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Background: Most dyspneic patients in internal medicine departments have co-morbidities that interfere with the clinical diagnosis. The role of brain natriuretic peptide (BNP) levels is well-established in the acute setting but not in hospitalized patients., Objectives: To evaluate the additive value of BNP tests in patients with dyspnea admitted to medical wards who did not respond to initial treatment., Methods: We searched the records of patients who were hospitalized in the department of internal medicine D at Sheba Medical Center during 2012 and were tested for BNP in the ward. Data collected included co-morbidity, medical treatments, diagnosis at presentation and discharge, lab results including BNP, re-hospitalization, and mortality at one year following hospitalization., Results: BNP results were found for 169 patients. BNP was taken 1.7 ± 2.7 days after hospitalization. According to BNP levels, dividing the patients into tertiles revealed three equally distributed groups with a distinctive character. The higher tertile was associated with higher rates of cardiac co-morbidities, including heart failure, but not chronic obstructive pulmonary disease. Higher BNP levels were related to one-year re-hospitalization and mortality. In addition, higher BNP levels were associated with higher rates of in-admission diagnosis change., Conclusions: BNP levels during hospitalization in internal medicine wards are significantly related to cardiac illness, the existence of heart failure, and patient prognosis. Thus, BNP can be a useful tool in managing dyspneic patients in this setting.

Emotional awareness and acceptance of emotion are associated with improved health in breast cancer (BC) patients. Art therapy (AT) uses visual art-making for expression and communication and has been shown to reduce psychological and physical symptoms in individuals with cancer. A major objective of AT is to encourage increases in emotion processing; however, few studies examine these changes. Purpose: To examine the effect of an eight-week AT group on emotion processing as a mechanism of symptom reduction in women with BC. Design: Randomized clinical trial. Sample: Twenty women diagnosed with breast cancer whom had completed primary treatment. Methods: Participants were randomized to participate in eight-weeks of AT or sham AT, which was a mandala coloring group. Participants answered questionnaires before and after the intervention. We used a Cohen's D calculator for effect sizes and a t-test to examine group differences. Findings: Statistically significant between-group differences in emotional awareness and acceptance of emotion were found after the intervention. We found large effect sizes between groups and over time in acceptance of emotion, emotional awareness and depressive symptoms. Conclusions: We conclude that emotion processing in AT may be a potential mechanism reducing depression and somatic symptoms in cancer patients. Implications for Psychosocial Providers: Art Therapy is a feasible intervention to increase emotional processing. A larger study is required to further examine its effect on psychological and physical symptoms in breast cancer patients.

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Low alanine aminotransferase (ALT) blood levels are known to be associated with frailty and increased risk of long-term mortality in certain populations. However, the contribution of this marker to long-term outcome has not been assessed in patients with chronic coronary heart disease., Objective: The aim of the current study was to assess the association between low ALT values and long-term, 22.8-year, all-cause mortality in this population., Participants: We examined the association of low ALT (<17 IU/l) with long-term all-cause mortality in the Bezafibrate Infarction Prevention (BIP) Registry population., Key Results: Appropriate laboratory and survival data were available for 6,575 patients, without known liver pathology, included in the BIP registry, with a median follow-up period of 22.8 years. The cumulative probability of all-cause mortality was significantly higher in the low ALT group compared with patients with higher ALT levels (65.6 % vs. 58.4 %; log-rank p < 0.001). Consistently, multivariate analysis, adjusted for multiple established predictors of mortality in this population, demonstrated that low ALT is independently associated with 11 % greater long-term (22.8 years) mortality risk [HR 1.11 (95 % confidence interval: 1.03-1.19; adjusted p < 0.01)]., Conclusions: Low ALT levels are associated with increased long-term mortality among middle-aged patients with stable coronary heart disease. This association remained statistically significant after adjustment for other well-established risk factors for mortality in this population.

Background: Monitoring the activity of ALT (SGPT) in the blood is part of the routine, clinical-laboratory follow-up in hospitalized patients. In most cases, activity levels which are above the normal range are considered pathology, mostly related to lysis of hepatocytes, as in cases of hepatitis. Little has been investigated and published in regard to cases in which the ALT activity level is lower than normal., Patients and Methods: Since normal ALT activity is regarded essential for normal metabolism and homeostasis, we decided to evaluate the extent to which low ALT levels are found in healthy and hospitalized patient populations and to characterize its circumstances and etiology. Furthermore, we measured the blood concentration of vitamin B6 (being the source for the ALT co-factor, Pyridoxal-5-Phosphate) in a random sample of patients with lower than normal ALT activity level., Results and Conclusions: The results of the current study showed a high prevalence, exceeding a third of hospitalized patients in internal medicine departments have low levels of ALT in the serum, and that a linear correlation (p = 0.0004, r = 0.47) exists between lower than normal ALT activity and low concentrations of vitamin B6 in the serum. The authors attribute these findings to a high prevalence of frailty amongst hospitalized patients. We aim to conduct further investigations intended to better characterize quantifiable parameters of frailty amongst our patient population.

