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Aims: The aim of this study was to evaluate the feasibility, safety and outcomes of TAVI performed via the suprasternal brachiocephalic approach in selected patients at high or prohibitive surgical risk who are not eligible for transfemoral or subclavian TAVI., Methods and Results: From March 2014 to March 2016, 26 high-risk patients without transfemoral or subclavian access options were considered for TAVI via a suprasternal brachiocephalic approach. The feasibility of the suprasternal brachiocephalic approach was determined according to computed tomography findings. In 23 (88.4%) patients the procedure was performed as intended, whereas in three (11.5%) patients the approach was converted to a right carotid access. Both self-expanding (n=20, 76.9%) and balloon-expandable prostheses (n=6, 23.1%) were used. At 30 days, no patient had died; there was one major stroke (3.8%) and there were three major vascular access site-related complications (11.5%). After a median follow-up of 317 days (57-705), two patients had died, both from cardiovascular causes, and 19 out of 24 survivors (79.2%) were in New York Heart Association functional Class I or II., Conclusions: This single-centre case series suggests that TAVI using the suprasternal brachiocephalic approach is feasible in selected patients and may represent an additional alternative route in patients who are not eligible for other approaches.

Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with N G -nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-β 1 -stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts., Competing Interests: The authors declare no competing financial interests.

Horizontal gene transfer (HGT) is pervasive in viruses and thought to be a key mechanism in their evolution. On the other hand, strong selective constraints against increasing genome size are an impediment for HGT, rapidly purging horizontally transferred sequences and thereby potentially hindering evolutionary innovation. Here, we explore experimentally the evolutionary fate of viruses with simulated HGT events, using the plant RNA virus Tobacco etch virus (TEV), by separately introducing two functional, exogenous sequences to its genome. One of the events simulates the acquisition of a new function though HGT of a conserved AlkB domain, responsible for the repair of alkylation or methylation damage in many organisms. The other event simulates the acquisition of a sequence that duplicates an existing function, through HGT of the 2b RNA silencing suppressor from Cucumber mosaic virus. We then evolved these two viruses, tracked the maintenance of the horizontally transferred sequences over time, and for the final virus populations, sequenced their genome and measured viral fitness. We found that the AlkB domain was rapidly purged from the TEV genome, restoring fitness to wild-type levels. Conversely, the 2b gene was stably maintained and did not have a major impact on viral fitness. Moreover, we found that 2b is functional in TEV, as it provides a replicative advantage when the RNA silencing suppression domain of HC-Pro is mutated. These observations suggest a potentially interesting role for HGT of short functional sequences in ameliorating evolutionary constraints on viruses, through the duplication of functions., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

This work deals with the mechanical characterization by depth-sensing indentation (DSI) of PLLA and PLDA composites reinforced with micro-particles of Mg (up to 15wt%), which is a challenging task since the indented volume must provide information of the bulk composite, i.e. contain enough reinforcement particles. The composites were fabricated by combining hot extrusion and compression moulding. Physico-chemical characterization by TGA and DSC indicates that Mg anticipates the thermal degradation of the polymers but does not compromise their stability during processing. Especial emphasis is devoted to determine the effect of strain rate and Mg content on mechanical behavior, thus important information about the visco-elastic behavior and time-dependent response of the composites is obtained. Relevant for the intended application is that Mg addition increases the elastic modulus and hardness of the polymeric matrices and induces a higher resistance to flow. The elastic modulus obtained by DSI experiments shows good agreement with that obtained by uniaxial compression tests. The results indicate that DSI experiments are a reliable method to calculate the modulus of polymeric composites reinforced with micro-particles. Taking into consideration the mechanical properties results, PLA/Mg composite could be used as substitute for biodegradable monolithic polymeric implants already in the market for orthopedics (freeform meshes, mini plates, screws, pins, …), craniomaxillofacial, or spine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Current literature suggests that personality disorder comorbidity negatively contributes to both the severity and prognosis of other disorders; however, little literature has been devoted to its influence on borderline personality disorder (BPD). The objective of the present work is to study comorbidity with other personality disorders in a severe clinical sample of patients with BPD, and its relationship with global functionality., Methods: A sample of 65 patients with severe borderline personality disorder was included in the study. Clinical and functionality measures were applied in order to study comorbidity of BPD with other disorders and its relationship with functionality. Associations with other comorbid PDs were analyzed with t-tests and linear correlations., Results: Most patients (87%) presented comorbidity with other PDs. Almost half of the sample (42%) presented more than two PDs, and cluster A (paranoid) and C (obsessive and avoidant) PD were more frequent than cluster B (histrionic and antisocial). Only the presence of avoidant PD predicted a worse functional outcome in the long term (U Mann Withney p<0.01)., Conclusions: Severely impaired BPD patients present greater comorbidity with cluster A and C PDs. Comorbid avoidant personality disorder might negatively predict for prognosis.

