence regarding whether substitution of folate and vitamin B12 is beneficial, for example, in cerebrovascular disease, dementia and depression.

Homocisteína y óxido nítrico en preeclámpticas en pre y posparto / Homocysteine and nitric oxide in preeclamptic patients in pre and postpartum

Comparar las concentraciones de homocisteína y óxido nítrico en preeclámpticas y embarazadas normotensas en pre y posparto y establecer una relación de ambos compuestos en los diferentes períodos estudiados. Los grupos consistieron en 35 preeclámpticas (grupo A) y 35 embarazadas normotensas (grupo B; controles). Las muestras de sangre para determinar la concentración de homocisteína y óxido nítrico se recolectaron antes del parto y las del posparto se recolectaron a los siete días y a las seis semanas en ambos grupos. Maternidad "Dr. Nerio Belloso", Hospital Central "Dr. Urquinaona", Maracaibo. Se encontraron diferencias estadísticamente significativas en la edad gestacional al momento del estudio, presión arterial sistólica y diastólica, peso del recién nacido y presencia de proteinuria (P < 0,05). Las concentraciones de homocisteína durante el preparto y el posparto fueron significativamente superiores en las preeclámpticas comparadas con las del grupo B (P < 0,05). Con relación a las concentraciones de óxido nítrico, se observó diferencias estadísticamente significativas entre el grupo A y B en todos los períodos en estudio (P < 0,05). Se observó una fuerte correlación negativa significativa entre homocisteína y óxido nítrico en el preparto, a los siete días y a las seis semanas del posparto (P < 0,001). Las preeclámpticas presentan concentraciones más elevadas de homocisteína y más bajas de óxido nítrico comparado con embarazadas normotensas y con una fuerte correlación negativa entre ellas en el período pre y posparto.

To compare the concentrations of homocysteine and nitric oxide in preeclamptic and normotensive pregnant women in pre and post-partum and to establish a relation between both compounds in the different studied periods. Groups consisted in 35 preeclamptic patients (group A) and 35 normotensive pregnant women (group B, controls). Blood samples to determine homocysteine and nitric oxide concentrations were recollected before labor and seven days and six weeks after delivery. Maternidad "Dr. Nerio Belloso", Hospital Central "Dr. Urquinaona", Maracaibo. There were significant statically differences in gestational age at the moment of study, systolic and diastolic pressure, newborn weight and presence of proteinuria (P < 0.05). Homocysteine concentrations during pre and post-partum were significantly higher in preeclamptic compared with group B (P < 0.05). In relation to nitric oxide concentrations, there were statically significant differences between group A and B in all studied periods (P < 0.05). There was also a significant negative strong correlation between homocysteine and nitric oxide previous to delivery, at seven days and six weeks of post-partum (P < 0.001). Preeclamptic presented higher concentrations of homocysteine and lower of nitric oxide compared to normotensive pregnant women with a negative strong correlation between them in pre and post-partum.

Efecto de la suplementación con las vitaminas B12, B6 y ácido fólico en los niveles de homocisteina y lípidos plasmáticos en pacientes con hiperlipoproteinemia secundaria tipo IV / Effect of the supplementation of vitamins B12, B6 and folic acid on homocysteine and plasmatic lipics in patients with hyperlipoproteinemic secondary type IV

Los casos de hiperlipoproteinemia secundaria tipo IV se manifiestan por una marcada elevación de triglicéridos, colesterol normal o elevado y homocisteina ligeramente elevada. Se investigó el efecto del suplemento de las vitaminas B12, B6, y ácido fólico, sobre los niveles de homocisteina y lípidos plasmáticos, en 24 pacientes masculinos, edad de 35-68 años inclusive, con hiperlipoproteinemia secundaria tipo IV e isquemia del miocardio, sin previo tratamiento con hipolipemiante. Los pacientes fueron suplementados con dosis terapéuticas en tabletas de vitamina B12, (500 µg/día), B6, (600 mg/día) y ácido fólico (20 mg/día), durante 120 días. Se determinó homocisteina, trigliceridos, colesterol total y fraccionado, a (basal), 30, 60, 90 y 120 días. Se aplicaron análisis estadísticos descriptivos, coeficiente de correlación de Pearson, prueba "t", grado de confianza p<0,005; con programa estadístico SPSS versión 8.0. Los resultados mostraron disminución de homocisteina (basal) de 17,1 µmol/L a 13,18 ± 0,83 µmol/L. Los triglicéridos (TG), colesterol total (CT), lipoprote´nas de baja densidad (LDL), lipoproteínas de muy baja densidad (VLDL) disminuyeron (21,8 mg/dl; 8,5 mg/dl; respectivamente) por µmol/L de homocisteína reducido, con (p<.001) para los triglicéridos, al final del período experimental. Las lipoproteínas de alta densidad (HDL) incrementaron 1,1 mg/dl y el riesgo coronario disminuyó en un 24 por ciento. Se concluye que dosis terapéuticas de las vitaminas B12, B6 y ácido folico, pueden ser efectivas para reducir las concentraciones de homocisteina y lípidos en plasma, con una disminución del riesgo coronario, en este tipo de pacientes, sin que ocurran efectos colaterales de neuropatías