Background: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N- methylglycine and inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia., Methods: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients., Results: Significant improvement was observed after one week of treatment on PANSS sub-scale of 'positive symptoms' (Z= -2.68; P=0.007) and 'general psychopathology' (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively., Limitations: This was a short period, open label pilot study with small sample size per dosage group., Conclusions: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia.

Copper deficiency had been suggested to link between fructose-enriched diet (FED) and the development of non-alcoholic fatty liver disease (NAFLD). In this study, we characterized changes in hepatic copper concentrations and hepatic oxidative milieu, in rats with the metabolic syndrome and NAFLD as a result of FED with pharmacological manipulations to reduce blood pressure or plasma triglycerides. Changes in plasma and hepatic copper concentrations were correlated with changes observed in the immunohistochemical hepatic expression of copper-zinc-superoxide dismutase (CuZnSOD; SOD1), metallothionein (MT) and nitrotyrosine (NITT). FED administration was associated with a 2.2-fold reduction in hepatic copper concentrations, a decrease in the hepatic SOD1 expression, disappearance of the hepatic MT expression and increase in the hepatic NITT expression. Bezafibrate administration restored the hepatic copper concentrations and the hepatic SOD1 expression to levels that were observed in the control rats. A significant positive correlation between hepatic copper concentrations and the values of hepatic SOD1 expression of each animal included in this study was found. Administration of either captopril or bezafibrate increased hepatic MT expression, however, to levels that were lower than those observed in the control group. Administration of either amlodipine, or captopril or bezafibrate to the FED rats, had no effect on hepatic NITT expression. NAFLD development in FED rats is associated with a decrease in hepatic copper concentrations that is associated with a decrease in the hepatic SOD1 expression. Bezafibrate administration increases hepatic copper concentrations and restores the hepatic SOD1 expression., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Increased blood levels of alanine amino transferase (ALT, also known as SGPT; serum glutamic pyruvic transaminase) serve as a marker of liver injury by various mechanisms. Less is known about the clinical implications associated with low-normal ALT levels. Previous studies showed low ALT levels to be associated with poor long-term outcomes among elderlies, serving as a biomarker for increased incidence of frailty and subsequent risk of mortality. However, it has not been determined yet whether low-normal ALT values might be predictive of frailty and mortality in younger, middle-aged adults., Methods: We conducted a historical prospective cohort analysis., Results: A total of 23,506 adults with ALT levels within the normal range, at the mean age of 48 ± 11 years, participating in an annual screening program for preventive medicine, were followed-up for a median period of 8.5 years during which 638 died. Low-normal ALT values (serum ALT activity <17IU/L) were found to be predictive for increased risk of all-cause mortality (HR=1.6; 95% CI 1.34-1.92; p<0.001). Statistically significant correlation was demonstrated even after applying a multifactorial model correction for age, gender, eGFR, low albumin, arterial hypertension, diabetes mellitus and ischemic heart disease., Conclusions: We suggest that low-normal ALT values may serve as an independent predictive marker for increased long-term mortality in middle-aged adults., (Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Increased homocysteine plasma levels were reported in patients with schizophrenia and Levine et al. (2002) suggested that such increase characterizes mainly males. In the following study we examined whether such increased levels also characterize male siblings of schizophrenia patients. Forty-four pairs of schizophrenia patients and their corresponding healthy male siblings were recruited and sampled for homocysteine. We also had age-matched controls for each of the sibling. The median homocysteine plasma level for patients was 13.0 µMol/L and 11.7 µMol/L for their male siblings compared with a median of 10.9 µMol/L for the siblings' controls. There was no significant difference between homocysteine plasma level in patients and their siblings. Significant difference was found for homocysteine plasma level between the siblings' group and their matched controls. A partial correlation of Ln plasma homocysteine level between patients and their siblings was found to be close to a zero correlation of -0.089, p=0.57 for the whole study group and -0.15, p=0.38 in the male-male patient-sibling pairs. Our results show that elevated homocysteine plasma level may characterize schizophrenia patients' male siblings, a finding that seems to agree with previous studies suggesting elevated homocysteine level as a risk factor for developing schizophrenia., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Glutaric aciduria type I (GA-I) is an autosomal recessive disease caused by a deficiency of the mitochondrial enzyme glutaryl CoA dehydrogenase (GCDH). This metabolic block causes increased urinary concentrations of glutaric and 3-hydroxyglutaric acids. The accumulation and excretion of glutarylcarnitine esters leads to secondary carnitine deficiency. GA-I has an incidence of 1:30,000. The clinical hallmark of GA-I is an acute encephalopathic crisis, with bilateral striatal necrosis presented by severe dystonic dyskinetic disorder. Most patients have their first symptoms during infancy, but some have a less severe form of the disease and some may even remain asymptomatic.

