The Influence of Vitamin D on Neurodegeneration and Neurological Disorders: A Rationale for its Physio-pathological Actions.

Vitamin D is a steroid hormone implicated in the regulation of neuronal integrity and many brain functions. Its influence, as a nutrient and a hormone, on the physiopathology of the most common neurodegenerative diseases is continuously emphasized by new studies. This review addresses what is currently known about the action of vitamin D on the nervous system and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. Further vitamin D research is necessary to understand how the action of this "neuroactive" steroid can help to optimize the prevention and treatment of several neurological diseases.

Multiple Sclerosis: kFLC index values related to gender.

BACKGROUND: Multiple sclerosis (MS) is a chronic multifactorial inflammatory and neurodegenerative disease of the central nervous system (CNS). The identification of biomarkers with good diagnostic and prognostic power is of great importance for monitoring and treating MS patients. METHODS: We analyzed serum and cerebrospinal fluid of 228 patients, with different neurological disorders and with MS to confirm our previous results and determine a possible gender difference of kFLC Index cut-off. RESULTS: We have obtained a kFLC Index cut-off of 12.5 (100% specificity and 90.4% sensitivity) and 11 (100% specificity and 97.5% sensitivity) for women and men with MS respectively. CONCLUSIONS: This study reinforces the importance that kFLC Index could have as a diagnostic aid to detect MS. Our data highlight a difference in the cut-off of the kFLC Index calculated by gender; male patients with a kFLC Index value greater than 11 are at higher risk to develop MS respect females having the same result.

Transcriptional activity of human endogenous retroviruses in human peripheral blood mononuclear cells.

Human endogenous retroviruses (HERVs) have been implicated in human physiology and in human pathology. A better knowledge of the retroviral transcriptional activity in the general population and during the life span would greatly help the debate on its pathologic potential. The transcriptional activity of four HERV families (H, K, W, and E) was assessed, by qualitative and quantitative PCR, in PBMCs from 261 individuals aged from 1 to 80 years. Our results show that HERV-H, HERV-K, and HERV-W, but not HERV-E, are transcriptionally active in the test population already in the early childhood. In addition, the transcriptional levels of HERV-H, HERV-K, and HERV-W change significantly during the life span, albeit with distinct patterns. Our results, reinforce the hypothesis of a physiological correlation between HERVs activity and the different stages of life in humans. Studies aiming at identifying the factors, which are responsible for these changes during the individual's life, are still needed. Although the observed phenomena are presumably subjected to great variability, the basal transcriptional activity of each individual, also depending on the different ages of life, must be carefully considered in all the studies involving HERVs as causative agents of disease.

Homocysteine, cysteine, folate and vitamin B12 status in type 2 diabetic patients with chronic kidney disease.

BACKGROUND: Hyperhomocysteinemia (hHcy) is a risk factor in the progression of chronic kidney disease (CKD). In type 2 diabetes (T2D), hHcy is strongly associated with increased risk of cardiovascular disease. Vitamin B12 and folic acid supplementation have been reported to lower homocysteine (tHcy) levels, but no data on plasma tHcy, cysteine (Cys), folate and vitamin B12 levels in T2D-CKD patients are reported. PROCEDURES: tHcy and Cys levels were analyzed in 178 T2D-CKD patients by high performance liquid chromatography (HPLC) with fluorescence detection. In addition, we determined folate and vitamin B12 levels using a chemiluminescence method. RESULTS: tHcy and Cys levels were increased in T2D patients, and this rise positively correlated with the CKD stage (P < 0.001). Folate levels were comparable to controls at various CKD stages, whereas vitamin B12 levels were lower, except at stage IV. We did not find any correlation between B-vitamins and levels of tHcy and Cys, regardless of the CKD stage. CONCLUSIONS: This is the first study reporting tHcy, Cys and B-vitamins status in T2D-CKD patients. Although limited to our cohort of 178 patients, our findings could be helpful in clarifying the conflicting literature regarding B-vitamins supplementation. Further studies are necessary before any Hcy-lowering therapy can be safely established in T2D-CKD subjects.

Performances of capillary electrophoresis and HPLC methods in HbA1c determination: diagnostic accuracy in HbS and HbD-Iran variants' presence.

