Methylation of the Sclerostin (SOST) Gene in Serum Free DNA: A New Bone Biomarker?

Introduction: Cell-free DNA (cfDNA) methylation is an important molecular biomarker, which provides information about the regulation of gene expression in the tissue of origin. There is an inverse correlation between SOST gene methylation and expression levels. Methods: We analyzed SOST promoter methylation in cfDNA from serum, and compared it with DNA from blood and bone cells from patients undergoing hip replacement surgery. We also measured cfDNA methylation in 28 osteoporotic patients at baseline and after 6 months of antiosteoporotic therapy (alendronate, teriparatide, or denosumab). Results: SOST gene promoter methylation levels in serum cfDNA were very similar to those of bone-derived DNA (79% ± 12% and 82% ± 7%, respectively), but lower than methylation levels in blood cell DNA (87% ± 10%). Furthermore, there was a positive correlation between an individual's SOST DNA methylation values in serum and bone. No differences in either serum sclerostin levels or SOST methylation were found after 6-months of therapy with antiosteoporotic drugs. Conclusions: Our results suggest that serum cfDNA does not originate from blood cells, but rather from bone. However, since we did not confirm changes in this marker after therapy with bone-active drugs, further studies examining the correlation between bone changes of SOST expression and SOST methylation in cfDNA are needed to confirm its potential role as a bone biomarker.

Comparison of metabolic effects of aripiprazole, quetiapine and ziprasidone after 12 weeks of treatment in first treated episode of psychosis.

This randomized open-label study compared the incidence of metabolic side effects of aripiprazole, ziprasidone and quetiapine in a population of medication-naïve first-episode psychosis patients. A total of 202 subjects were enrolled. Body weight, body mass index, leptin, fasting lipids and fasting glycaemic parameters were measured at baseline and at 3 months follow-up. A hundred and sixty-six patients completed the follow-up and were included in the analyses. A high proportion of patients experienced a significant weight increase (>7% of their baseline weight): 23% ziprasidone (n=12), 32% with quetiapine (n=16) and 45% with aripiprazole (n=31). Patients treated with aripiprazole gained significantly more weight than the patients in the ziprasidone group (1.2 kg [SD=4.1] versus 4.3 kg [SD=4.8], respectively). The increase in leptin levels was greater in women treated with aripiprazole than in those treated with ziprasidone (p=0.030). Mean prolactin levels significantly increased in patients treated with quetiapine and ziprasidone but not in those treated with aripiprazole. Patients treated with quetiapine and aripiprazole showed a significant increase in total cholesterol and LDL-cholesterol plasma levels. Quetiapine-treated patients resulted in a higher increase in LDL-cholesterol than patients treated with ziprasidone (p=0.021). No other significant differences between groups were found. No significant changes in glycaemic parameters were observed. Our results suggest that ziprasidone has a lower liability for inducing weight gain and lipid abnormalities than aripiprazole or quetiapine.

Course of weight gain and metabolic abnormalities in first treated episode of psychosis: the first year is a critical period for development of cardiovascular risk factors.

Data on the long-term metabolic side-effects associated with antipsychotics are scarce. Prospective longitudinal studies in medication-naive patients with a first episode of psychosis are a valuable source of information as they provide an assessment prior to the antipsychotic exposure and minimize the effect of potential confounding factors. The aim of this study was to assess the course of weight gain and the incidence of metabolic abnormalities during the first 3 yr of antipsychotic treatment. Data were collected from a cohort of 170 first-episode psychosis patients. They were randomly assigned to haloperidol (32%); olanzapine (32%) and risperidone (36%). The dose used was flexible. The initial antipsychotic treatment was changed when required, based on clinical response and tolerability. The results showed that the mean weight gain at 3 yr was 12.1 kg (s.d. = 10.7). It appeared to increase rapidly during the first year (85% of the total mean weight gain) and then stabilized gradually over time. Total cholesterol, LDL-cholesterol and triglyceride levels followed a similar trajectory with a significant increase only during the first year. No significant changes were detected in the mean values of glycaemic parameters. Two patients with a family history of diabetes developed diabetes type II. At short-term the factors positively associated with weight gain were lower body mass index, male gender and olanzapine treatment. At long-term, functional status and clinical response were the main predictors. The results of our study indicate that the first year of antipsychotic treatment is a critical period for weight gain and metabolic changes. Identification of weight gain patterns may help to inform studies that aim to prevent or mitigate the metabolic adverse events associated with antipsychotic therapy.

Double treatment with paricalcitol-associated calcifediol and cardiovascular risk biomarkers in haemodialysis.

