Cardiovascular health among two ethnic groups living in the same region: A population-based study.

BACKGROUND: Poor cardiovascular health (CVH) among ethnic/racial minorities, studied primarily in the USA, may reflect lower access to healthcare. We examined factors associated with minority CVH in a setting of universal access to healthcare. METHODS AND RESULTS: CVH behaviors and factors were evaluated in a random population sample (551 Arabs, 553 Jews) stratified by sex, ethnicity and age. More Jews (10%) than Arabs (3%) had 3 ideal health behaviors. Only one participant had all four. Although ideal diet was rare (≤1.5%) across groups, Arabs were more likely to meet intake recommendations for whole grains, but less likely to meet intake recommendations for fruits/vegetables and fish. Arabs had lower odds of attaining ideal levels for body mass index and physical activity. Smoking prevalence was 57% among Arab men and 6% among Arab women. Having four ideal health factors (cholesterol, blood pressure, glucose, smoking) was observed in 2% and 8% of Arab and Jewish men, respectively, and 13% of Arab and Jewish women. Higher prevalence of ideal total-cholesterol corresponded to lower high-density lipoprotein cholesterol among Arabs. No participant met ideal levels for all 7 metrics and only 1.8% presented with 6. Accounting for age and lower socioeconomic status, Arabs were less likely to meet a greater number of metric goals (odds ratio (95% confidence interval): 0.62 (0.42-0.92) for men, and 0.73 (0.48-1.12) for women). CONCLUSIONS: Ideal CVH, rare altogether, was less prevalent among the Arab minority albeit universal access to healthcare. Health behaviors were the main contributors to the CVH disparity.

Titin mutation in familial restrictive cardiomyopathy.

BACKGROUND: Familial restrictive cardiomyopathy (RCM) caused by a single gene mutation is the least common of the inherited cardiomyopathies. Only a few RCM-causing mutations have been described. Most mutations causing RCM are located in sarcomere protein genes which also cause hypertrophic cardiomyopathy (HCM). Other genes associated with RCM include the desmin and familial amyloidosis genes. In the present study we describe familial RCM with severe heart failure triggered by a de novo mutation in TTN, encoding the huge muscle filament protein titin. METHODS AND RESULTS: Family members underwent physical examination, ECG and Doppler echocardiogram studies. The family comprised 6 affected individuals aged 12-35 years. Linkage to candidate loci was performed, followed by gene sequencing. Candidate loci/gene analysis excluded 18 candidate genes but showed segregation with a common haplotype surrounding the TTN locus. Sequence analysis identified a de novo mutation within exon 266 of the TTN gene, resulting in the replacement of tyrosine by cysteine. p.Y7621C affects a highly conserved region in the protein within a fibronectin-3 domain, belonging to the A/I junction region of titin. No other disease-causing mutation was identified in cardiomyopathy genes by whole exome sequencing. CONCLUSIONS: Our study shows, for the first time, that mutations in TTN can cause restrictive cardiomyopathy. The giant filament titin is considered to be a determinant of a resting tension of the sarcomere and this report provides genetic evidence of its crucial role in diastolic function.

The impact of genetic and environmental factors on homocysteine levels in preterm neonates.

BACKGROUND: Hyperhomocysteinemia may be associated with vascular complications in adults. Whereas pediatric thrombosis risk peaks in neonates, data on homocysteine (Hcy) levels assessed in term and preterm infants during the perinatal period are scarce. In the present study, we aimed to establish Hcy reference values for preterm infants and study their potential associations with the early post-natal health status. Plasma Hcy and hematocrit levels and MTHFR polymorphisms (C677T and A1298C substitution) were studied in a large cohort of preterm infants in a tertiary referral medical center during an 18-month period. Data were collected on maternal history and delivery as well as on post-natal complications. RESULTS: The study cohort included 167 infants whose mean gestational age was 30.98 ± 2.34 weeks (range: 26-36 weeks), mean birth weight 1327.6 ± 327 g, and mean Hcy level 7.99 ± 3.27 (range: 2.2-21.2) µmol/L. Maternal intake of folic acid was inversely associated with the babies' Hcy levels (P = 0.0001). Increased Hcy levels positively correlated with birth weight, gestational age (P < 0.005), total number of pregnancies (P = 0.012), and presence of MTHFR polymorphism. Higher Hcy levels were associated with feeding (P = 0.008), especially total parenteral nutrition (P = 0.0001). There was no correlation between Hcy levels and any vascular post-natal complications. CONCLUSIONS: During their post-natal hospitalization, preterm infants may have relatively high, that is, within the adult normal range, Hcy levels which are influenced by genetic and environmental factors. Despite the fact that no correlation was found between Hcy levels and post-natal complications, these associations should be further studied.