Individuals with the metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) have an increased incidence of infection and infection-related mortality. Rats given fructose-enriched diet (FED) develop the MS including NAFLD. In this study, we characterized changes in splenocyte apoptosis in FED rats given medications to treat various components of the MS. Apoptosis of splenocytes may induce immunosuppression. Splenocyte apoptosis was evaluated by activated caspase-3 immunohistochemistry in the periarterial sheath (PALS), (a T cell area), follicles (B cell area), marginal (B cell area) and in the red pulp zones. FED administration caused an enormous increase in splenocyte apoptosis in all of the spleen zones: PALS (+2966%), follicles (+3025%), marginal (+5228%) and red pulp (+7000%). Administration of captopril to the FED rats was associated with a further increase in the splenocyte apoptosis only in the marginal (150%), PALS (+105%) and red pulp (+67%) zones. Bezafibrate administration to the FED rats was associated with no further increase in apoptosis rates. Amlodipine administration to the FED rats was associated with almost complete amelioration of the splenocyte apoptosis that was induced by the FED diet. These pharmacological manipulations were also associated with changes in the hepatic lipids composition, and oxidative milieu that did not correlate to the changes in splenocyte apoptosis. NAFLD in FED rats is associated with an increase in splenic apoptosis. Agents administered to treat components of the MS in FED rats may lead to divergent changes in the splenic histology and splenocyte apoptosis., (© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.)

In our search of new biomarkers for multiple sclerosis (MS), we aimed to characterize the immunoglobulin (Ig) free light chains (FLC) in patients' cerebrospinal fluid (CSF) and serum, and to evaluate the diagnostic utility of FLC monomer-dimer patterns for MS. FLC were analyzed by Western blotting and mass spectroscopy. CSF and serum samples were examined for the presence of oligoclonal Ig bands by a conventional laboratory test for MS. Three distinct pathological FLC monomer-dimer patterns, typical of MS but not of other neurological diseases, were revealed. In 31 out 56 MS patients the highly increased CSF levels of κ monomers and dimers were demonstrated. In 18 MS patients, the increased κ-FLC levels were accompanied by highly elevated λ dimers. Five MS cases showed no significant elevation in κ-FLC, but they displayed abnormally high λ dimer levels. The intensity of the immunoreactive FLC bands was measured to account for κ and λ monomer and dimer levels and their ratios in the CSF and serum. Combined usage of different FLC parameters allowed the determination of the appropriate FLC threshold values to diagnose MS. The developed method showed higher sensitivity and specificity (96% and 90%, respectively), as compared to those of the conventional OCB test (82% and 70%, respectively). Our study highlights the role of the differential analysis of monomeric and dimeric κ- and λ-FLC for the precise diagnosis of MS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Refeeding of elderly frail patients after food deprivation is commonly associated with a high mortality rate., Objective: To evaluate the effect of refeeding on metabolite fluctuation of blood carnitine fatty acids (15 compounds) and free amino acids (14 compounds)., Methods: Metabolite fluctuation was followed up in an exploratory, cohort, and noninterventional study in elderly and frail patients (84.5 ± 5 years) after a long period of food deprivation. Patients in the study group were refed by enteral nutrition (EN) and were followed up during 7 days for blood metabolites (n = 27). Patients in the control group (n = 26) had been fed by EN for more than 3 months. Refeeding was initiated with 10 kcal/kg/d and gradual increases of 200 kcal/d for 3 days afterwards. Blood metabolites were assayed in a sample of 25 µL., Results: On food deprivation, the concentrations of all even monocarboxylic carnitine fatty acids were much higher in the study group than in the EN control group (P < .01). Upon refeeding, a remarkable decrease in all carnitine fatty acids was observed. In addition, significant daily fluctuations were observed for most metabolites in the study group of the refed patients as compared with the EN control group (P < .01). The highest fluctuations were observed following refeeding in the 7 patients who later died., Conclusion: A significant metabolic instability is observed on refeeding even with a slow refeeding schedule of 10 kcal/kg/d. Measurement of metabolomics parameters may be used for the evaluation of malnutrition, refeeding status, and optimization of the enteral formula.

Background: Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2)., Methods: Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations., Results: Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions., Conclusions: This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.

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.