We developed biodegradable polymeric coatings loaded with increasing amounts of dexamethasone on composites based on polylactic acid and Mg particles for bone repair. Incorporation of Mg particles into the polymeric matrix improves the compressive behaviour of the polymer. Mg-containing composites release Mg 2+ ions into the culture medium and improve mesenchymal stem cell (MSC) viability, enhance their osteogenic potential and promote the release of angiogenic factors. Dexamethasone-loaded coatings deposited on composites delay Mg 2+ ion dissolution while releasing controlled amounts of the drug, which are highly dependent on initial payload. Release kinetic of dexamethasone from the coatings exhibits a fast initial release of the drug followed by a slower secondary release. Bioactivity of the released dexamethasone was explored by monitoring dose-dependent responses of MSCs and macrophages. Biological effects exerted by the released drug are similar to those observed in cells treated with solutions of the glucocorticoid, indicating that the method employed for inclusion of dexamethasone into the coatings does not impair its bioactive behaviour. Culturing MSCs on dexamethasone-releasing coatings enhances extracellular matrix production and initial induction to osteogenic commitment as a function of drug payload. Dexamethasone incorporated into the coatings presents anti-inflammatory activity, as shown by the decrease in the production of cytokines and angiogenic factors by macrophages and MSCs. Deposition of dexamethasone-releasing coatings on polymer/Mg composites appears to be a promising approach to delay composite degradation at the early stage of implantation and may be useful to attenuate inflammation and adverse foreign body reactions.

Leptin is a protein involved in the regulation of food intake and in the immune and inflammatory responses, among other functions. Evidences demonstrate that obesity is directly associated with high levels of leptin, suggesting that leptin may directly link obesity with the elevated cardiovascular and renal risk associated with increased body weight. Adverse effects of leptin include oxidative stress mediated by activation of NADPH oxidase. The aim of this study was to evaluate the effect of L-carnitine (LC) in rat renal epithelial cells (NRK-52E) exposed to leptin in order to generate a state of oxidative stress characteristic of obesity. Leptin increased superoxide anion (O2 (•) -) generation from NADPH oxidase (via PI3 K/Akt pathway), NOX2 expression and nitrotyrosine levels. On the other hand, NOX4 expression and hydrogen peroxide (H2 O2 ) levels diminished after leptin treatment. Furthermore, the expression of antioxidant enzymes, catalase, and superoxide dismutase, was altered by leptin, and an increase in the mRNA expression of pro-inflammatory factors was also found in leptin-treated cells. LC restored all changes induced by leptin to those levels found in untreated cells. In conclusion, stimulation of NRK-52E cells with leptin induced a state of oxidative stress and inflammation that could be reversed by preincubation with LC. Interestingly, LC induced an upregulation of NOX4 and restored the release of its product, hydrogen peroxide, which suggests a protective role of NOX4 against leptin-induced renal damage. J. Cell. Biochem. 117: 2281-2288, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Flat fatigue specimens of biomedical Ti6Al4V ELI alloy were surface-processed by high pressure waterjet peening (WJP) without abrasive particles using moderate to severe conditions that yield roughness values in the range of those obtained by commercial grit blasting (BL) with alumina particles. Fatigue behavior of WJP and BL specimens was characterized under cyclical uniaxial tension tests (R=0.1). The emphasis was put on a comparative analysis of the surface and subsurface induced effects and in their relevance on fatigue behavior. Within the experimental setup of this investigation it resulted that blasting with alumina particles was less harmful for fatigue resistance than abrasiveless WJP. BL specimens resulted in higher subsurface hardening and compressive residual stresses. Specimens treated with more severe WJP parameters presented much higher mass loss and lower compressive residual stresses. From the analysis performed in this work, it follows that, in addition to roughness, waviness emerges as another important topographic parameter to be taken into account to try to predict fatigue behavior. It is envisaged that optimization of WJP parameters with the aim of reducing waviness and mass loss should lead to an improvement of fatigue resistance., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Neuroimaging is crucial in the presurgical evaluation of patients with medically refractory epilepsy. To improve the moderate sensitivity of [(18) F]fluorodeoxyglucose-positron emission tomography ((18) F-FDG-PET), our aim was to evaluate the usefulness of statistical parametric mapping (SPM) to localize the seizure-onset zone (SOZ) in PET studies deemed normal by visual assessment., Methods: Fifty-five patients with medically refractory epilepsy whose (18) F-FDG-PET was visually evaluated as normal were retrospectively included. Twenty of these patients had undergone surgical intervention. PET images were analyzed by SPM8 using a corrected p-value of p < 0.05 and three uncorrected p-values of p < 0.0001, p < 0.001, and p < 0.005, matched with minimum cluster sizes of k > 0, k > 20, k > 100, and k > 200, respectively. The SPM-identified potential seizure zone (SZ) was compared to the SOZ, which was determined by consensus during patient management meetings in the epilepsy unit, taking into account presurgical tests. Studies in which the SPM-identified potential SZ was concordant with the SOZ were considered "correctly localizing.", Results: The SPM threshold combination with the least restrictive p-value and greatest minimum cluster size achieved the highest rate of correctly localizing studies. When p < 0.005/k > 200 was used, 40% (22/55) of studies were correctly localizing, and the concordance obtained in the surgically intervened subgroup was substantial (к = 0.607, 95% confidence interval [CI] 0.258-0.957), which was comparable to the concordance obtained by magnetic resonance imaging (MRI) (к = 0.783, 95% CI 0.509-1.000)., Significance: SPM offers improved SOZ localization in (18) F-FDG-PET studies that are negative on visual assessment. For this purpose, statistical parametric maps could be thresholded with liberal p-values and restrictive cluster sizes., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