BACKGROUND: Glycated hemoglobin (HbA1c) provides a useful estimate of mean glycemia in patients with diabetes and is directly related to risks for diabetes complications. The aim of this study is to compare a capillary electrophoresis method and two high-performance liquid chromatography (HPLC) cation-exchange analyzers (Variant II (Bio-Rad Laboratories, Inc., Hercules, CA) and G8 (Tosoh Biosciences, San Francisco, CA)) to identify the most reliable method in Hb variants' presence. METHODS: Measurements of HbA1c were carried out in blood samples from 200 Tor Vergata Hospital patients, using G8 Tosoh, and from 107 San Filippo Neri Hospital patients, using Variant II Bio-Rad methods. All samples were analyzed by Capillarys 2 Flex Piercing (FP; Sebia, Lisses, France). RESULTS: There was a good concordance between the results of capillary electrophoresis and HPLC methods (R(2) = 0.99, P < 0.0001 for G8 HPLC; R(2) = 0.99, P < 0.0001 for Variant II HPLC). During the study, we observed that some Hb variants, HbS and HbD-Iran, can alter the HbA1c level. CONCLUSIONS: Since the HbA1c test is now recommended for diagnosing diabetes, and minimal variation of the concentration affects the clinical therapy, it is very important that the results are reliable and interference-free. Capillarys 2-FP analyzer is suitable for this purpose and sometimes it showed some advantages with respect to the HPLC analyzers tested, especially when Hb variants are present.

Influence of dialysis techniques and alternate vitamin supplementation on homocysteine levels in patients with known MTHFR genotypes.

BACKGROUND: Treatment with folic acid and vitamin B12 appears capable of reducing total plasma homocysteine levels (tHcy), but it is unknown whether vitamin B12 alone reduces tHcy values. In this study we investigate the effects of alternate vitamins supplementation on homocysteine levels in patients treated by diffusive and convective dialysis techniques. METHODS: 74 patients were randomized blindly into two groups of 37 subjects each. The first group was treated initially with vitamin B12 for 2 months and with folic acid for the following 2 months. The second group was treated initially with folic acid. A wash out period of 2 months followed the treatment in both groups. RESULTS: Total homocysteine levels decreased in both groups following the alternate vitamins therapy and dialysis, without significant difference between diffusive and convective techniques. Surprisingly, after the wash-out period, tHcy increased remarkably, regardless of the dialysis procedure used. At the end of the study, folate levels showed a higher reduction with haemodialysis compared to haemodiafiltration. In contrast, vitamin B12 levels showed a significant increase using diffusive haemodialysis, confirming a decisive role of membrane performance. CONCLUSIONS: In conclusion we show for the first time that, even if total homocysteine levels decreased in both dialysis procedures, the convective techniques demonstrate a superior capacity on the reduction of tHcy levels compared to the diffusive method. Moreover, the lower depletion of vitamin B12 by diffusive techniques could determine a higher reduction of folate levels, demonstrating the decisive role of the membrane performance in the treatment of this patients.

Human endogenous retroviruses and ADHD.

OBJECTIVES: Several lines of evidences suggest that human endogenous retroviruses (HERVs) are implicated in the development of many complex diseases with a multifactorial aetiology and a strong heritability, such as neurological and psychiatric diseases. Attention deficit hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that results from a complex interaction of environmental, biological and genetic factors. Our aim was to analyse the expression levels of three HERV families (HERV-H, K and W) in patients with ADHD. METHODS: The expression of retroviral mRNAs from the three HERV families was evaluated in peripheral blood mononuclear cells (PBMCs) from 30 patients with ADHD and 30 healthy controls by quantitative RT-PCR. RESULTS: The expression levels of HERV-H are significantly higher in patients with ADHD compared to healthy controls, while there are no differences in the expression levels of HERV-K and W. CONCLUSIONS: Since the ADHD aetiology is due to a complex interaction of environmental, biological and genetic factors, HERVs may represent one link among these factors and clinical phenotype of ADHD. A future confirmation of HERV-H overexpression in a larger number of ADHD patients will make possible to identify it as a new parameter for this clinical condition, also contributing to deepen the study on the role of HERVs in the neurodevelopment diseases.

Atherosclerosis, dyslipidemia, and inflammation: the significant role of polyunsaturated Fatty acids.