Although coffee is a widely used, pharmacologically active beverage, its impact on the cardiovascular system is controversial. To explore the effect of acute caffeine ingestion on brachial artery flow-mediated dilation (FMD) in subjects without coronary artery disease (CAD; controls) and patients with CAD, we prospectively assessed brachial artery FMD in 40 controls and 40 age- and gender-matched patients with documented stable CAD on 2 separate mornings 1 week to 2 weeks apart. After overnight fasting, discontinuation of all medications for ≥12 hours, and absence of caffeine for >48 hours, participants received capsules with caffeine 200 mg or placebo. One hour after drug ingestion, participants underwent brachial artery FMD and nitroglycerin-mediated dilation (NTG) using high-resolution ultrasound. As expected, patients with CAD were more often diabetic, hypertensive, obese, dyslipidemic, and smoked more than controls (p <0.01 for all comparisons). Aspirin, Clopidogrel, angiotensin-converting enzyme inhibitors, β blockers, and statins were significantly more common in patients with CAD than in controls (p <0.01 for all comparisons). At baseline, FMD, but not NTG, was significantly lower in patients with CAD compared to controls. Acute caffeine ingestion significantly increased FMD (patients with CAD 5.6 ± 5.0% vs 14.6 ± 5.0%, controls 8.4 ± 2.9% vs 18.6 ± 6.8%, p <0.001 for all comparisons) but not NTG (patients with CAD 13.0 ± 5.2% vs 13.8 ± 6.1%, controls 12.9 ± 3.9% vs 13.9 ± 5.8%, p = NS for all comparisons) and significantly decreased high-sensitivity C-reactive protein (patients with CAD 2.6 ± 1.4 vs 1.4 ± 1.2 mg/L, controls 3.4 ± 3.0 vs 1.2 ± 1.0 mg/L, p <0.001 for all comparisons) in the 2 groups compared to placebo. In conclusion, acute caffeine ingestion significantly improved endothelial function assessed by brachial artery FMD in subjects with and without CAD and was associated with lower plasma markers of inflammation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

C-reactive protein (CRP) is a plasma protein involved in inflammation. While its levels have been associated with stroke, cognitive impairment and depression, the association with clinical characteristics of Parkinson's disease (PD) is unknown. A total of 73 consecutive patients with PD (46 males, age 68.8 ± 11.5 years) were evaluated regarding motor as well as cognitive and psychiatric features of PD. Plasma CRP levels were determined and tests for associations with disease parameters were performed. The average level of CRP was 3.9 ± 4.1 μmol/L, and 45.2% of the patients (n = 33) had a level above 3.0 μmol/L. Patients in the high CRP group tended to be older (71.4 ± 9.2 vs. 66.7 ± 12.9 years; p = 0.08) and coronary artery disease (CAD) was more common (36 vs. 10%, p < 0.05) in the high CRP group, but no differences were found between the groups regarding gender, disease duration, levodopa dose, motor scores or most of the neuropsychiatric complications such as severity of depression, psychosis, dementia, cognitive decline or frontal lobe dysfunction. Reported depression (at present or in the past) was more common in the high CRP group (54.5 vs. 25%, p = 0.01). CRP levels in patients with PD are associated with a higher prevalence of CAD, but are not associated with PD duration or severity, or with neuropsychiatric complications other than reported depression.

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.

Background: Calcium concentrations in serum are maintained within an exquisitely narrow range. Our aim was to examine the association between serum calcium and albumin-adjusted calcium (calcium(adj)) levels and stroke outcome in a cohort of unselected patients with acute stroke., Methods: Consecutive patients hospitalized due to acute stroke (ischemic or intracerebral hemorrhage) throughout a large medical center were systematically assessed and followed for 1 year. Baseline total calcium and calcium(adj) levels were collapsed into groups of low (<8.6 mg/dl), normal (8.7-9.9 mg/dl) and high (>10 mg/dl) levels and linear and quadratic relations with outcome were examined., Result: Among 784 patients (mean age 70.7 ± 12.5 years, 42.5% females), the mean ± SD total calcium level was 9.3 ± 0.6 mg/dl. For total calcium, the adjusted hazard ratio (HR) for all-cause death over 1 year was 1.83 [95% confidence interval (CI) 1.22-2.75] among patients with low versus normal levels. For calcium(adj), the adjusted HR for all-cause death among women was over 3-fold higher among patients with high calcium(adj) levels versus those with normal levels (3.31; 95% CI 1.70-6.46), while no such associations were observed among men. In models developed to estimate the linear and quadratic relations, each unit increment in total calcium squared was associated with an increased adjusted HR of all-cause death over 1 year (p = 0.02) confirming nonlinear associations, and each unit increment in calcium(adj) squared was associated with an increased adjusted HR of all-cause death over 1 year among women (p < 0.001) but not among men (p = 0.70)., Conclusions: Serum calcium concentrations are a marker of mortality in acute stroke patients, but the associations are not linear, increasing at both extremes of calcium levels. Our findings suggest that long-term survival is optimal in a distinct range of serum calcium levels., (Copyright © 2010 S. Karger AG, Basel.)