The ductile-to-brittle transition (DBT) behavior of two similar Fe-Cr-Al oxide dispersion strengthened (ODS) stainless steels was analyzed following the Cottrell-Petch model. Both alloys were manufactured by mechanical alloying (MA) but by different forming routes. One was manufactured as hot rolled tube, and the other in the form of hot extruded bar. The two hot forming routes considered do not significantly influence the microstructure, but cause differences in the texture and the distribution of oxide particles. These have little influence on tensile properties; however, the DBT temperature and the upper shelf energy (USE) are significantly affected because of delamination orientation with regard to the notch plane. Whereas in hot rolled material the delaminations are parallel to the rolling surface, in the hot extruded material, they are randomly oriented because the material is transversally isotropic.

Introduction: Double-lumen endotracheal tubes (DL-ETT) and bronchial blockers (BB) have both been used for lung isolation in video-assisted thoracic surgery (VATS). Though not well studied, it is widely thought that a DL-ETT provides faster and better quality lung collapse. The aim of this study was to compare a BB technique vs a left-sided DL-ETT strategy with regard to the time and quality of lung collapse during one-lung ventilation (OLV) for elective VATS., Methods: Forty patients requiring OLV for VATS were randomized to receive a BB (n = 20) or a left-sided DL-ETT (n = 20). The primary endpoint was the time from pleural opening (performed by the surgeon) until complete lung collapse. The time was evaluated offline by reviewing video recorded during the VATS. The quality of lung deflation was also graded offline using a visual scale (1 = no lung collapse; 2 = partial lung collapse; and 3 = total lung collapse) and was recorded at several time points after pleural incision. The surgeon also graded the time to complete lung collapse and quality of lung deflation during the procedure. The surgeon's guess as to which device was used for lung isolation was also recorded., Results: Of the 40 patients enrolled in the study, 20 patients in the DL-ETT group and 18 in the BB group were analyzed. There mean (standard deviation) time to complete lung collapse of the operative lung was significantly faster using the BB compared with using the DL-ETT [7.5 (3.8) min vs 36.6 (29.1) min, respectively; mean difference, 29.1 min; 95% confidence interval, 1.8 to 7.2; P < 0.001]. Overall, a higher proportion of patients in the BB group than in the DL-ETT group achieved a quality of lung collapse score of 3 at five minutes (57% vs 6%, respectively; P < 0.004), ten minutes (73% vs 14%, respectively; P = 0.005), and 20 min (100% vs 25%, respectively; P = 0.002) after opening the pleura. The surgeon incorrectly guessed the type of device used in 78% of the BB group and 50% of the DL-ETT group (P = 0.10)., Conclusion: The time and quality of lung collapse during OLV for VATS was significantly better when using a BB than when using a left-sided DL-ETT. Surgeons could not reliably determine which device was being used based on the time and quality of lung collapse. This trial was registered at ClinicalTrials.gov number, NCT01615263.