Phospholipids play an essential role in cell membrane structure and function. The length and number of double bonds of fatty acids in membrane phospholipids are main determinants of fluidity, transport systems, activity of membrane-bound enzymes, and susceptibility to lipid peroxidation. The fatty acid profile of serum lipids, especially the phospholipids, reflects the fatty acid composition of cell membranes. Moreover, long-chain n-3 polyunsatured fatty acids decrease very-low-density lipoprotein assembly and secretion reducing triacylglycerol production. N-6 and n-3 polyunsatured fatty acids are the precursors of signalling molecules, termed "eicosanoids," which play an important role in the regulation of inflammation. Eicosanoids derived from n-6 polyunsatured fatty acids have proinflammatory actions, while eicosanoids derived from n-3 polyunsatured fatty acids have anti-inflammatory ones. Previous studies showed that inflammation contributes to both the onset and progression of atherosclerosis: actually, atherosclerosis is predominantly a chronic low-grade inflammatory disease of the vessel wall. Several studies suggested the relationship between long-chain n-3 polyunsaturated fatty acids and inflammation, showing that fatty acids may decrease endothelial activation and affect eicosanoid metabolism.

Vitamin D deficiency in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder affecting, among others, the endocrine system, with derangement of steroid hormones functions. Vitamin D is a steroid recognized for its role in calcium homeostasis. In addition, vitamin D influences muscle metabolism by genomic and non-genomic actions, including stimulation of the insulin-like-growth-factor 1 (IGF1), a major regulator of muscle trophism. To verify the presence of vitamin D deficit in DM1 and its possible consequences, serum 25-hydroxyvitamin D (25(OH)D), calcium, parathormone (PTH), and IGF1 levels were measured in 32 DM1 patients and in 32 age-matched controls. Bone mineral density (BMD) and proximal muscle strength were also measured by DXA and a handheld dynamometer, respectively. In DM1 patients, 25(OH)D levels were reduced compared to controls, and a significant decrease of IGF1 was also found. 25(OH)D levels inversely correlated with CTG expansion size, while IGF1 levels and muscle strength directly correlated with levels of 25(OH)D lower than 20 and 10 ng/ml, respectively. A significantly higher percentage of DM1 patients presented hyperparathyroidism as compared to controls. Calcium levels and BMD were comparable between the two groups. Oral administration of cholecalciferol in 11 DM1 patients with severe vitamin D deficiency induced a normal increase of circulating 25(OH)D, ruling out defects in intestinal absorption or hepatic hydroxylation. DM1 patients show a reduction of circulating 25(OH)D, which correlates with genotype and may influence IGF1 levels and proximal muscle strength. Oral supplementation with vitamin D should be considered in DM1 and might mitigate muscle weakness.

Tumor type M2-pyruvate-kinase levels in pleural fluid versus plasma in cancer patients: a further tool to define the need for invasive procedures.

OBJECTIVE: Pleural effusion is a common diagnostic problem and a challenge to the thoracic surgeon. The analysis of serum and body fluids for tumor markers is an established diagnostic procedure. Among various markers, tumors are linked to the overexpression of a glycolytic isoenzyme, M2-pyruvate-kinase (M2-PK). This preliminary study evaluated this enzyme as a tumor marker to differentiate malignant from benign pleural effusion. METHODS: The tumor M2-PK concentration was measured in the EDTA-plasma and pleural fluid of 34 patients with an established diagnosis of cancer, either primary of the chest (18) or secondary to chest (16) and in 34 controls with benign effusion. The concentration was quantitatively determined by an enzyme-linked immunosorbent assay. The cut-off level between negative and positive values of the tumor M2-PK was defined as the benign group's mean+2SD (95% percentile). True-positives, false-positives, true-negatives, and false-negatives, were determined with 'positive' referring to histologically proven malignant effusion and 'negative' referred to as nonmalignant effusions. Sensitivity, specificity, positive predictive value, and negative predictive value were assessed. RESULTS: The cut-off value was established at 7.61 U/ml for plasma and 32.9 U/ml for pleural fluid. Both plasma and pleural fluid levels of tumor M2-PK were significantly higher in patients with known chest malignancy, either primary or metastatic, compared to nonmalignant effusions (p<0.001). Sensitivity in pleural fluid was significantly higher compared to plasma (85.7% vs 76.2%; p<0.01). Moreover, negative predictive value was higher for pleural fluid compared to plasma (79.4% vs 70.8; p<0.01) CONCLUSIONS: Tumor M2-PK marker is useful in differentiating malignant from benign pleural effusions. Moreover, its sensitivity and NPV in pleural fluid are significantly higher compared to plasma. The usefulness of such a test is not strictly diagnostic but aims at excluding poorly performing patients from further invasive procedures. Thus, the inclusion of M2-PK within a panel of well-known tumor markers such as CEA, MCA, Ca 125 and Ca 19-9, may help in increasing the overall sensitivity and specificity.