Refining patterns of MEF2C effects in white matter microstructure and psychiatric features.

Several GWAS reported Myocyte Enhancer Factor 2 C (MEF2C) gene associations with white matter microstructure and psychiatric disorders, and MEF2C involvement in pathways related to neuronal development suggests a common biological factor underlying these phenotypes. We aim to refine the MEF2C effects in the brain relying on an integrated analysis of white matter and psychiatric phenotypes in an extensively characterized sample. This study included 870 Brazilian adults (47% from an attention-deficit/hyperactivity disorder outpatient clinic) assessed through standardized psychiatric interviews, 139 of which underwent a magnetic resonance imaging scan. We evaluated variants in the MEF2C region using two approaches: 1) a gene-wide analysis, which uses the sum of polymorphism effects, and 2) SNP analyses, restricted to the independent variants within the gene. The outcomes included psychiatric phenotypes and fractional anisotropy for brain images. Results: The gene-wide analyses pointed to a nominal association between MEF2C and the Temporal Portion of the Superior Longitudinal Fasciculus (SLFTEMP). The SNP analysis identified four independent variants significantly associated with SLFTEMP and one (rs4218438) with Substance Use Disorder. Our findings showing specific associations of MEF2C variants with temporal-frontal circuitry components may help to elucidate how the MEF2C gene underlies a broad range of psychiatric phenotypes since these regions are relevant to executive and cognitive functions.

PEMFCs Model-Based Fault Diagnosis: A Proposal Based on Virtual and Real Sensors Data Fusion.

Proton Exchange Membrane Fuel Cells (PEMFCs) are critical components in renewable hybrid systems, demanding reliable fault diagnosis to ensure optimal performance and prevent costly damages. This study presents a novel model-based fault diagnosis algorithm for commercial hydrogen fuel cells using LabView. Our research focused on power generation and storage using hydrogen fuel cells. The proposed algorithm accurately detects and isolates the most common faults in PEMFCs by combining virtual and real sensor data fusion. The fault diagnosis process began with simulating faults using a validated mathematical model and manipulating selected input signals. A statistical analysis of 12 residues from each fault resulted in a comprehensive fault matrix, capturing the unique fault signatures. The algorithm successfully identified and isolated 14 distinct faults, demonstrating its effectiveness in enhancing reliability and preventing performance deterioration or system shutdown in hydrogen fuel cell-based power generation systems.

Measuring Heat Stress for Human Health in Cities: A Low-Cost Prototype Tested in a District of Valencia, Spain.

Nowadays, the measurement of heat stress indices is of principal importance due to the escalating impact of global warming. As temperatures continue to rise, the well-being and health of individuals are increasingly at risk, which can lead to a detrimental effect on human performance and behavior. Hence, monitoring and assessing heat stress indices have become necessary for ensuring the safety and comfort of individuals. Thermal comfort indices, such as wet-bulb globe temperature (WBGT), Tropical Summer Index (TSI), and Predicted Heat Strain (PHS), as well as parameters like mean radiant temperature (MRT), are typically used for assessing and controlling heat stress conditions in working and urban environments. Therefore, measurement and monitoring of these parameters should be obtained for any environment in which people are constantly exposed. Modern cities collect and publish this relevant information following the Smart City concept. To monitor large cities, cost-effective solutions must be developed. This work presents the results of a Heat Stress Monitoring (HSM) system prototype network tested in the Benicalap-Ciutat Fallera district in Valencia, Spain. The scope of this work is to design, commission, and test a low-cost prototype that is able to measure heat stress indices. The Heat Stress Monitoring system comprises a central unit or receiver and several transmitters communicating via radiofrequency. The transmitter accurately measures wind speed, air temperature, relative humidity, atmospheric pressure, solar irradiation, and black globe temperature. The receiver has a 4G modem that sends the data to an SQL database in the cloud. The devices were tested over one year, showing that radio data transmission is reliable up to 700 m from the receiver. The system's power supply, composed of a Photovoltaic panel and Lithium-ion batteries, provided off-grid capabilities to the transmitter, with a tested backup autonomy of up to 36 days per charge. Then, indicators such as WBGT, TSI, and MRT were successfully estimated using the data collected by the devices. The material cost of a 12-point network is around EUR 2430 with a competitive price of EUR 190 per device.