BACKGROUND: The deficit of 25-hydroxyvitamin D (25OHD) associated with secondary hyperparathyroidism (SHPT) is a frequent finding in chronic kidney disease (CKD) patients on haemodialysis (HD). These events are associated with increased morbidity and mortality rates of cardiovascular (CV) origin. Adequate 25OHD serum levels as well as the use of selective vitamin D receptor activators (VDRA) have been shown to have beneficial and independent effects on bone mineral metabolism and cardiovascular risk. Currently, there is still controversy regarding the type of supplementation needed by CKD patients on HD. OBJECTIVE: The aim of our study was to evaluate whether there is a benefit of combination therapy with 25OHD, calcifediol and a VDRA, oral paricalcitol, on bone-mineral metabolism and inflammatory markers, compared to single treatment with each of these in a group of patients on HD. MATERIAL AND METHOD: We performed a prospective study of 6 months, involving 26 patients in our HD unit. We randomised patients into two groups: group 1 (G1) received oral paricalcitol treatment at doses of 1 mcg/day. Group 2 (G2) was treated with 1 ampoule calcifediol/wk (0.266 mg/wk=16 000U) orally. After 3 months of treatment, calcifediol and paricalcitol were added to the G1 and G2 respectively at the same doses, keeping these treatments together for 3 months to complete the 6 months of follow-up. Laboratory tests were performed at months 0, 3 and 6, measuring in all patients serum markers of 25OHD, calcium (Ca), phosphorus (P) and PTH. Bone turnover markers measured were: alkaline phosphatase (AP), aminoterminal propeptide of procollagen type 1 (Pinp1) and carboxyl-terminal telopeptide of type I collagen (CrossLaps), and inflammatory markers: IL-8. We also collected data on levels of insulin, glucose, haemoglobin, erythropoiesis-stimulating agents (ESAs) and rates of resistance to EPO and HOMA (homeostasis model assessment). RESULTS: We detected a deficit of 25-hydroxyvitamin D in all patients studied, with a mean of 13.67 ± 4.81 ng/ml. Supplementation with oral calcifediol significantly corrects this deficit without evidence of toxicity (35.36 ± 33.68 ng/ml in G1 at 6 months and 59.21 ± 26.50 ng/ml in G2 at 3 months). Paricalcitol treatment significantly reduces PTH levels in G1 at 3 months (P<.039). We also noted a decrease in bone marker Pinp1 with paricalcitol, pointing to a possible direct effect on bone cells (P<.001). Both treatment with paricalcitol and with calcifediol produced a significant decrease in levels of IL-8 (P<.001), a known inflammatory marker, drawing attention to a trend towards better response to erythropoiesis-stimulating agents (ESAs), possibly related to the decrease in inflammation. The HOMA index did not change significantly. CONCLUSION: Based on our results, we cannot conclude that the association of calcifediol and paricalcitol produces advantages over the effect of each drug separately. In addition, Paricalcitol by itself appears to have a direct effect on cellular bone remodelling.

Tratamiento doble con calcifediol asociado a paricalcitol y biomarcadores de riesgo cardiovascular en hemodiálisis / Double treatment with paricalcitol-associated calcifediol and cardiovascular risk biomarkers in haemodialysis

Introducción: El déficit de 25-hidroxivitamina D (25OHD) asociado a un hiperparatiroidismo secundario son hallazgos frecuentes en pacientes con enfermedad renal crónica (ERC) en hemodiálisis (HD). Estos hechos se asocian con un incremento de la morbimortalidad de origen cardiovascular (CV). Niveles séricos adecuados de 25OHD, así como el uso de activadores selectivos del receptor de vitamina D (AsRVD), han demostrado tener efectos beneficiosos sobre el metabolismo óseo-mineral y el riesgo CV de manera independiente. Actualmente aún existe controversia respecto al tipo de suplementación que precisan los pacientes con ERC en HD. Objetivo: El objetivo de nuestro estudio fue evaluar si existe beneficio alguno en el tratamiento combinado de 25OHD, calcifediol oral y AsRVD, paricalcitol oral sobre el metabolismo óseo-mineral y marcadores inflamatorios, respecto al tratamiento único con cada uno de ellos, en un grupo de pacientes de HD. Material y métodos: Realizamos un estudio prospectivo de 6 meses de duración sobre 26 pacientes de nuestra (..) (AU)

Background: The deficit of 25-hydroxyvitamin D (25OHD) associated with secondary hyperparathyroidism (SHPT) are frequent findings in patients with chronic kidney disease (CKD) on hemodialysis (HD). These events are associated with increased morbidity and mortality of cardiovascular (CV). 25OHD adequate serum levels as well as the use of selective activators of the vitamin D receptor (AsRVD) have been shown to have beneficial effects on bone metabolism and mineral and cardiovascular risk independently. Currently there is still controversy regarding the type of supplementation needed by patients with CKD on HD. Aims: The aim of our study was to evaluate whether there is benefit in combination therapy with 25OHD, calcifediol and a AsRVD, oral paricalcitol on bone-mineral metabolism and inflammatory markers, compared to single treatment with each of them in a group HD patients. Material and methods: A prospective study of 6 months, over 26 patients in our HD unit. We randomized patients into two groups: group 1 (G1) received oral paricalcitol treatment at doses of 1mcg/day. Group 2 (G2) was treated with 1 ampoule calcifediol/wk (0.266mg/wk=16.000U) orally. After 3 months of treatment, was added (..) (AU)

Long-term effect of haloperidol, olanzapine, and risperidone on plasma prolactin levels in patients with first-episode psychosis.