La homocisteína como factor de riesgo en la enfermedad cardiovascular / The Homocysteine whon factor of riesk in the cardiovascular

La homocisteína (Hcy) es un aminoácido sulfurado no esencial que es producido como intermediario en el ciclo de la metionina. Una vez en plasma la Hcy es rápidamente oxidada. Sin embargo, se ha encontrado que una elevación de la Hcy (más de 15 mmoles/L), puede estar relacionada con causas genéticas, deficiencias nutricionales, la edad, el género, algunas patologías y el uso de ciertos fármacos. Mc Cully en 1969, planteó la posible relación de la hiperhomocisteinemia (HHcy) como un factor de riesgo de la enfermedad vascular a nivel cardiaco, cerebral y periférico. Desde entonces, se han realizado estudios a nivel básico y epidemiológico para comprobar esta hipótesis. Se proponen diversos mecanismos: estrés oxidativo, disfunción endotelial, disminución de óxido nítrico, aumentos de factores de la coagulación e inflamatorios, entre otros. El efecto de la HHcy parece ser multifactorial y afectaría tanto la estructura de la pared vascular como el sistema de coagulación. En conclusión, ahora que se ha visto incrementado el nivel de conocimiento de cómo la hiperhomocisteinemia está unida a un aumento en el riesgo de las enfermedades vasculares, especialmente de ICC y a pesar de las fuertes evidencias que enlazan los niveles elevados de homocisteína con los eventos coronarios y la mortalidad

Cervical dysplasia: early intervention.

Cervical cancer is the second-most common cancer in young women and is one of the most common causes of cancer deaths among women, particularly in minorities and in impoverished countries. Cervical dysplasia, a premalignant lesion that can progress to cervical cancer, is caused primarily by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV). Not all women with the virus develop cervical dysplasia or cervical cancer. It has been postulated there are multiple host factors that contribute to progression of disease. Many of these factors, such as nutrient deficiencies, can be reversed, which will result in regression of dysplastic lesions. Studies have shown dietary intervention and nutrient supplementation to be effective in preventing cervical cancer. Additionally, local escharotic treatment combined with systemic treatment shows significant potential in reducing dysplasia. Recent advances in vaccination technology demonstrate the effectiveness of an HPV vaccine. The vaccine, however, may have many social and cost-prohibiting limitations, as well as health side effects.

Homocisteína plasmática en pacientes con síndrome de ovarios poliquísticos / Plasma homocysteine to patients with polycystic ovary syndrome

Determinar los niveles de homocisteína en pacientes jóvenes con síndrome de ovarios poliquísticos y resistencia a la insulina no tratadas. 19 pacientes que padecían síndrome de ovarios polisquíticos se incluyeron en nuestro estudio. El grupo control consistió en 10 mujeres, con menstruaciones regulares y ovarios por ultrasonografía normales. Se realizaron pruebas hormonales, perfil lipídico, evaluaciones ecográficas y determinación de homocisteína. Hospital Central "Dr. Urquinaona". Maracaibo. Se encontró evidencia de niveles significativamente altos de homocisteína en pacientes con síndrome de ovarios poliquíticos al compararlas con los controles (12,3 ±3,1 vs. 6,8 ± 1,5 ng/dL; p<0,05). El nivel promedio de insulina sérica fue significativamente mayor (23,3 ± 10,4 vs. 12,4 ±1,2 mUmL; p<0.05) y los niveles de globulina fijadora de hormonas sexuales fueron significativamente menores (1,76 ± 0,6 vs. 3,5 ± 0,9 mg/mL; p<0,001) en los casos de síndrome de ovarios poliquísticos al compararlos con los controles, confirmando una mayor incidencia de este trastorno metabólico en el síndrome. Estas observaciones aportaron evidencia de diferencias significativas en las concentraciones plasmáticas de homocisteína entre pacientes con síndrome de ovarios poliquísticos normales, aunque los niveles promedio de homocisteína dentro de límites normales para ambos grupos.

Homocysteine prevents total parenteral nutrition (TPN)-induced cholestasis without changes in hepatic oxidative stress in the rat.