Identification of Pre-Renal and Intrinsic Acute Kidney Injury by Anamnestic and Biochemical Criteria: Distinct Association with Urinary Injury Biomarkers.

Acute kidney injury (AKI) is a syndrome of sudden renal excretory dysfunction with severe health consequences. AKI etiology influences prognosis, with pre-renal showing a more favorable evolution than intrinsic AKI. Because the international diagnostic criteria (i.e., based on plasma creatinine) provide no etiological distinction, anamnestic and additional biochemical criteria complement AKI diagnosis. Traditional, etiology-defining biochemical parameters, including the fractional excretion of sodium, the urinary-to-plasma creatinine ratio and the renal failure index are individually limited by confounding factors such as diuretics. To minimize distortion, we generated a composite biochemical criterion based on the congruency of at least two of the three biochemical ratios. Patients showing at least two ratios indicative of intrinsic AKI were classified within this category, and those with at least two pre-renal ratios were considered as pre-renal AKI patients. In this study, we demonstrate that the identification of intrinsic AKI by a collection of urinary injury biomarkers reflective of tubular damage, including NGAL and KIM-1, more closely and robustly coincide with the biochemical than with the anamnestic classification. Because there is no gold standard method for the etiological classification of AKI, the mutual reinforcement provided by the biochemical criterion and urinary biomarkers supports an etiological diagnosis based on objective diagnostic parameters.

Mycobacterium tuberculosis Cell Wall Antigens Induce the Formation of Immune Complexes and the Development of Vasculitis in an Experimental Murine Model.

Tuberculosis (TB) of the central nervous system (CNS) presents high mortality due to brain damage and inflammation events. The formation and deposition of immune complexes (ICs) in the brain microvasculature during Mycobacterium tuberculosis (Mtb) infection are crucial for its pathobiology. The relevance of ICs to Mtb antigens in the pathogenesis of CNS-TB has been poorly explored. Here, we aimed to establish a murine experimental model of ICs-mediated brain vasculitis induced by cell wall antigens of Mtb. We administered a cell wall extract of the prototype pathogenic Mtb strain H37Rv to male BALB/c mice by subcutaneous and intravenous routes. Serum concentration and deposition of ICs onto blood vessels were determined by polyethylene glycol precipitation, ELISA, and immunofluorescence. Histopathological changes in the brain, lung, spleen, liver, and kidney were evaluated by hematoxylin and eosin staining. Our results evidenced that vasculitis developed in the studied tissues. High serum levels of ICs and vascular deposition were evident in the brain, lung, and kidneys early after the last cell wall antigen administration. Cell wall Mtb antigens induce strong type III hypersensitivity reactions and the development of systemic vasculitis with brain vascular changes and meningitis, supporting a role for ICs in the pathogenesis of TB.

The course of attention-deficit/hyperactivity disorder through midlife.

The course of ADHD from childhood up to young adulthood has been characterized in several studies. However, little is known about the course of symptoms into middle age and beyond. This study aims to evaluate predictors of ADHD trajectories in midlife based on three assessments. The follow-up sample comprised 323 adults with ADHD, evaluated at baseline and seven and thirteen years later, from the average ages of 34 up to 47 years old. ADHD status at reassessments was used to characterize trajectories. Demographics, ADHD features, comorbidities, and polygenic scores for ADHD and genetically correlated psychiatric disorders were evaluated to predict ADHD trajectories. Study retention rate was 67% at T2 (n = 216) and 62% at T3 (n = 199). Data from patients evaluated three times showed that 68.8% coursed stable, 25.5% unstable, and 5.7% remission trajectory of ADHD. Women, individuals with more severe syndromes, higher frequency of comorbidities at reassessments, and genetic liability to depression present a higher probability of a stable trajectory. Our findings shed light on midlife ADHD trajectories and their gender, genomic and clinical correlates.