A new procedure of free light chain (FLC) analysis was developed to assist the diagnosis of multiple sclerosis (MS). In this procedure, Western blotting technique was used to analyze monomeric and dimeric FLCs in the cerebrospinal fluid (CSF) and serum of patients with MS and other neurological diseases. The intensity of immunoreactive FLC bands was quantified by a specially developed software. Analysis of the obtained monomer/dimer patterns of κ and λ type FLCs allowed the determination of the diagnostically useful FLC parameters. The combined use of three FLC indices accounting for monomeric FLC-κ level and κ/λ ratio values in the CSF and serum was found to be of promising diagnostic importance for differentiation of MS from other non-MS neurological diseases., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Plasma homocysteine associates positively with cardiovascular disease. C-to-T substitution at base 677 of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene associates with increased plasma homocysteine. The association of adiponectin with cardiovascular disease is unclear. This study of survivors of a 30-year cohort of the Jewish Israeli population, 310 men and 273 women (mean age, 70.5 ± 7.0 years for both), investigated the relationship between adiponectin and homocysteine, and between adiponectin and the MTHFR C677T genotype. Serum adiponectin associated positively with total homocysteine in both men (r = 0.27, P < .001) and women (r = 0.22, P < .001). In women, the TT MTHFR genotype associated with lower median adiponectin levels, 8.98 mg/L, compared with 9.88 and 10.57 mg/L for TC and CC, respectively (P = .05; CC vs TT, P = .01). In men, the trend was opposite, but not statistically significant: 7.90, 7.03, and 6.88 mg/L for TT, TC, and CC genotypes, respectively (P = .5). This study demonstrated a positive association between homocysteine and adiponectin in both elderly men and women and a statistically significant association between adiponectin and MTHFR C677T genotypes in women only., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 +/- 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.

Background: High levels of plasma homocysteine constitute a risk for cardiovascular disease. Physical activity, known to reduce CVD risk, has been related to levels of Hcy. Recently, higher Hcy was shown to be associated with lower cardiovascular fitness in women but not in men., Objectives: To further explore the relationship between cardiorespiratory fitness and plasma total homocysteine levels in a large cohort of adult males and females., Methods: This cross-sectional study included 2576 fitness and Hcy examinations in adults (62% males) aged 30-59 years randomly drawn from a population undergoing a periodic health examination in the Sheba Medical Center's Executive Screening Survey. Blood tests were collected for tHcy and a sub-maximal exercise test was performed to estimate cardiorespiratory fitness. Information on CVD/CVD risk factors (coronary heart disease, cerebrovascular accident, diabetes, hypertension or dyslipidemia) was self-reported., Results: Mean tHcy plasma levels were 14.4 +/- 7.7 and 10.2 +/- 3.0 micromol/ml, and mean maximal oxygen uptake 36.5 +/- 11.7 and 292 +/- 9.5 ml/kg/min for males and females, respectively. A multiple regression analysis, adjusting for age, body mass index and CVD/CVD risk factors, showed no association between cardiorespiratory fitness and level of tHcy in males (P = 0.09) or in females (P = 0.62)., Conclusions: In this sample no association was found between level of cardiorespiratory fitness and plasma tHcy in men or women. The inconsistency of findings and the small number of studies warrant further research of the association between cardiorespiratory fitness and tHcy, an association that may have clinical implications for the modifications of cardiovascular risk factors.

Background: Motor disturbances in vitamin B6-deficient animals were described. Some clinical experiments showed that vitamin B6 may ameliorate different drug-induced movement disorders, including tardive dyskinesia (TD). The aim of this study was to compare plasma pyridoxal-5-phosphate (PLP) levels in schizophrenic patients with and without TD., Method: This study was conducted in the Be'er Sheva Mental Health Center from February 2006 to August 2006. Eighty-nine schizophrenic inpatients (40 have TD, 22 men and 18 women, 20-66 yrs old [mean, 48 yrs] and 49 schizophrenic inpatients, 30 men and 19 women, 21-66 yrs old (mean, 49 yrs), without any symptoms of motor disturbances [the control group]) were enrolled in the study. Measurement of PLP is performed by high-performance liquid chromatography separation in all patients., Results: There was a significant difference in plasma PLP levels between patients with TD and those without TD. The discrepancy between the groups was almost entirely attributable to the PLP levels of male patients: 12.4 +/- 11.4 vs 29.0 +/- 12.9 nM in men (P < 0.001), and 19.7 +/- 14.8 vs 22.0 +/- 13.6 nM in women (P > 0.5)., Conclusions: Our results suggest that schizophrenic and schizoaffective male patients with TD have lower PLP plasma levels than non-TD patients.

The objectives of the present study were to determine the concentrations of plasma homocysteine in a large (n = 562) cohort of patients with retinal vein occlusion (RVO) and to compare them with the values observed in other vascular thrombotic and atherosclerotic conditions. Results were compared with those observed in patients with deep vein thrombosis (n = 1700), pulmonary embolism (n = 542), transient ischemic attack (n = 1301), cerebrovascular accident (n = 1299), myocardial infarction (n = 3087), as well as peripheral artery occlusive disease (n = 1946). No differences were found between the age-adjusted estimated marginal mean +/- SE for homocysteine concentrations in individuals with RVO and in those who had other atherosclerotic and atherothrombotic diseases The respective concentrations for RVO, deep vein thrombosis, pulmonary embolism, transient ischemic attack, cerebrovascular accident, myocardial infarction, and peripheral artery occlusive disease were 13.8 +/- 0.4, 14.7 +/- 0.3, 14.3 +/- 0.5, 14.2 +/- 0.3,14.6 +/- 0.3, 13.8 +/- 0.2, 14.4 +/- 0.2 pmol/l for men and 11.4 +/- 0.4, 10.7 +/- 0.2, 10.8 +/- 0.3, 10.8 +/- 0.2, 11.8 +/- 0.2, 11.2 +/- 0.2 pmol/l for women. In conclusion, the concentrations of homocysteine observed in patients with RVO are similar to those detected in other thrombotic and atherosclerotic vascular disorders. In view of the fact that this is a common disorder of the elderly, increased homocysteine concentrations often reported in patients with RVO could reflect the underlying atherothrombotic condition and might not necessarily be specifically related to the RVO per se. This information is relevant in researching the potential etiopathologic role, if any, of increased homocysteine concentrations in RVO.

