Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene

Hypophosphatasia (HPP) is a genetic disease caused by one or several mutations in ALPL gene encoding the tissue-nonspecific alkaline phosphatase affecting the mineralization process. Due to its low prevalence and lack of recognition, this metabolic disorder is generally confused with other more frequent bone disorders. An assessment of serum total alkaline phosphatase (ALP) levels was performed in 78,590 subjects. Pyridoxal-5′-phosphate (PLP) concentrations were determined and ALPL gene was sequenced in patients potentially affected by HPP. Functional validation of the novel mutations found was performed using a cell-based assay. Our results showed persistently low serum ALP levels in 0.12% of subjects. Among the studied subjects, 40% presented with HPP-related symptoms. Nine of them (~28%) had a history of fractures, 5 (~16%) subjects showed chondrocalcinosis and 4 (~13%) subjects presented with dental abnormalities. Eleven subjects showed increased PLP concentrations. Seven of them showed ALPL gene mutations (2 of the mutations corresponded to novel genetic variants). In summary, we identified two novel ALPL gene mutations associated with adult HPP. Using this protocol, almost half of the studied patients were diagnosed with HPP. Based on these results, the estimated prevalence of mild HPP in Spain could be up to double than previously reported.Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (with support from NIH P41-GM103311)grants from Alexion and FEIOMM, by Instituto de Salud Carlos III (grants PI18-00803 and PI18-01235)co-funding from FEDER and by Junta de Andalucía (grant PI-0207-2016)GM-N is supported by the predoctoral program from Instituto de Salud Carlos III (FI17/00178) and by the Research Initiation Grants for Official Master Students program from the University of Granada (2017)PJR is a Ramon y Cajal Researcher from the MINECO (RYC-2015-18383) at GENyO and University of Granada

Fiber intake and all-cause mortality in the Prevención con Dieta Mediterránea (PREDIMED) study

Background: Few observational studies have examined the effect of dietary fiber intake and fruit and vegetable consumption on total mortality and have reported inconsistent results. All of the studies have been conducted in the general population and typically used only a single assessment of diet. Objective: We investigated the association of fiber intake and whole-grain, fruit, and vegetable consumption with all-cause mortality in a Mediterranean cohort of elderly adults at high cardiovascular disease (CVD) risk by using repeated measurements of dietary information and taking into account the effect of a dietary intervention. Design: We followed up 7216 men (55-75 y old) and women (60-75 y old) at high CVD risk in the Prevención con Dieta Mediterránea (PREDIMED) trial for a mean of 5.9 y. Data were analyzed as an observational cohort. Participants were initially free of CVD. A 137-item validated food-frequency questionnaire administered by dietitians was repeated annually to assess dietary exposures (fiber, fruit, vegetable, and whole-grain intakes). Deaths were identified through the continuing medical care of participants and the National Death Index. An independent, blinded Event Adjudication Committee adjudicated causes of death. Cox regression models were used to estimate HRs of death during follow-up according to baseline dietary exposures and their yearly updated changes. Results: In up to 8.7 y of follow-up, 425 participants died. Baseline fiber intake and fruit consumption were significantly associated with lower risk of death [HRs for the fifth compared with the first quintile: 0.63 (95% CI: 0.46, 0.86; P = 0.015) and 0.59 (95% CI: 0.42, 0.82; P = 0.004), respectively]. When the updated dietary information was considered, participants with fruit consumption .210 g/d had 41% lower risk of all-cause mortality (HR: 0.59; 95% CI: 0.44, 0.78). Associations were strongest for CVD mortality than other causes of death. Conclusion: Fiber and fruit intakes are associated with a reduction in total mortality. PREDIMED was registered at controlled-trials.com as ISRCTN35739639. © 2014 American Society for Nutrition.Peer Reviewe

Adelante / Endavant

Séptimo desafío por la erradicación de la violencia contra las mujeres del Institut Universitari d’Estudis Feministes i de Gènere "Purificación Escribano" de la Universitat Jaume

Beta-Adrenergic Receptor 1 Selective Antagonism Inhibits Norepinephrine-Mediated TNF-Alpha Downregulation in Experimental Liver Cirrhosis