Pathophysiological mechanisms underlying a rat model of triple whammy acute kidney injury.

Simultaneous administration of certain antihypertensive (renin-angiotensin system inhibitors and diuretics) and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a renal toxicity syndrome known as "triple whammy" acute kidney injury (TW-AKI), yet poorly characterized at the pathophysiological level, as no specific experimental model exists on which to conduct preclinical research. Herein, we generated and characterized a rat model of TW-AKI (0.7 mg/kg/day trandolapril +400 mg/kg/day ibuprofen +20 mg/kg/day furosemide). Double treatments involving the NSAID caused a subclinical acute kidney injury, as they reduced glomerular filtration rate to a significant but not sufficient extent to increase Crpl concentration. Only the triple treatment generated an overt AKI with increased Crpl provided that animals were under partial water ingestion restriction. Histological examination revealed no evidence of tissue renal injury, and no proteinuria or makers of renal damage were detected in the urine. These findings, along with a normal fractional excretion of sodium and glucose, indicated that these drug combinations produce a prerenal type of AKI. In fact, blood pressure and renal blood flow were also reduced (most markedly following the triple combination), although renal dysfunction was more pronounced than expected for the corresponding pressure drop, supporting a key pathological role of the interference with renal autoregulation mechanisms. In summary, prerenal TW-AKI only occurs when volemia is challenged (i.e., by furosemide in partially water-deprived animals) under the effects of renin-angiotensin system inhibitors and NSAIDs. This model will facilitate further pathophysiological knowledge for a better diagnosis and clinical handling of this syndrome.

Off-axis spiral phase mirrors for generating high-intensity optical vortices.

In this work, we present a novel, to the best of our knowledge, and practical method for generating optical vortices in high-power laser systems. Off-axis spiral phase mirrors are used at oblique angles of incidence in the beam path after amplification and compression, allowing for the generation of high-power optical vortices in almost any laser system. An off-axis configuration is possible via modification of the azimuthal gradient of the spiral phase helix and is demonstrated with a simple model using a discrete spiral staircase. This work presents the design, fabrication, and implementation of off-axis spiral phase mirrors in both low- and high-power laser systems.

A meta-analysis of preclinical studies using antioxidants for the prevention of cisplatin nephrotoxicity: implications for clinical application.

Cisplatin is an effective chemotherapeutic drug whose clinical use and efficacy are limited by its nephrotoxicity, which affects mainly the renal tubules and vasculature. It accumulates in proximal and distal epithelial tubule cells and causes oxidative stress-mediated cell death and malfunction. Consequently, many antioxidants have been tested for their capacity to prevent cisplatin nephrotoxicity. In this study, we made a systematic review of the literature and meta-analyzed 152 articles, which tested the nephroprotective effect of isolated compounds or mixtures of natural origin on cisplatin nephrotoxicity in preclinical models. This meta-analysis identified the most effective candidates and examined the efficacy obtained by antioxidants administered by the oral and intraperitoneal routes. By comparing with a recent, similar meta-analysis performed on clinical studies, this article identifies a disconnection between preclinical and clinical research, and contextualizes, discusses, and integrates the existing preclinical information toward the optimized selection of candidates to be further explored (clinical level). Despite proved efficacy, this article discusses the barriers limiting the clinical development of natural mixtures, such as those in extracts from Calendula officinalis flowers and Heliotropium eichwaldii roots. On the contrary, isolated compounds are more straightforward candidates, among which arjunolic acid and quercetin stand out in this meta-analysis.

Systematic review and meta-analysis of the efficacy of clinically tested protectants of cisplatin nephrotoxicity.