Introduction: Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination., Methodology: An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV)., Results: Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk., (Copyright © 2016 SEP y SEPB. Published by Elsevier España. All rights reserved.)

The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of antidepressant pharmacotherapy as the presence of residual depressive symptoms is associated with an increased risk of relapse. Treatment guidelines recommend selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or atypical antidepressants as first-line treatment for moderate to severe MDD. Desvenlafaxine, administered as desvenlafaxine succinate, is an serotonin-norepinephrine reuptake inhibitor approved for the treatment of adults with MDD at the recommended dose of 50 mg/day. The aim of this integrated analysis was to assess the efficacy and safety of desvenlafaxine 50 and 100 mg/day compared with placebo in adult outpatients with MDD. The analysis used data from nine fixed-dose, short-term, placebo-controlled studies in adult outpatients diagnosed with MDD who had depressive symptoms for at least 30 days. Data from 4279 and 4317 patients were pooled for the efficacy and safety analyses, respectively. Statistically significant improvements were observed with desvenlafaxine 50 and 100 mg/day versus placebo for all efficacy endpoints assessed, including improvements in depressive symptoms, response and remission rates, as well as functional and cognitive outcomes. Treatment with desvenlafaxine 50 and 100 mg/day was generally safe and well tolerated. The findings of this integrated analysis of data from a large population of patients with MDD confirmed the antidepressant efficacy of both desvenlafaxine doses and add to previous evidence supporting the efficacy of desvenlafaxine.

In this work, we investigated a new approach to incorporate Mg particles within a PDLLA matrix using a solvent-free commercially available process. PDLLA/Mg composites were manufactured by injection moulding and the effects of Mg incorporated into PDLLA on MSC and macrophage responses were evaluated. Small amounts of Mg particles (≤ 1 wt %) do not cause thermal degradation of PDLLA, which retains its mechanical properties. PDLLA/Mg composites release hydrogen, alkaline products and Mg(2+) ions without changing pH of culture media. Mg-containing materials provide a noncytotoxic environment that enhances MSC viability. Concentration of Mg(2+) ions in extracts of MSCs increases with the increment of Mg content in the composites. Incorporation of Mg particles into PDLLA stimulates FN production, ALP activity, and VEGF secretion in MSCs, an effect mediated by degradation products dissolved from the composites. Degradation products of PDLLA induce an increase in MCP-1, RANTES, and MIP-1α secretion in macrophages while products of composites have minimal effect on these chemokines. Regulation of MSC behavior at the biomaterial's interface and macrophage-mediated inflammatory response to the degradation products is related to the incorporation of Mg in the composites. These findings suggest that including small amounts of Mg particles into polymeric devices can be a valuable strategy to promote osseointegration and reduce host inflammatory response., (© 2015 Wiley Periodicals, Inc.)