<div><h3>Background</h3><p>Bacterial translocation is a frequent event in cirrhosis leading to an increased inflammatory response. Splanchnic adrenergic system hyperactivation has been related with increased bacterial translocation. We aim at evaluating the interacting mechanism between hepatic norepinephrine and inflammation during liver damage in the presence of bacterial-DNA.</p> <h3>Animals and Methods</h3><p>Forty-six mice were included in a 16-week protocol of CCl₄-induced cirrhosis. Laparotomies were performed at weeks 6, 10, 13 and 16. A second set of forty mice injected with a single intraperitoneal dose of CCl₄ was treated with saline, 6-hydroxidopamine, Nebivolol or Butoxamine. After 5 days, mice received <em>E. coli</em>-DNA intraperitoneally. Laparotomies were performed 24 hours later. Liver bacterial-DNA, norepinephrine, TNF-alpha, IL-6 and beta-adrenergic receptor levels were measured.</p> <h3>Results</h3><p>Bacterial-DNA translocation was more frequent in CCl₄-treated animals compared with controls, and increased as fibrosis progressed. Liver norepinephrine and pro-inflammatory cytokines were significantly higher in mice with <em>vs</em> without bacterial-DNA (319.7±120.6 vs 120.7±68.6 pg/g for norepinephrine, 38.4±6.1 vs 29.7±4.2 pg/g for TNF-alpha, 41.8±7.4 vs 28.7±4.3 pg/g for IL-6). Only beta-adrenergic receptor-1 was significantly increased in treated <em>vs</em> control animals (34.6±7.3 <em>vs</em> 12.5±5.3, p = 0.01) and correlated with TNF-alpha, IL-6 and norepinephrine hepatic levels in animals with bacterial-DNA. In the second set of mice, cytokine levels were increased in 6-hydroxidopamine and Nebivolol (beta-adrenergic receptor-1 antagonist) treated mice compared with saline. Butoxamine (beta-adrenergic receptor-2 antagonist) didn’t inhibit liver norepinephrine modulation of pro-inflammatory cytokines.</p> <h3>Conclusions</h3><p>Beta-adrenergic receptor-1 mediates liver norepinephrine modulation of the pro-inflammatory response in CCl₄-treated mice with bacterial-DNA.</p> </div

Liver NE, cytokine and ADRB levels in control and CCl4-treated mice in basal and protocol Stages.

*<p> <i>p<0,05 compared with basal and the stage control group;</i></p>$<p> <i>p<0,05 compared with CCl4-mice in Stage 1</i></p><p> <i>Stage 1: liver bactDNA≤25%; Stage 2: liver bactDNA>65%; ADRB: beta-adrenergic receptor</i></p

Interaction between inflammatory and sympathetic activities in the liver.

<p>Correlations between ADRB1 levels and NE, TNF-alpha and IL-6 levels in the liver of CCl₄-treated mice according to bactDNA translocation. r: Spearman’s rank correlation coefficient in bactDNA+ mice; NE: norepinephrine; ADRB1: beta-1 adrenergic receptor; bactDNA: bacterial DNA.</p

Design of study protocols.

<p>(A) Study Protocol I. Balb/c mice were included in a 16-week protocol for induction of liver cirrhosis by oral administration of CCl₄. A subgroup of animals (six CCl₄-treated and four control mice) was subjected to laparotomy at different study weeks to follow progression of fibrosis, inflammation, bactDNA translocation and NE hepatic levels. CCl₄: carbon tetrachloride; ig.: intragastrically. (B) Study Protocol II. CCl₄-treated Balb/c mice were distributed to receive saline, 6-OHD for sympathetic denervation, Nebivolol for beta-adrenergic receptor (ADRB)-1 blockade, or Butoxamine for ADRB-2 blockade. Within each group, animals were further distributed to receive saline or <i>E. coli</i>-DNA. Laparotomies were performed in all subgroups. CCl₄: carbon tetrachloride; ip: intraperitoneally; 6-OHD: 6-hydroxydopamine; sc: subcutaneously;</p

Inflammatory and sympathetic activities in the liver.

<p>(A) Liver levels of NE, TNF-alpha and IL-6 in CCl₄-treated mice according to bactDNA translocation into liver. *p<0.05 compared with bactDNA-negative CCl₄-treated mice. (B) Correlations between liver NE, TNF-alpha and IL-6 in CCl₄-treated mice according to bactDNA translocation into liver. r: Spearman’s rank correlation coefficient in bactDNA+ mice; NE: norepinephrine; bactDNA: bacterial DNA.</p