INTRODUCTION: Cisplatin is a potent antineoplastic drug that has been widely used to treat a number of solid tumors. However, a high incidence of renal damage observed in patients has led researchers to search for alternate strategies that prevent or at least reduce the cisplatin-induced nephrotoxicity. The objective of the present study was to conduct a systematic review and a subsequent meta-analysis to evaluate and identify compounds with effective antitumor activity and lesser side effects that could provide protection against cisplatin-induced nephrotoxicity. METHODS: The study included all placebo-controlled trials published up to December 2017 that met the inclusion criteria. A total of 22 articles were finally included to extract the following information: number of patients, doses of cisplatin and protectant, qualitative (acute kidney injury incidence) and quantitative (plasma creatinine, blood urea nitrogen, and creatinine clearance) indicators of renal function. The odds ratio or the mean difference (95% confidence interval) of each parameter was calculated for each study and group of studies. RESULTS: The results of this meta-analysis show that there is great variability in the nephroprotective capacity of a variety of products evaluated. Of all the compounds tested, only magnesium sulfate and cystone were found to exert protective effects. However, more studies need to be conducted to confirm these results. CONCLUSIONS: The administration of 1 g of Mg i.v. seems to be the best strategy for the prevention of cisplatin nephrotoxicity.

Laser-assisted in-situ keratomileusis (LASIK) with a mechanical microkeratome compared to LASIK with a femtosecond laser for LASIK in adults with myopia or myopic astigmatism.

BACKGROUND: Laser-assisted in-situ keratomileusis (LASIK) is a surgical procedure that corrects refractive errors. This technique creates a flap of the outermost parts of the cornea (epithelium, bowman layer, and anterior stroma) to expose the middle part of the cornea (stromal bed) and reshape it with excimer laser using photoablation. The flaps can be created by a mechanical microkeratome or a femtosecond laser. OBJECTIVES: To compare the effectiveness and safety of mechanical microkeratome versus femtosecond laser in LASIK for adults with myopia. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 2); Ovid MEDLINE; Embase; PubMed; LILACS; ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no date or language restrictions. We searched the reference lists of included trials. We searched the electronic databases on 22 February 2019. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of LASIK with a mechanical microkeratome compared to a femtosecond laser in people aged 18 years or older with more than 0.5 diopters of myopia or myopic astigmatism. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 16 records from 11 trials enrolling 943 adults (1691 eyes) with spherical or spherocylindrical myopia, who were suitable candidates for LASIK. Five hundred and forty-seven participants (824 eyes) received LASIK with a mechanical microkeratome and 588 participants (867 eyes) with a femtosecond laser. Each trial included between nine and 360 participants. In six trials, the same participants received both interventions. Overall, the trials were at an uncertain risk of bias for most domains. At 12 months, data from one trial (42 eyes) indicates no difference in the mean uncorrected visual acuity (logMAR scale) between LASIK with a mechanical microkeratome and LASIK with a femtosecond laser (mean difference (MD) -0.01, 95% confidence interval (CI) -0.06 to 0.04; low-certainty evidence). Similar findings were observed at 12 months after surgery, regarding participants achieving 0.5 diopters within target refraction (risk ratio (RR) 0.97, 95% CI 0.85 to 1.11; 1 trial, 79 eyes; low-certainty evidence) as well as mean spherical equivalent of the refractive error 12 months after surgery (MD 0.09, 95% CI -0.01 to 0.19; 3 trials, 168 eyes [92 participants]; low-certainty evidence). Based on data from three trials (134 eyes, 66 participants), mechanical microkeratome was associated with lower risk of diffuse lamellar keratitis compared with femtosecond laser (RR 0.27, 95% CI 0.10 to 0.78; low-certainty evidence). Thus, diffuse lamellar keratitis was a more common adverse event with femtosecond laser than with mechanical microkeratome, decreasing from an assumed rate of 209 per 1000 people in the femtosecond laser group to 56 per 1000 people in the mechanical microkeratome group. Data from one trial (183 eyes, 183 participants) indicates that dry eye as an adverse event may be more common with mechanical microkeratome than with femtosecond laser, increasing from an assumed rate of 80 per 1000 people in the femtosecond laser group to 457 per 1000 people in the mechanical microkeratome group (RR 5.74, 95% CI 2.92 to 11.29; low-certainty evidence). There was no evidence of a difference between the two groups for corneal haze (RR 0.33, 95% CI 0.01 to 7.96; 1 trial, 43 eyes) and epithelial ingrowth (RR 1.04, 95% CI 0.11 to 9.42; 2 trials, 102 eyes [50 participants]). The certainty of evidence for both outcomes was very low. AUTHORS' CONCLUSIONS: Regarding the visual acuity outcomes, there may be no difference between LASIK with mechanical microkeratome and LASIK with femtosecond laser. Dry eye and diffuse lamellar keratitis are likely adverse events with mechanical microkeratome and femtosecond laser, respectively. The evidence is uncertain regarding corneal haze and epithelial ingrowth as adverse events of each intervention. The limited number of outcomes reported in the included trials, some with potentially significant risk of bias, makes it difficult to draw a firm conclusion regarding the effectiveness and safety of the interventions investigated in this review.