This work studies the feasibility of using repetitive-nano-impact tests with a cube-corner tip and low loads for obtaining quantitative fracture toughness values in thin and brittle coatings. For this purpose, it will be assumed that the impacts are able to produce a cracking, similar to the pattern developed for the classical fracture toughness tests in bulk materials, and therefore, from the crack developed in the repetitive impacts it will be possible to evaluate the suitability of the classical indentation models (Anstins and Laugier) for measuring fracture toughness. However, the length of this crack has to be lower than 10% of the total coating thickness to avoid substrate contributions. For this reason, and in order to ensure a small plastic region localized at the origin of the crack tip, low load values (or small distance between the indenter tip and the surface) have to be used. In order to demonstrate the validity of this technique, repetitive-nano-impact will be done in a fine and dense oxide layer (α-Al2O3), which has been developed on the top of oxide dispersion strengthened (ODS) FeCrAl alloys (PM 2000) by thermal oxidation at elevated temperatures. Moreover, it will be shown how it is possible to know with each new impact the crack geometry evolution from Palmqvist crack to half-penny crack, being able to study the proper evolution of the different values of fracture toughness in terms of both indentation models and as a function of the strain rate, ε̇, decreasing. Thereby, fracture toughness values for α-Al2O3 layer decrease from ~4.40MPam , for high ϵ̇ value (10(3)s(-1)), to ~3.21MPam, for quasi-static ϵ̇ value (10(-3)s(-1)). On the other hand, ϵ̇ a new process to obtain fracture toughness values will be analysed, when the classical indentation models are not met. These values are typically found in the literature for bulk α-Al2O3, demonstrating the use of repetitive-nano-impact tests which not only provide qualitative information about fracture resistance of the materials but it also can be used to obtain quantitative information as fracture toughness values in the case of brittle materials., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Absorbable medical devices must be developed in order to have an appropriate degradation rate in agreement with the healing rate of bone in the implantation site. In this work, biodegradable composites formed by a polylactic acid matrix reinforced with 10%wt. magnesium microparticles were processed and their in vitro degradation investigated during 28 days. A joint analysis of the amount of H2 released, the changes in pH in buffered (PBS) and non-buffered media (distilled water), the variations in mass, microstructure and the mechanical performance of the specimens was developed. The main aim was to elucidate the relevance of Mg particles shape on tailoring the degradation kinetics of these novel composites. The results show that the shape of the Mg reinforcing particles plays a crucial role in the degradation rate of PLA/Mg composites, with spherical particles promoting a lower degradation rate than irregular particles. This fact is only partially due to the smaller surface area to volume ratio of the spherical particles. Irregular particles promote a faster formation of cracks and, therefore, an increasingly faster degradation of the polymeric matrix. In every case, the amount of H2 released by the composites was well below that released by monolithic Mg. The pH of PBS during degradation remained always within 7.2 and 7.4. PLA/Mg reinforced with spherical particles retains more than 90% of its mechanical properties after 7 days of immersion and more than 60% after 28 days., Statement of Significance: The increasing demand for temporary orthopaedic implants is the driving force to seek new strategies to decrease costs and simultaneously improve patients comfort as well as simplify surgical procedures. Resorbable medical devices must be developed in order to have an appropriate degradation rate in agreement with the healing rate of bone. We are presenting for the first time results of the degradation kinetics of a new material based on polylactic acid reinforced with 10%wt. Mg microparticles. This work analyzes the relevance of Mg particle shape (irregular and spherical) on tailoring the degradation behaviour of these composites. Conclusions withdrawn from this study help to customize bioabsorbable materials in order to meet the requirements for a specific application and patient., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

We investigated a Ti6Al4V alloy modified by means of laser peening in the absence of sacrificial coatings. As a consequence of the temperature rise during laser focusing, melting and ablation generated an undulated surface that exhibits an important increase in the content of titanium oxides and OH- ions. Human mesenchymal stem cells and osteoblasts cultured on the oxidized alloy develop noticeable filopodia and lamellipodia. Their paxillin-stained focal adhesions are smaller than in cells attached to the untreated alloy and exhibit a marked loss of colocalization with the ends of actin stress fibers. An important imbalance of phosphorylation and/or dephosphorylation of the focal adhesion kinase is detected in cells grown on the oxidized alloy. Although these mechanisms of adhesion are deeply altered, the surface treatment does not affect cell attachment or proliferation rates on the alloy. Human mesenchymal stem cells cultured on the treated alloy in media containing osteogenic inducers differentiate towards the osteoblastic phenotype to a higher extent than those on the untreated surface. Also, the specific functions of human osteoblasts cultured on these media are enhanced on the treated alloy. In summary, laser peening tailors the Ti6Al4V surface to yield an oxidized layer with increased roughness that allows the colonization and activities of bone-lineage cells.