Background: Exercise training can improve aerobic capacity and symptoms in congestive heart failure (CHF) patients., Aims: To test the feasibility of exercise training in advanced CHF patients, and examine the potential benefit from peripheral vascular and muscular conditioning as well as improved central hemodynamic and neurohumoral status., Methods and Results: Thirty NYHA functional class III, CHF patients (mean age 61+/-13 yr, ejection fraction 27+/-4%, VO2max 11.3+/-3.9 ml/kg/min) were enrolled. Exercise capacity, cardiovascular parameters and serum levels of brain natriuretic peptide (NT-proBNP) were determined at baseline and after 18 weeks of moderate intensity exercise training. Twenty eight (93%) patients, who completed the exercise program, experienced marked improvements in the 6 min walk (+39%) and exercise duration on the modified Bruce protocol (+66%). Smaller improvements were recorded in the cardiac index (a 15% increase), in the maximal oxygen consumption (a 13% increase in VO2max), in the left ventricular ejection fraction (an 11% increase) and in the systemic vascular resistance and pulmonary artery pressure (an 11% decrease). NT-proBNP levels were not significantly affected. They correlated with exercise capacity and VO2max on baseline measurement, but these correlations were not found after training., Conclusion: Rehabilitation is feasible, even in advanced CHF, and leads to markedly improved exercise performance, but does not affect the level of the principal neurohumoral marker of prognosis - NT-proBNP. Resting cardiovascular performance and maximal oxygen consumption improve less than functional capacity, suggesting that an important benefit is derived from muscle conditioning and improved peripheral vascular response to exercise.

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.

Oxidative stress may initiate significant hepatocyte injury in subjects with fatty liver. We characterized changes in hepatic oxidative anti-oxidative parameters in rats given a fructose-enriched diet (FED) with and without medications to reduce blood pressure or plasma triglycerides. FED rats had an increase in malondialdehyde (MDA) concentration, a reduction in alpha-tocopherol concentration, a reduction in paraoxonase (PON) activity, an increase in glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) activity. Amlodipine increased PON and GSH-Px, but decreased GSSG-R activity and alpha-tocopherol concentration. Captopril decreased MDA concentration and the activity of both GSH-Px and GSSG-R, but increased alpha-tocopherol concentration and PON activity. Bezafibrate increased alpha-tocopherol concentration and PON activity, but decreased the activity of GSSG-R. Animals with fatty liver exhibit an increase in peroxidative stress but also a defect in anti-oxidative pathways. Drugs administered to treat hypertension and hypertriglyceridemia could lead to a variety of changes in the hepatic oxidative, anti-oxidative milieu.

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.

It has been suggested that an elevated serum or plasma homocysteine level may be a risk factor for neuropsychiatric conditions such as Alzheimer's disease, schizophrenia, and depression. Because depression is closely related to anxiety disorders, and because it has been suggested that stress may be associated with an elevated homocysteine level, we studied whether serum homocysteine levels are elevated in patients with posttraumatic stress disorder (PTSD). Total serum homocysteine levels in 28 male patients with PTSD were compared to those of 223 healthy controls. The effect of PTSD on the serum homocysteine level was significant (F=42.96, P<.0001). In a regression model for the PTSD patients, the duration of PTSD was found to predict serum homocysteine levels (t=2.228, P=.035). Our results suggest that elevated levels of homocysteine in male patients with PTSD may be related to pathophysiological aspects associated with the chronicity of this disorder., (2007 Wiley-Liss, Inc.)

Background: We have previously reported that homocysteine levels are elevated in euthymic bipolar patients with functional deterioration. The current study was designed to extend this finding by examining the relationship between neuropsychological functioning and homocysteine levels in euthymic bipolar patients., Methods: Fifty-seven euthymic bipolar outpatients were assessed for serum levels of homocysteine, folic acid, and vitamin B-12 and administered a battery of neuropsychological tests., Results: We found that male bipolar subjects showed higher average homocysteine levels than a comparison group of normal subjects, that poorer functioning on a task of executive function (Wisconsin Card Sort) was related to higher homocysteine levels, and that folic acid or vitamin B-12 levels did not significantly affect neuropsychological functioning., Limitations: These results, while suggesting some relationship between higher homocysteine levels, bipolar illness, and impairment in cognitive function do not establish any causative effects., Conclusions: The findings of this study confirm that in euthymic bipolar patients, higher homocysteine levels are associated with poorer performance in some neuropsychological tests. Treatment trials will be required before it will be known if the putative decrements in the executive function of bipolar patients can be reversed, or at least retarded, if homocysteine levels are reduced (as, for example, by dietary addition of B vitamin supplements).