OBJECTIVE: The main goal of this study was to assess the long-term effect of haloperidol, olanzapine, and risperidone on serum prolactin levels in a naturalistically treated first-episode psychosis population. METHODS: Patients included in this study were drawn from a prospective, randomized, open-label clinical trial. Prolactin levels were measured in 110 patients with medication-naive first-episode psychosis at baseline, 3 months, and 1 year. RESULTS: A repeated-measures analysis of variance revealed a significant difference between treatments (F = 17.28, P < 0.001). At 1-year follow-up, most patients in the haloperidol and olanzapine arms had prolactin values that fell within the reference range. Patients treated with risperidone experienced a significant increase at 3 months resulting in prolactin levels above the reference range in 90% of men and 87% of women. The levels showed a tendency to decrease at 1 year, although still more than 70% of the values remained above the normative range. Sexual adverse drug reactions at 1 year assessed by the Udvalg for Kliniske Undersogelser scale showed that a higher percentage (39.3%) of patients had symptoms in the risperidone group compared to the olanzapine group (24%) or haloperidol group (20%), but the difference did not reach statistical significance (P = 0.281). CONCLUSION: Olanzapine and haloperidol treatments do not significantly affect serum prolactin levels at long term. After 1 year, elevated prolactin levels persist in most patients treated with risperidone.

Alterations of liver function test in patients treated with antipsychotics.

The prevalence of alterations of liver function tests in patients treated with a wide range of antypsychotics is unknown. The aim of this study was to analyze the effects of antipsychotics on liver function tests in a population of schizophrenic outpatients. Concentrations of AST, ALT, GGT, alkaline phosphatase, albumin, and bilirubin were determined in 54 patients fitting DSM-IV criteria of schizophrenia, and the same number of sex- and age-matched healthy subjects. Assessments included the Clinical Global Impression (CGI) and the Positive and Negative Syndrome Scale (PANSS) in addition to treatment related variables. Transaminases concentrations were slightly elevated in study patients compared to healthy controls, but without statistical significance. Alkaline phosphatase showed higher values in schizophrenic patients. Albumin and bilirubin were lower in study patients. Liver function tests abnormalities were found in about 10% of schizophrenic patients treated with antipsychotics. Treatment with depot phenotiazines induces alteration in these tests more frequently than treatment with other antipsychotics. PANSS negative subscale scores directly correlated with alkaline phosphatase and inversely correlated with albumin. A substantial number of patients in treatment with antipsychotic drugs present alterations of liver function tests. Both pharmacological and clinical factors could be related with these alterations.

Effect of transdermal nitroglycerin on inflammatory mediators in patients with peripheral atherosclerotic vascular disease.

OBJECTIVE: To demonstrate that nitroglycerin improves biological markers of arterial inflammation in patients with peripheral vascular disease. BACKGROUND: Atherosclerosis is an inflammatory disease in which there is an increase in active inflammation markers such as C-reactive protein and other factors released by endothelial cells. Nitroglycerin acts by a chemical liberation of nitric oxide. We have previously published the results from several controlled clinical trials confirming an anti-inflammatory action of nitroglycerin. METHODS: Forty patients with peripheral vascular disease entered a randomized, double-blind, placebo-controlled pilot study for 6 weeks. Twenty-one patients were treated with continuous application of a transdermal nitroglycerin patch (15 mg/24 hours) on the anterior face of the thigh. Venous blood samples were obtained before treatment and 2 and 6 weeks after. We measured plasma levels of C-reactive protein, cGMP (also intraplatelet cGMP), E-selectin, ICAM, VCAM-1, IL-6, and nitrites/nitrates. RESULTS: No biological parameter was modified in the placebo group. On the contrary, nitroglycerin significantly reduced plasma levels of C-reactive protein and sE-selectin and increased the levels of intraplatelet cGMP. CONCLUSIONS: The results of this preliminary study show that nitroglycerin has an anti-inflammatory action in patients with peripheral vascular disease. This may provide a new therapeutic approach to understanding the efficacy of nitrovasodilators in the improvement of atherosclerotic syndromes.