[proPSA: a precursor of prostate-specific antigen, may improve the early diagnosis of prostate cancer].

Since its introduction as a mass-screen parameter for early detection of prostate cancer, PSA was credited for a significant revolution in the management of prostate disease. But over 2 decades of global experience with this marker have emphasized that the recommended threshold value of 4.0 ng/ml may not be valid in distinguishing tumor growth from benign proliferation of the prostate in over 30% of the cases. Hence, more advanced tools of PSA evaluation have been introduced such as "PSA velocity", "PSA density" or age-related PSA". Recently, precursor molecules of PSA were identified, which are assumed to be zymogen structures devoid of proteolytic activity. These precursor species known as pro-PSAs possess an additional "tail" ranging in size from 2 to 7 extra amino acids at the N terminus of PSA, and represent a fraction of the non-complex or "free PSA", that has usually been identified as a marker for non-cancerous proliferation of the prostate. Interestingly, one of these proPSA structures in particular, [-2]proPSA, has demonstrated to be more specifically indicative of prostate tumor growth in numerous clinical studies. Lately, a chemiluminescence kit has been approved by the European Health Agency as a more specific marker for diagnosis of prostate malignancy, mostly in men with PSA levels ranging from 2-10 ng/ml.

Immunoglobulin free light chain dimers in human diseases.

Immunoglobulin free light chain (FLC) kappa (κ) and lambda (λ) isotypes exist mainly in monomeric and dimeric forms. Under pathological conditions, the level of FLCs as well as the structure of monomeric and dimeric FLCs and their dimerization properties might be significantly altered. The abnormally high fractions of dimeric FLCs were demonstrated in the serum of patients with multiple myeloma (MM) and primary systemic amyloidosis (AL), as well as in the serum of anephric patients. The presence of tetra- and trimolecular complexes formed due to dimer-dimer and dimer-monomer interactions was detected in the myeloma serum. Analysis of the amyloidogenic light chains demonstrated mutations within the dimer interface, thus raising the possibility that these mutations are responsible for amyloidogenicity. Increased κ monomer and dimer levels, as well as a high κ/λ monomer ratio, were typically found in the cerebrospinal fluid from patients with multiple sclerosis (MS). In many MS cases, the elevation of κ FLCs was accompanied by an abnormally high proportion of λ dimers. This review focuses on the disease-related changes of the structure and level of dimeric FLCs, and raises the questions regarding their formation, function, and role in the pathogenesis and diagnosis of human diseases.

URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews.

BACKGROUND: Hereditary renal hypouricemia may be complicated by nephrolithiasis or exercise-induced acute renal failure. Most patients described so far are of Japanese origin and carry the truncating mutation W258X in the uric acid transporter URAT1 encoded by SLC22A12. Recently, we described severe renal hypouricemia in Israeli patients with uric acid transporter GLUT9 (SLC2A9) loss-of-function mutations. Renal hypouricemia in Iraqi Jews has been previously reported, but its molecular basis has not been ascertained. METHODS: Three Jewish Israeli families of Iraqi origin with hereditary hypouricemia and hyperuricosuria were clinically characterized. DNA was extracted and the URAT1 gene was sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of URAT1 mutants found. RESULTS: A missense URAT1 mutation, R406C, was detected in all three families. Two affected siblings were found to carry in addition a homozygous missense URAT1 mutation, G444R. Both mutations dramatically impaired urate uptake into X. laevis oocytes. Moreover, we demonstrate for the first time that URAT1 facilitates urate efflux, which was abolished in the mutants, indicating also a secretion defect. Homozygous patients had serum uric acid concentrations of 0.5-0.8 mg% and a fractional excretion of uric acid of 50-85%. Most individuals studied were asymptomatic, two had nephrolithiasis and none developed exercise-induced acute renal failure. CONCLUSIONS: The URAT1 R406C mutation detected in all three families is likely to be the founder mutation in Iraqi Jews. Our findings contribute to a better definition of the different types of hereditary renal hypouricemia and suggest that the phenotype of this disorder depends mainly on the degree of inhibition of uric acid transport.

[Hepcidin--the discovery of a small protein with a pivotal role in iron homeostasis].