Objectives: External counter pulsation therapy (ECPT) offers symptomatic relief and improves ischemia in patients with refractory angina pectoris. We aimed to determine the effects of ECPT on circulating endothelial progenitor cells (EPCs)., Methods: We prospectively studied 25 patients with angina pectoris treated with ECPT (n = 15) or receiving standard care (n = 10). The number of EPCs positive for CD34 and kinase insert domain receptor (KDR) was determined by flow cytometry and the number of colony-forming units (CFUs) was assessed in a 7-day culture, before ECPT and after 9 weeks., Results: ECPT improved anginal score from a median of 3.0 to 2.0 (p < 0.001). Concomitantly, ECPT increased EPC number from a median of 10.2 to 17.8/10(5) mononuclear cells (p < 0.05), and CFUs from 3.5 to 11.0 (p = 0.01). Flow-mediated dilatation was improved by ECPT from 7.4 to 12.2% (p < 0.001) and correlated with EPC-CFUs (r = 0.461, p = 0.027). The levels of asymmetric dimethylarginine were reduced by ECPT from 0.70 to 0.60 micromol/l (p < 0.01). In contrast, the same parameters did not change in the control group, before and after follow-up., Conclusions: The present pilot study shows, for the first time, that ECPT is associated with increased number and colony-forming capacity of circulating EPCs., ((c) 2007 S. Karger AG, Basel.)

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.

Background: Tardive dyskinesia (TD) is a significant clinical problem. Vitamin B(6) is a potent antioxidant and takes part in almost all of the possible mechanisms that are suggested as being associated with appearance of TD. The aims of this study were (1) to reexamine the efficacy and safety of higher doses of vitamin B(6) versus placebo in a greater sample of patients for a longer time and (2) to evaluate the carryover effect of vitamin B(6)., Method: A 26-week, double-blind, placebo-controlled trial was conducted in a university-based research clinic from August 2002 to January 2005 on 50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD. In a double-blind crossover paradigm, all study subjects were randomly assigned to start treatment with either vitamin B(6) (daily dose of 1200 mg) or placebo. After 12 weeks of treatment and then a 2-week washout, subjects were crossed over to receive the other treatment for 12 weeks. The primary outcome measure was the change from baseline in Extra-pyramidal Symptom Rating Scale (ESRS) scores., Results: The mean decrease in ESRS clinical global impression scores from baseline to endpoint was 2.4 points in patients treated with vitamin B(6) and 0.2 points in patients treated with placebo (p < .0001). The mean decrease in the parkinsonism subscale score was 18.5 points and 1.4 points, respectively (p < .00001), and the mean decrease in the dyskinesia subscale score was 5.2 points and -0.8 points, respectively (p < .0001)., Conclusion: Vitamin B(6) appears to be effective in reducing symptoms of TD. The specific mechanisms by which vitamin B(6) attenuates symptoms of TD are not clear.

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., (2007 Wiley-Liss, Inc.)

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.

Objective: To examine plasma homocysteine, vitamin B(12), and folate levels in females with restricting and bingeing/purging eating disorders (EDs)., Method: Adolescent and adult female patients were compared to appropriate control groups with regard to plasma homocysteine levels., Results: The plasma homocysteine level of the adult ED patients was higher than that of controls for all age groups examined. In adolescents, no significant difference was found comparing ED patients younger than 16 years of age to control data, whereas in the 16-20 year age group, the plasma homocysteine level was significantly higher among the ED group, regardless of the type of ED. Vitamin B(12) and folate levels were within normal limits in all ED groups., Conclusion: Elevated plasma homocysteine levels were found in adult and older adolescent female ED patients (but not in younger adolescents) compared to controls. This finding is not related to deficiencies in vitamin B(12) or folate.

Background: Endothelial dysfunction is recognized as a major factor in the development of atherosclerosis and it has a prognostic value., Objectives: To detect the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects and patients with cardiovascular disease., Methods: We prospectively assessed brachial artery flow-mediated dilatation in 110 consecutive subjects (46 CVD patients and 64 healthy controls), mean age 57 +/- 11 years; 68 were men. After an overnight fast and discontinuation of all medications for > or = 12 hours, percent improvement in FMD and nitroglycerin-mediated vasodilatation were assessed using high resolution ultrasound., Results: %FMD but not %NTG was significantly lower in CVD patients (9.5 +/- 8.0% vs. 13.5 +/- 8.0%, P = 0.012) compared to healthy controls (13.4 +/- 8.0% vs. 16.7 +/- 11.0%, P = 0.084; respectively). In addition, an inverse correlation between %FMD and the number of traditional CVD risk factors was found among all study participants (r = -0.23, P = 0.015) and healthy controls (r = -0.23, P = 0.036). In a mean follow-up of 15 +/- 2 months, the composite CVD endpoints (all-cause mortality, myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with FMD < 6% compared to subjects with FMD > 6% (33.3% vs. 12.1%, P < 0.03, respectively)., Conclusions: Thus, brachial artery %FMD provides important prognostic information in addition to that derived from traditional risk factor assessment.