Measurement of Social Processes at the Neighborhood Level in Baltimore City.

Small-area ecological research is critical to inform place-based interventions at the neighborhood level; however, objective measurement of the social context has been limited. The current study extends the application of the Neighborhood Inventory for Environmental Typology (NIfETy) through the development and evaluation of measures of social context for a longer period of observation (3 years) and at a larger area of aggregation (census tract clusters) compared to previous studies using measures at the block-face level from a single observation. Observations from the 172-item inventory were collected from a random sample of block faces (n = 793) in Baltimore City annually over a three-year period. Through a multistep process including replication of previous measures, data reduction, and factor analysis, six unique neighborhood-level indices were generated to describe the environmental context: drug and alcohol use, violence, physical disorder, epicenter, youth activity, and improvements. An assessment of measurement consistency and validity provided support for some indices, while others had notable limitations. These indices can assist local policymakers and public health practitioners assessing the needs of individual neighborhoods and evaluating the effectiveness of place-based interventions designed to improve the neighborhood environment and population health outcomes.

Relationship between Night Shifts and Risk of Breast Cancer among Nurses: A Systematic Review.

BACKGROUND AND OBJECTIVES: The incidence of breast cancer worldwide has increased in recent decades, accounting for 1 in 3 neoplasms in women. Besides, nurses are mainly represented by the female collective, most of them, undertaking working conditions with intensive rotative and night shifts due to the 24-h pace of work of this profession. The objective of this study was to assess the possible relationship between shift work, especially night-time work, and the development of breast cancer among nurses. MATERIALS AND METHODS: A systematic review of the literature was carried out through the consultation of the following databases: Cochrane Plus Library, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Science, ScienceDirect, Scopus, and Dialnet. Records were selected between 2010 and 2020, in Spanish and English, which covered the association between breast cancer diagnosed among nursing professionals and rotating night shifts. RESULTS: A total of 12 studies were identified after critical reading. Most of the studies found an association between breast cancer and consecutive rotating night shifts prolonged over time. Among the associated factors, the alteration of the circadian rhythm influenced the expression of peripheral clock genes, which was the same as reproductive hormones. The risk of breast cancer in nurses increased during early adulthood and after 5 or more years with 6 or more consecutive nights. CONCLUSIONS: The different studies of this review show significant associations between breast cancer and prolonged rotating night shifts. Similarly, there is a relationship between the alterations in certain circadian rhythm markers (such as melatonin), epigenetic markers (such as telomeres), and breast cancer that would require more studies in order to corroborate these findings.

Effects of pericytes and colon cancer stem cells in the tumor microenvironment.

Colorectal cancer (CRC) is one type of tumor with the highest frequency and mortality worldwide. Although current treatments increase patient survival, it is important to detect CRC in early stages; however, most CRC, despite responding favorably to treatment, develop resistance and present recurrence, a situation that will inevitably lead to death. In recent years, it has been shown that the main reason for drug resistance is the presence of colon cancer stem cells (CSC). Pericytes are also capable of tumor homing and are important cellular components of the tumor microenvironment (TME), contributing to the formation of vessels and promoting metastasis; however, they have not been considered very important as a therapeutic target in cancer. In this review, we highlight the contribution of pericytes and cancer stem cells to some classical hallmarks of cancer, namely, tumor angiogenesis, growth, metastasis, and evasion of immune destruction, and discuss therapies targeting pericytes and cancer stem cells in CRC.