BACKGROUND: The role of oxidative stress in total parenteral nutrition (TPN)-associated cholestasis with liver glutathione depletion was recently shown. The aims of this study were to test the appearance of cholestasis and oxidative stress during TPN, and the hypothesis that reducing oxidative stress with a precursor of glutathione (GSH), homocysteine, would restore bile flow. METHODS: Three groups of rats (weight, 179-278 g) were studied: 1) D/aa group received dextrose and amino acids (3.4 g/d); 2) D/aa/L group received the same amount of amino acids, and lipids were added on an equicaloric basis (50 kcal/d) with a lowered amount of dextrose; and 3) a control group, which received dextrose perfusion and had free access to chow. A subgroup of D/aa/L rats (n = 6) received a TPN solution containing homocysteine. After 5 days of TPN, bile was collected during 2 hours. In liver homogenates, GSH, thiobarbituric acid reactive substances (TBARS), and carbonyl content of proteins (Prot-CO) were measured to test the level of oxidative stress and hepatic lipid and protein oxidation. RESULTS: After TPN, bile flow was significantly lower in the D/aa group than in the control group. Addition of lipids further decreased bile flow. Addition of homocysteine to TPN with lipids significantly increased bile flow. Aspartate aminotransferase increased significantly in both TPN groups compared with the control group. gamma-Glutamyl transpeptidase was not different among TPN groups. An increased hepatic lipid oxidation was demonstrated by TBARS level in both TPN groups when compared with the control group. However, the liver GSH contents were not different. Protein oxidation was also significantly increased by TPN. The addition of homocysteine to TPN solution increased bile flow without liver injury or changes of lipid and protein oxidation. DISCUSSION: This study shows that TPN administered to rats induces a decrease of bile flow and an oxidative stress but that the two changes are not directly correlated. Addition of lipids further impairs bile flow but does not increase the occurrence of liver injury. Consequently, it seems more likely that TPN primarily induces a cholestatic effect that in turn induces an oxidative stress rather than inducing an oxidative stress that leads to cholestasis. However, an association of both mechanisms is not totally excluded.

Is the tricuspid position suitable for testing replacement bioprosthetic valves in the sheep model?

BACKGROUND AND AIM OF THE STUDY: Glutaraldehyde may promote calcification in xenograft tissue by the action of toxic aldehyde group residues involved in the cross-link process. Post-fixation treatment with homocysteic acid (HA) neutralizes this toxicity by bonding aldehyde groups, and enhances biocompatibility on the basis of strongly electronegative sulfonic groups. Previous studies in a rat subcutaneous model showed significant long-term mitigation of mineralization of glutaraldehyde-fixed pericardium treated with HA. This study aimed to assess the anticalcific efficacy of HA in a valvular implant in growing sheep, and establish if the tricuspid position is suitable for testing replacement bioprosthetic valves. METHODS: Eleven stented 25 mm Pericarbon bioprostheses (seven HA-treated, four standard) were implanted in the tricuspid position of growing sheep. Infective endocarditis occurred in four prostheses. Among the remaining seven, three (two HA-treated, one standard) were explanted at 91 days (mid-term), and four (two HA-treated, two standard) at 140-141 days (long-term). All explants were studied by gross, X-ray, light, transmission and scanning electron microscopy, as well as by atomic absorption spectroscopy. RESULTS: No histological and ultrastructural difference in tissue preservation were observed between HA-treated and standard Pericarbon bioprostheses, either in the mid or long term. The mean calcium content of mid-term HA-treated explants was 9.55 mg/g compared with 16.26 mg/g in mid-term standard explants. Only one late standard explant failed as a result of severe stenosis caused by massive dystrophic calcification. Among four late explants, two showed significant increase in mineralization (HA-treated, 87.45 mg/g; standard, 181.20 mg/g), while two showed calcium contents similar to those in mid-term explants (HA-treated, 11.96 mg/g; standard, 17.32 mg/g). CONCLUSION: Post-fixation treatment with HA preserves structural properties after tricuspid implantation in growing sheep. The tricuspid implant in the sheep model failed to reproduce remarkable accelerated progressive calcification in all xenografts so as to demonstrate a significant difference between HA and standard explants. The tricuspid position for testing replacement bioprosthetic valves should be abandoned, and investigations repeated with the prosthesis in the mitral position.

The tole of homocysteine, folate and other B-vitamins in the development of atherosclerosis / El papel de hemocisteina, folate y otras vitaminas B in el desarrollo de aterosclerosis

Recently, elevated homocysteine blood concentrations have been identified as an independent risks factor for the develoment of atherosclerotic lesions. The amino acid homocysteine is metabolized in the human body involving the vitamins folic acid, B12 and B6 as essential cofactors and coenzymes, respectively. There is an inverse relationship between the status of the relevant B-vitamins and the homocysteine blood concentration. supplementation if these vitamins results in a significant reduction of the homocysteine level. Nutritive amounts seem to be sufficient to obtain this reduction, even in the case of elevated homocysteine levels