Roughening of Ti6Al4V by blasting with alumina or zirconia particles improves the mechanical fixation of implants by increasing the surface area available for bone/implant apposition. Additional thermal oxidation treatments of the blasted alloy have already shown to be a complementary low-cost solution to enhancing the in vitro biocompatibility and corrosion resistance of the alloy. In this work, the effects of oxidation treatment on a grit blasted Ti6Al4V biomedical alloy have been analysed in order to understand the net effect of the combined treatments on the alloy fatigue properties. Synchrotron radiation diffraction experiments have been performed to measure residual stresses before and after the treatments and microstructural and hardness changes have been determined. Although blasting of Ti6Al4V with small spherical zirconia particles increases the alloy fatigue resistance with respect to unblasted specimens, fatigue strength after oxidation decreases below the unblasted value, irrespective of the type of particle used for blasting. Moreover, at 700°C the as-blasted compressive residual stresses (700MPa) are not only fully relaxed but even moderate tensile residual stresses, of about 120MPa, are found beneath the blasted surfaces. Contrary to expectations, a moderate increase in hardness occurs towards the blasted surface after oxidation treatments. This can be attributed to the fact that grit blasting modifies the crystallographic texture of the Ti6Al4V shifting it to a random texture, which affects the hardness values as shown by additional experiments on cold rolled samples. The results indicate that the oxidation treatment performed to improve biocompatibility and corrosion resistance of grit blasted Ti6Al4V should be carried out with caution since the alloy fatigue strength can be critically diminished below the value required for high load-bearing components., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-κB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Osteoporosis is a frequent complication related to spinal cord injury (SCI), and data on osteoporosis treatment after SCI is scarce. Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis., Introduction: Osteoporosis development is a frequent complication related to SCI, especially at the sublesional level. Nevertheless, data on osteoporosis treatment after SCI is scarce, particularly short term after injury, when the highest bone loss is produced. The aim of this study was to analyze the efficacy of denosumab in the treatment of SCI-related osteoporosis., Methods: Fourteen individuals aged 39 ± 15 years with osteoporosis secondary to recent SCI (mean injury duration 15 ± 4 months) were treated with denosumab for 12 months. Bone turnover markers (BTMs) (PINP, bone ALP, sCTx), 25-hydroxyvitamin D (25OHD) levels and bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were assessed at baseline and at 12 months. All participants received calcium and vitamin D supplementation., Results: At 12 months, SCI denosumab-treated participants showed a significant increase in BMD at TH (+2.4 ± 3.6 %, p = 0.042), FN (+3 ± 3.6 %, p = 0.006), and LS (+7.8 ± 3.7 %, p < 0.001) compared to baseline values. Denosumab treatment was associated with significant decreases in BTMs (bone ALP -42 %, p < 0.001; PINP -58 %, p < 0.001, sCTx -57 %, p = 0.002) at 12 months. BMD evolution was not related to BTM changes or 25OHD serum levels. No skeletal fractures or serious adverse events were observed during follow-up., Conclusions: Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis.

The aim of the present study is to test the efficacy of palmitate paliperidone long-acting injection for patients with borderline personality disorder (BPD). A total of 16 patients with BPD were treated with intramuscular paliperidone palmitate (IMPP) over 12 weeks. Effectiveness measures included the CGI-BPD, HARS, MADRS, BIS-11, and STAXI-2. Functional improvement was assessed using the Global Assessment of Functioning scale. A list of adverse events was provided to clinicians and patients. Treatment with IMPP was associated with a significant average reduction of 1.6 (95% confidence interval: 1192-2008; P>0.01) in CGI-BPD scores and an average increase of psychosocial functioning as scored by the Global Assessment of Functioning scale of 13.3 (95% confidence interval: 8.35-18.31; P>0.01) was obtained. The treatment decreased impulsive-disruptive behaviors and improved general functioning. An acceptable tolerance was observed. The average weight gain was clinically irrelevant despite being statistically significant. No other relevant adverse side effects were reported, with the exception of galactorrhea, which required suspension of treatment in three patients. IMPP seems to be a well-tolerated alternative to other second-generation antipsychotics in the treatment of BPD. More controlled studies replicating these results should be proposed in the future.