Differences in magnitude and rate of change in adult obesity distribution by age and sex in Mexico, Colombia and Peru, 2005-2010.

OBJECTIVE: Unequal obesity distributions among adult populations have been reported in low- and middle-income countries, but mainly based on data of women of reproductive age. Moreover, incorporation of ever-changing skewed BMI distributions in analyses has been a challenge. Our study aimed to assess magnitude and rates of change in BMI distributions by age and sex. DESIGN: Shapes of BMI distributions were estimated for 2005 and 2010, and their changes were assessed, using the generalized additive model for location, scale and shape (GAMLSS) and assuming BMI follows a Box-Cox power exponential (BCPE) distribution. SETTING: Nationally representative, repeated cross-sectional health surveys conducted between 2005 and 2013 in Mexico, Colombia and Peru. SUBJECTS: Adult men and non-pregnant women aged 20-69 years. RESULTS: Whereas women had more right-shifted and wider BMI distributions than men in almost all age groups across the countries in 2010, men in their 30s-40s experienced more rapid increases in BMI between 2005 and 2010, notably in Peru. The highest increase in overweight and obesity prevalence was observed among Peruvian men of 35-39 years, with a 5-year increase of 21 percentage points. CONCLUSIONS: The BCPE-GAMLSS method is an alternative to analyse measurements with time-varying distributions visually, in addition to conventional indicators such as means and prevalences. Consideration of differences in BMI distributions and their changes by sex and age would provide vital information in tailoring relevant policies and programmes to reach target populations effectively. Increases in BMI portend increases of obesity-associated diseases, for which preventive and preparative actions are urgent.

N-acetylcysteine transforms necrosis into apoptosis and affords tailored protection from cisplatin cytotoxicity.

Nephrotoxicity is the main limitation to the dosage and anticancer efficacy of cisplatin. Cisplatin produces tubular epithelial cell apoptosis and necrosis depending on the concentration of the drug. Protection from cisplatin nephrotoxicity must therefore tackle both cell death modes. For its ability to reduce cisplatin reactivity, in addition to its antioxidant effect, we tested and found that N-acetylcysteine (NAC) was most effective at inhibiting cisplatin cytotoxicity. NAC has no significant effect on cell death induced by either cycloheximide or Fas activation, indicating a rather selective action. Pt-DNA-binding experiments suggest that the differential effectiveness of NAC is due to its capacity to quench cisplatin reactivity inside the cell. NAC abolishes cisplatin-induced apoptosis, and transforms the necrosis induced by high concentrations of cisplatin into apoptosis. In fact, NAC allows the anti-apoptotic molecule Bcl-2 to reduce the cell death caused by pro-necrotic concentrations of cisplatin, to a significantly greater extent than in the absence of NAC. In rats, a dosage of NAC that significantly ameliorates cisplatin nephrotoxicity, has little effect on gentamicin nephrotoxicity. These characteristics provide NAC with a rationale as a potential nephroprotectant specifically tailored to and especially effective for therapeutic courses with platinated antineoplastics, which prompts to deepening into further preclinical knowledge, and to initiate clinical studies with NAC and mixed therapies composed of NAC and antiapoptotic drugs.

Probing the Time Structure of the Quark-Gluon Plasma with Top Quarks.

