The Use of Brain Natriuretic Peptide as a Decision-supporting Tool in Hospitalized Patients.

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.

[Low ALT activity amongst patients hospitalized in internal medicine wards is a widespread phenomenon associated with low vitamin B6 levels in their blood].

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.

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.

Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2.

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.

Is C-reactive protein level a marker of advanced motor and neuropsychiatric complications in Parkinson's disease?

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.

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.

Serum calcium levels and long-term mortality in patients with acute stroke.

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.

Homozygous SLC2A9 mutations cause severe renal hypouricemia.

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.

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.

[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.

Chronic kidney disease and clinical outcome in patients with acute stroke.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for cardiovascular disease and stroke. Our aim was to examine the association between estimated glomerular filtration rate (GFR) and stroke outcome and to assess whether CKD and its severity affect stroke outcome in a large cohort of unselected patients with acute stroke. METHODS: We examined the association between baseline estimated GFR and CKD and 1-year outcomes in 821 consecutive patients with acute stroke (ischemic or hemorrhagic). GFR was estimated by 2 methods: the Modification of Diet in Renal Disease and the Mayo Clinic quadratic equation. An estimated GFR rate 60 mL/min/1.73 m(2), whereas those based on the Mayo Clinic equation were 2.3 (1.1 to 4.7) and 3.3 (1.6 to 7.1), respectively. The adjusted ORs for Barthel Index

Cardiorespiratory fitness and plasma homocysteine levels in adult males and females.

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.

Neuropsychological correlates of homocysteine levels in euthymic bipolar patients.

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).

Elevated serum homocysteine levels in male patients with PTSD.

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.

The effects of external counter pulsation therapy on circulating endothelial progenitor cells in patients with angina pectoris.

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.

Comparative analysis of homocysteine concentrations in patients with retinal vein occlusion versus thrombotic and atherosclerotic disorders.

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.

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.

[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.