Background: Follow-up studies revealed that subjects with borderline personality disorder (BPD) present high rates of clinical remission, although psychosocial functioning often remains impaired. The aim of this study is to evaluate the efficacy of a cognitive rehabilitation intervention versus a psychoeducational program on psychosocial functioning in subjects with BPD., Methods: A multicenter, randomized, and positive-controlled clinical trial was conducted. Seventy outpatients with BPD were randomized to cognitive rehabilitation or psychoeducational group interventions. Participants were evaluated after completion of the intervention period (16 weeks) and after the follow-up period (6 months). Psychosocial functioning, clinical and neuropsychological outcomes were evaluated., Results: No main effects of group or group x time were observed on functionality but a significant effect of time was found. Post-hoc analyses showed that only cognitive rehabilitation increased psychosocial functioning significantly at endpoint. Psychoeducation showed a significant enhancement of depressive symptoms., Conclusions: Cognitive rehabilitation and psychoeducational interventions appeared to show good efficacy in improving disabilities in daily life in subjects with BPD. These interventions are easily implemented in mental health settings and have the advantage of improving general functioning and clinical symptoms., Trial Registration: Clinicaltrials.gov: NCT02033044. Registered 9 January 2014.

To evaluate the effectiveness of pregabalin in patients with resistant generalized anxiety disorder (GAD) and severe depressive symptoms, we carried out a post-hoc analysis of a multicenter, prospective, and observational 6-month study. We included patients who were at least 18 years old, fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for GAD, showed inadequate responses to previous courses of antidepressant treatment, had Montgomery-Asberg Rating Scale scores of at least 35, had not received pregabalin previously, and were prescribed pregabalin upon entry into this study. We included 1815 patients fulfilling the DSM-IV criteria for GAD, and 133 (7.3%) fulfilled the selection criteria for these analyses. Ninety-seven percent of the patients received pregabalin (mean dose: 222 mg/day) in combination with other psychotropics. The Hamilton Anxiety Scale total score was reduced by a mean of 20.3 points (95% confidence interval, 22.1-18.4) (57.2% reduction) at month 6. Pregabalin also ameliorated comorbid depressive symptoms, with a reduction in the mean score of the Montgomery-Asberg Rating Scale of 22.3 points (95% confidence interval, 24.2-20.4) (56.6% reduction). Our results suggest that pregabalin, as part of a combination regimen with antidepressants and/or benzodiazepines, might be effective for the treatment of patients with GAD who have shown inadequate response to previous antidepressants and have severe depressive symptoms.

The carryover effect is a recurring issue in the pharmaceutical field. It may strongly influence the final outcome of an average bioequivalence study. Testing a null hypothesis of zero carryover is useless: not rejecting it does not guarantee the non-existence of carryover, and rejecting it is not informative of the true degree of carryover and its influence on the validity of the final outcome of the bioequivalence study. We propose a more consistent approach: even if some carryover is present, is it enough to seriously distort the study conclusions or is it negligible? This is the central aim of this paper, which focuses on average bioequivalence studies based on 2 × 2 crossover designs and on the main problem associated with carryover: type I error inflation. We propose an equivalence testing approach to these questions and suggest reasonable negligibility or relevance limits for carryover. Finally, we illustrate this approach on some real datasets., (Copyright © 2015 John Wiley & Sons, Ltd.)

Unlabelled: Spinal cord injury (SCI) has been associated with a marked bone loss after injury and a consequent increased risk of osteoporosis. The evaluation of bone mineral density shortly after SCI is a simple and effective method for predicting the development of osteoporosis during the first year after SCI., Introduction: Spinal cord injury (SCI) has been associated with a marked bone loss after injury and a consequent increased risk of osteoporosis and fractures. The aim of this study was to analyze the factors associated with osteoporosis development short-term after SCI., Methods: We included patients with complete recent SCI (<6 months) evaluating bone turnover markers (P1NP, bone ALP, and sCTx), 25-OH-vitamin D (25OHD) levels, and lumbar and femoral BMD (Lunar, Prodigy) at baseline, 6 and 12 months after SCI. The risk factors for osteoporosis analyzed included the following: age, gender, BMI, toxic habits, bone turnover markers, 25OHD levels, lumbar and femoral BMD, level, severity and type of SCI, and days-since-injury. Osteoporosis was defined according to WHO criteria., Results: Thirty-five patients aged 35 ± 16 years were included, and 52 % developed osteoporosis during the 12-month follow-up. These latter patients had lower BMD values at femur and lumbar spine and higher bone turnover markers at baseline. On multivariate analysis, the principal factors related to osteoporosis development were as follows: total femur BMD <1 g/cm(2) (RR, 3.61; 95 % CI 1.30-10.06, p = 0.002) and lumbar BMD <1.2 g/cm(2) at baseline (0.97 probability of osteoporosis with both parameters under these values). Increased risk for osteoporosis was also associated with increased baseline values of bone ALP (>14 ng/mL) (RR 2.40; 95 % CI 1.10-5.23, p = 0.041) and P1NP (>140 ng/mL) (RR 3.08; 95 % CI 1.10-8.57, p = 0.017)., Conclusions: The evaluation of BMD at the lumbar spine and femur short-term after SCI is a simple, effective method for predicting the development of osteoporosis during the first year after SCI. Our results also indicate the need to evaluate and treat these patients shortly after injury.