The tiny droplets of quark gluon plasma (QGP) created in high-energy nuclear collisions experience fast expansion and cooling with a lifetime of a few fm/c. Despite the information provided by probes such as jet quenching and quarkonium suppression, and the excellent description by hydrodynamical models, direct access to the time evolution of the system remains elusive. We point out that the study of hadronically decaying W bosons, notably in events with a top-antitop quark pair, can provide key novel insight into the time structure of the QGP. This is because of a unique feature, namely a time delay between the moment of the collision and that when the W-boson decay products start interacting with the medium. Furthermore, the length of the time delay can be constrained by selecting specific reconstructed top-quark momenta. We carry out a Monte Carlo feasibility study and find that the LHC has the potential to bring first limited information on the time structure of the QGP. Substantially increased LHC heavy-ion luminosities or future higher-energy colliders would open opportunities for more extensive studies.

Influence Of Angiogenic Mediators And Bone Remodelling In Paget´s Disease Of Bone.

Paget´s disease of bone (PDB) is characterized by increased bone resorption followed by an excessive compensatory bone formation, with an abnormal bone structure with altered mechanical properties. Pagetic bone also has a higher vascularization and marrow fibrosis. Despite of pagetic bone being a highly vascularized tissue, there are no studies on the plasma levels of angiogenic mediators in the different states of the disease; moreover, the effect of PDB treatment on plasma levels of these angiogenic mediators is not very well known. The aim of this study was to analyse plasma levels of cytokines implicated in the increased bone turnover (OPG, RANKL, sclerostin) and hypervascularization (VEGF, PGF, ENG) observed in PDB and their evolution and response to zoledronic acid treatment in 70 PDB patients, 29 with an active disease measured by plasma alkaline phosphatase (ALP). Plasma ALP concentration was higher in active PDB than in inactive PDB patients, whereas there were no differences in OPG, RANKL, sclerostin, VEGF, PGF and ENG plasma levels between active and inactive PDB patients. ALP decreased at 3 and 12 months after zoledronic acid treatment. RANKL levels were reduced and sclerostin levels were increased after 12 months of treatment. PGF levels were lower 12 months after zoledronic acid treatment, whereas there were no differences in plasma VEGF and ENG after zoledronic acid treatment. Summarizing, zoledronic acid treatment is associated to decreases in plasma levels of ALP, RANKL, sclerostin and P1GF in active PDB patients. This treatment may reduce bone turnover and might reduce the pathological vascularisation typical of pagetic bone.

Regulation of miR-29b and miR-30c by vitamin D receptor activators contributes to attenuate uraemia-induced cardiac fibrosis.

BACKGROUND: Uraemic cardiomyopathy, a process mainly associated with increased myocardial fibrosis, is the leading cause of death in chronic kidney disease patients and can be prevented by vitamin D receptor activators (VDRAs). Since some microRNAs (miRNAs) have emerged as regulators of the fibrotic process, we aimed to analyse the role of specific miRNAs in VDRA prevention of myocardial fibrosis as well as their potential use as biomarkers. METHODS: Wistar rats were nephrectomized and treated intraperitoneally with equivalent doses of two VDRAs: calcitriol and paricalcitol. Biochemical parameters, cardiac fibrosis, miRNA (miR-29b, miR-30c and miR-133b) levels in the heart and serum and expression of their target genes collagen I (COL1A1), matrix metalloproteinase 2 (MMP-2) and connective tissue growth factor (CTGF) in the heart were evaluated. RESULTS: Both VDRAs attenuated cardiac fibrosis, achieving a statistically significant difference in the paricalcitol-treated group. Increases in RNA and protein levels of COL1A1, MMP-2 and CTGF and reduced expression of miR-29b and miR-30c, known regulators of these pro-fibrotic genes, were observed in the heart of chronic renal failure (CRF) rats and were attenuated by both VDRAs. In serum, significant increases in miR-29b, miR-30c and miR-133b levels were observed in CRF rats, which were prevented by VDRA use. Moreover, vitamin D response elements were identified in the three miRNA promoters. CONCLUSIONS: VDRAs, particularly paricalcitol, attenuated cardiac fibrosis acting on COL1A1, MMP-2 and CTGF expression, partly through regulation of miR-29b and miR-30c. These miRNAs and miR-133b could be useful serum biomarkers for cardiac fibrosis and also potential new therapeutic targets.