Background: Amiodarone is a very effective antiarrhytmic drug. However its use may be accompanied by side effects. Hyperglobulinemia was not described in association with amiodarone treatment., Materials and Methods: Fifteen patients, who developed hyperglobulinemia while on amiodarone therapy, were identified among the patients hospitalized in our hospital. Serum globulin concentration was measured prior to, during and after amiodarone therapy., Results: In 11 of the 15 patients with amiodarone-associated hyperglobulinemia, amiodarone treatment had to be stopped because of amiodarone-induced complications, nine of them had pneumonitis. Mean serum globulin level rose during amiodarone therapy from 2.48 +/- 0.51 g/dL to 4.11 +/- 0.71 g/dL (p = 0.001), and declined after it was stopped to 2.80 +/- 0.49 g/dL (p = 0.001). In 50 patients treated by amiodarone, serum globulin was similar to that found in 50 patients with ischemic heart disease not treated by amiodarone [2.64 +/- 0.39 g/dL and 2.56 +/- 0.29 g/dL respectively (p = 0.21)]., Conclusions: In some patients amiodarone therapy may be associated with hyperglobulinemia. The incidence of this association is not known. Most of the patients with amiodarone-associated hyperglobulinemia have amiodarone-induced toxicity, mainly pneumonitis. Amiodarone therapy does not cause a general increase in serum globulins. Hyperglobulinemia may be a marker for a damaged organ, or it may have a pathogenetic role in the induction of pneumonitis.

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.

We have prospectively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease. A nested case-control design was used. Total homocysteine concentration was measured in baseline fasting serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention Study (n = 3,090) who developed coronary events during 6.2 years of follow-up (n = 69). They were matched for age and gender with controls without subsequent cardiovascular events. Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 mumol/l increment was associated with a 25% higher risk.

Homocysteine is a sulfur containing amino acid that has been widely investigated for its putative role in cardiovascular and neuropsychiatric disorders. It has been suggested that homocysteine has implications especially in young, male schizophrenia patients. In this prospective case-control study, we compared plasma homocysteine levels in a group of adolescent schizophrenia inpatients (aged 14-21 years; n=23) to normal healthy controls (n=51). Mean plasma homocysteine levels were significantly higher in the patient group than in the control group (15.40+/-2.00 and 9.78+/-0.33 micromol/L, respectively, p<0.032). The difference was almost entirely attributable to the male schizophrenia subgroup (18.18+/-5.65 in male patients vs. 10.31+/-5.33 micromol/L in female patients). The group x sex interaction was statistically significant (p=0.0035). These data indicate that a subgroup of male adolescent schizophrenia patients has high homocysteine blood levels. The role of homocysteine in the pathophysiology of adolescent-onset schizophrenia merits further investigation.

Objective: To determine whether plasma homocysteine (Hcy) levels are associated with clinical characteristics, neuropsychological and psychiatric manifestations and cardiovascular comorbidity in patients with Parkinson disease (PD)., Background: Elevated Hcy levels are linked to atherosclerosis, vascular disease, depression, and dementia. Patients with PD treated with L-dopa have been shown to have elevated Hcy levels., Design/methods: Idiopathic PD patients were evaluated using the Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, Parkinson Psychosis Rating Scale, Beck Depression Inventory, Frontal Assessment Battery, Mini-Mental Status Examination, and several tests for frontal type cognitive functions. Fasting blood samples were collected for the measurement of Hcy, and carotid B-mode ultrasound was performed to measure intima-media thickness of the common carotid arteries., Results: Seventy-two consecutive PD patients (46 men; average age, 68.7 +/- 11.6 years; average disease duration, 7.0 +/- 4.7 years) were recruited. All but 10 patients were treated with L-dopa. The average level of Hcy was 16.4 +/- 7.8 micromol/L, and 38.9% of the patients had Hcy level above the reference range (>15.0 micromol/L). The Hcy levels were associated with PD duration as they were with L-dopa treatment duration but were not associated with the parameters of disease severity or with L-dopa dose. The Hcy levels were associated neither with the common carotid intima-media thickness nor with cardiovascular morbidity. No association was found between Hcy and the neuropsychiatric features of PD such as depression, cognitive performance, or psychosis., Conclusions: Hyperhomocystinemia is common in L-dopa-treatedPD patients but was not associated with neuropsychological complications (depression, dementia, and cognitive decline associated with frontal lobe functioning or psychosis), enhanced disease severity, or vascular comorbidity.