Hepcidin is a small protein comprised of 25 amino acids, synthesized in the liver. It was first described in 2001 as a component of the innate immunity due to its antimicrobial activity. Soon after, hepcidin was recognized as a key component in iron homeostasis, involved in maladies of iron overload or iron deficiency. Hepcidin acts by binding to the transmembrane protein ferroportin, in charge of exporting iron from cells. Upon binding to ferroportin, the latter is internalized into cytoplasmic lysosomes and is hydrolyzed, thus iron is accumulating in cells, and hypoferremia ensues. In hereditary and juvenile types of hemochromatosis, iron overload could be partially due to the down-regulation of hepcidin by the mutated genes HFE and HJV. In ferroportin disease, hepcidin synthesis is not inhibited, yet cells are still overloaded with iron due to mutations in ferroportin, preventing the binding of hepcidin and iron export from cell to the blood. Hepcidin has also been implicated in the scenario related to as "anemia of inflammation". In this condition significant hypoferremia develops as a result of acute sepsis, but also in wake of infections, chronic inflammation, rheumatic diseases and in certain malignancies. Such scarcity of iron leads to anemia that may not be corrected by erythropoietin treatment, and hepcidin synthesis in such anemic state is dramatically elevated. Future therapeutic approach may attempt administering synthetic hepcidin, or its antagonists, to correct states of iron overload or scarcity.

Detection of alpha1 integrin in urine of patients with immunoglobulin A nephropathy.

BACKGROUND: The alpha1beta1 integrin is a cell surface membrane heterodimer composed of noncovalently linked alpha1 and beta1 polypeptides that is up-regulated on activated and proliferating mesangial cells. METHODS: A double-sandwich enzyme-linked immunosorbent assay that detects alpha1 integrin in a specific and dose-dependent manner at concentrations greater than 150 ng/mL was used to evaluate whether intact alpha1 polypeptides are secreted in the urine samples of 29 patients with various kidney diseases and in those of 5 healthy individuals. RESULTS: alpha1 Integrin was detected in 8 of the 29 patients including 3 of 3 patients with biopsy-proven immunoglobulin A nephropathy and 3 of 3 clinically suspected but non-biopsy-proven immunoglobulin A nephropathy with evidence of active nephritis. No alpha1 integrins were found in samples of 5 healthy controls. CONCLUSIONS: alpha1 Integrin polypeptides can be detected in human urine, particularly in immunoglobulin A nephropathy. Further extensive studies are required to clarify the significance of secretion of alpha1 integrins in urine of patients with kidney disease.

N-terminal pro B-type natriuretic peptide (N-BNP) levels in cystic fibrosis patients.

BACKGROUND: The diagnosis of right heart failure and pulmonary hypertension in cystic fibrosis (CF) patients with advanced pulmonary disease is sometimes difficult on clinical grounds alone. B-type natriuretic peptide (BNP) & N-terminal pro-B-type natriuretic peptide (N-BNP) levels were found to be useful in differentiating heart failure from various pulmonary diseases. However, its level was never measured in CF patients. The aim of this study was to measure N-BNP level in CF patients without heart failure. METHODS: The study included 49 patients. Of these, 32 had CF and 17 were control subjects who were matched by age and sex variables to the study group. We looked for a correlation between N-BNP and lung function test, genetic profile, height percentiles, and weight percentiles. N-BNP level was measured using an immunoassay that contains polyclonal antibodies that recognize epitopes located in the N-terminal part of proBNP. RESULTS: N-BNP level among CF patients without heart failure, after age and sex adjustments, was similar to the control group (Median: 47 pg/ml vs. 38 pg/ml, P = 0.248, interquartile range: 33-99 pg/ml vs. 31-76 pg/ml). A correlation between N-BNP level to age was found in both groups (CF: R = -0.398; P = 0.024, CONTROL: R = -0.054; P = 0.024). There was no correlation between N-BNP level to FEV1, O2 saturation and nutritional status. Among CF patients, eight (25%) had a mildly elevated N-BNP level whereas none was found in the control group (P = 0.038). CONCLUSION: We conclude that N-BNP level among CF patients is similar to the normal population and that it has no correlation to lung function impairment. Therefore, measurement of elevated N-BNP level in CF patients might be a predictor to the development of pulmonary hypertension and heart failure.

The organotellurium compound ammonium trichloro(dioxoethylene-o,o')tellurate reacts with homocysteine to form homocystine and decreases homocysteine levels in hyperhomocysteinemic mice.

Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) is an organotellurium compound with pleiotropic functions that has been associated with antitumoral, immunomodulatory and antineurodegenerative activities. Tellurium compounds with a +4 oxidation state, such as AS101, react uniquely with thiols, forming disulfide molecules. In light of this, we tested whether AS101 can react with the amino acid homocysteine both in vitro and in vivo. AS101 conferred protection against homocysteine-induced apoptosis of HL-60 cells. The protective mechanism of AS101 against homocysteine toxicity was directly mediated by its chemical reactivity, whereby AS101 reacted with homocysteine to form homocystine, the less toxic disulfide form of homocysteine. Moreover, AS101 was shown here to reduce the levels of total homocysteine in an in vivo model of hyperhomocysteinemia. As a result, AS101 also prevented sperm cells from undergoing homocysteine-induced DNA fragmentation. Taken together, our results suggest that the organotellurium compound AS101 may be of clinical value in reducing total circulatory homocysteine levels.

High-dose vitamin B6 decreases homocysteine serum levels in patients with schizophrenia and schizoaffective disorders: a preliminary study.

UNLABELLED: Vitamin B6 plays an essential role in the normal functioning of the central nervous system. Normal homocysteine (Hcy) serum level is maintained by remethylation of Hcy to methionine by enzymes that require folic acid and vitamin B12 and by catabolism to cysteine by a vitamin B6-dependent enzyme. These findings may be consistent with the hypothesis that the vitamin B6 status may influence plasma Hcy levels. The aims of this preliminary study were (1) to determine whether a correlation exists between Hcy and vitamin B6 levels in patients with schizophrenia and schizoaffective disorders and (2) to investigate whether treatment with high-dose vitamin B6 may reduce Hcy levels in these patients. METHODS: In this preliminary study, we enrolled 11 patients with schizophrenia or schizoaffective disorders (7 men and 4 women; mean age +/- SD, 50 +/- 12 years) receiving high doses of vitamin B6 treatment (1200 mg/d) for 12 weeks. Blood samples for the assessment of pyridoxal-5-phosphate and Hcy serum levels were obtained at baseline and after 12 weeks of treatment. RESULTS: Age was significantly positively correlated with Hcy levels at baseline (r = 0.392, P = 0.004). All other parameters, including diagnosis, disease duration, and pyridoxal-5-phosphate serum level, were not correlated with Hcy serum levels at baseline. After vitamin B6 treatment, Hcy serum levels significantly decreased (14.2 +/- 3.4 vs. 11.8 +/- 2.0 micromol/L, respectively, t = 2.679, P = 0.023); this decrease being statistically significant in men but not in women. CONCLUSIONS: High doses of vitamin B6 lead to a decrease in Hcy serum level in male patients with schizophrenia or schizoaffective disorder.

Physical activity is inversely associated with total homocysteine levels, independent of C677T MTHFR genotype and plasma B vitamins.

The homocysteine level is considered to be a product of genetic and lifestyle interactions, mainly mutated methylenetetrahydrofolate reductase (MTHFR) and the intake of folate, vitamin B12 and pyridoxine, and their blood levels. Physical activity has been associated with lower homocysteine levels in some population studies, especially among elderly subjects. To further elucidate the observed association between homocysteine and physical activity, while accounting for the effect of the MTHFR C677T genotype, and of plasma levels of folate and B12 vitamins, a cross-sectional study of 620 males and females, aged 70.5 +/- 6.8 years, was carried out. Information on lifestyle habits was collected and laboratory examinations of 12-h fasting total plasma homocysteine, folate, and vitamin B12, as well as DNA analysis for MTHFR C677T variant, were performed. Median total homocysteine values were 11.4 micromol/l for males and 9.4 for females; p < 0.001. Smoking and ethnic origin were not found to be associated with homocysteine levels. Physically active subjects had significantly lower total homocysteine levels when adjusted for sex (p = 0.01). Significant inverse correlations were found between body mass index, plasma folate, B12 and homocysteine levels. Homocysteine levels of the CC, CT and TT genotypes were 9.7, 10.6 and 10.2 mumol/l, respectively (p = 0.002, controlling for sex). In a multiple linear regression model, a sedentary lifestyle increased homocysteine levels by 7% as compared to an active one (p = 0.03) controlling for sex, age, body mass index, folate, vitamin B12, and C677T genotype, all of which were also found to be significantly associated with homocysteine levels. Any level of physical activity was found to be independently associated with lower homocysteine levels in an elderly population, controlling for MTHFR genotype, plasma B-vitamins, age, sex, smoking and BMI. This study emphasizes the importance of maintaining a physically active lifestyle in the elderly.

Homocysteine levels in newly admitted schizophrenic patients.

We previously found a marked elevation of plasma homocysteine in young male schizophrenic patients in hospital. It seemed important to determine if this finding is already present in newly admitted schizophrenic patients. Serum homocysteine levels were studied in 184 consecutively admitted schizophrenic patients and 305 control subjects from an employee screening program. Homocysteine levels were markedly increased in this population of newly admitted schizophrenic patients, especially in young males. Newly admitted male schizophrenic patients have elevated homocysteine levels that cannot be explained on the basis of poor hospital nutrition. Smoking may raise homocysteine by 1-2 microM/L but this is not a large enough effect to explain our findings.

Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus.

OBJECTIVE: Although anemia is frequent in inflammatory rheumatic diseases, data regarding vitamin B12 status is scarce. The purpose of this study was to analyze the incidence and nature of B12 and folic acid (FA) deficiencies in a cohort of rheumatic patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and systemic lupus erythematosus (SLE). METHODS: Levels of B12, FA, and parameters of anemia were recovered or examined in 276 outpatients. In those with recent findings of low serum B12 levels, further studies of serum homocysteine (Hcy) and urine methylmalonic acid (MMA) levels were performed. RESULTS: The incidence of anemia was high: 49%, 46%, and 35%, in RA, SLE, and PsA, respectively. Low levels of serum B12 were also frequent (24%), with almost similar occurrence in the three disease groups. Deficiency in FA was rare (<5%). Mean levels of both vitamins did not differ significantly among the three groups. No correlation between serum B12 levels and anemia was found. In the 15 patients with recently detected low B12 levels, Hcy and MMA were evaluated before and following B12 therapy. In ten of them, baseline Hcy levels were high, while MMA was increased in one patient only. Response to B12 administration, i.e., a decrease in Hcy and/or MMA levels, was noticed in four patients only, suggesting that only 26% of the low-serum-B12 patients had true B12 deficiency. CONCLUSIONS: The incidences of anemia and decreased serum B12 levels were high in these three groups of rheumatic patients. However, true tissue deficiency seems to be much rarer.

Life-style habits and homocysteine levels in an elderly population.

BACKGROUND AND AIMS: Increased plasma total homocysteine (Hcy) is a known cardiovascular disease (CVD) risk factor, related to several components of the established CVD risk profile. Observational studies support the role of modifying life-style related risk factors such as diet, physical activity and alcohol consumption in CVD prevention. Regular physical activity protects against coronary artery disease, possibly through its role in controlling risk factors such as hypertension, diabetes mellitus and obesity, but also independently. The aim of our study was to test the hypothesis that there is an association between physical activity, life-style habits and plasma Hcy levels in an elderly population. METHODS: In this cross-sectional study, 423 males and females aged 69.0 +/- 6.7 years completed an interview and laboratory examinations. Our main outcome measure was plasma levels of Hcy. RESULTS: Mean Hcy values were 10.5 +/- 5.5 micromol/L (11.4 +/- 6.1 for males and 9.3 +/- 4.5 for females; p < 0.001). Smoking and BMI were not found to be associated with Hcy levels. Physically active subjects, as well as B vitamin supplement users, had significantly lower Hcy levels (p = 0.002 and p = 0.004, respectively). In a multiple linear regression model, the Hcy level was 10% higher amongst participants with a sedentary life-style, 17% higher amongst males, 1% higher for each one-year increment in age, and 10% higher amongst participants who used no B vitamin supplements. CONCLUSIONS: Any level of physical activity was found to be an independent life-style habit associated with a lower Hcy level in an elderly population. This study supports existing recommendations for elderly persons to maintain a physically active life-style.

Thrombophilia does not increase risk for neonatal complications in preterm infants.

The association between thrombophilia and neonatal complications was evaluated in a single-center prospective study. Prevalence of genetic prothrombotic markers (FVL, MTHFR, FIIG20210A) and levels of plasma homocysteine were assayed in 166 premature (mean gestational age: 30.9+/-2.3 weeks) and low birth weight (mean weight: 1327+/-319 grams) infants. The incidence of any neonatal complications was compared in infants with and without thrombophilia. A total of 38 infants were defined as "thrombophilic" due to heterozygous FVL (n=4) and/or FIIG20210A (n=8, including one case of combination with FVL) or homozygous 677T MTHFR (n=22) or homocysteine plasma levels above 15 micro mole/liter. Neonatal complications included: small for gestational age (28.8%), respiratory distress syndrome (51.8%), broncho-pulmonary dysplasia (10.2%), patent ductus arteriosus (12.7%), intraventricular hemorrhage (17%), periventricular leucomalacia (8.4%), retinopathy of prematurity (15.1%) and necrotizing enterocolitis in 1.2% of infants. No thrombosis was documented. The prevalence of perinatal complications and the severity of diseases were similar among infants with or without thrombophilia (p = 0.564). Our data suggest that preterm infants with thrombophilia are not at increased risk for developing neonatal complications.