Objective: High plasma testosterone levels have been associated with aggression, sexual behaviour and social status. The aim of this paper was to study the correlation between basal plasma testosterone levels and personality variables in healthy participants., Materials and Methods: Fifty-four participants were randomly enrolled into this study. Basal plasma testosterone levels were measured between 8:30 am and 10 am. After 24 hours of blood drawing, each subject completed personality questionnaires., Results: Positive correlation between basal plasma testosterone levels and anti-social personality traits in both genders was observed (r = 0.336 and P < 0.018). Also, a positive correlation was observed between basal plasmatestosterone levels and criminal thinking traits (r = 0. 376, P < 0.05) and Millon compulsive (r = 0.386, P < 0.010) in both genders. In female participants, a positive correlation between basal plasmatestosterone levels and psychoticism (r = 0. 25, P < 0.019) and Cloninger AUTO TCI (r = 0.507, P < 0.004) was observed. In males participants positive correlation between baseline plasmatic Testosterone levels and Millon Antisocial trait (r = 0. 544, P < 0.19) and Millon Hypomania trait (r = 0. 485, P < 0.41) and Millon Drug Abuse trait (r = 0.632, P < 0.05) was reported., Conclusion: Our results suggest gender differences in clinical and personality variables related with basal plasma testosterone level. In men, high plasma testosterone levels were associated with clinical traits, substance abuse and hypomania. Women with higher basal testosterone levels showed higher scores on personality self-direction traits.

This aim of this study is to determine the elastoplastic properties of Ni-free Al3FeSi2 intermetallic coatings grown on medical stainless steel under different experimental conditions. Elastoplastic properties are defined by the plasticity index (PI), which correlates the hardness and the Young's modulus. Special emphasis is devoted to correlate the PI with the wear resistance under sliding contact, determined by scratch testing, and fracture toughness, determined by using a novel method based on successive impacts with small loads. With regard to the substrate, the developed coatings are harder and exhibit a lower Young's reduced modulus, irrespective of the experimental conditions. It has been shown that preheating of the samples prior to hot dipping and immersion influences the type and volume fraction of precipitates, which in turn also affect the nanomechanical properties. The higher the preheating temperature is, the greater the Young's reduced modulus is. For a given preheating condition, an increase of the immersion time yields a decrease in hardness. Although apparent friction coefficients of coated specimens are smaller than those obtained on AISI 316 LVM, they increase when using preheating or higher immersion times during processing, which correlates with the PI. The presence of precipitates produces an increase in fracture toughness, with values greater than those presented by samples processed on melted AlSi alloys with lower Si content (12 wt%). Therefore, these intermetallic coatings could be considered "hard but tough", suitable to enhance the wear resistance, especially when using short periods of immersion., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The release of cardiac biomarkers of myocardial injury after transcatheter aortic valve replacement (TAVR) is common, but no data exist on patients undergoing TAVR through a transaortic approach. We aimed to evaluate the incidence and prognostic significance of the increase in cardiac biomarkers in nontransfemoral TAVR candidates, comparing transaortic and transapical approaches., Methods: After excluding patients deemed suitable for transfemoral TAVR, 251 consecutive patients (transaortic, 45; transapical, 206) were prospectively evaluated. Creatine kinase-myocardial band and cardiac troponin T levels were measured at baseline and at 6, 12, 24, 48, and 72 hours after TAVR. Baseline and 6- to 12-month echocardiographic and clinical follow-up were performed., Results: After TAVR, cardiac troponin T increased above the upper normal values in all patients (peak value 0.64 μg/L [IQR, 0.39 to 1.03 μg/L]), whereas creatine kinase-myocardial band levels increased in 88% of patients (transaortic 51%, transapical 96%, p < 0.001; peak value 20.1 μg/L [interquartile range, 14.3 to 31.6 μg/L]). Compared with the transaortic approach, the transapical approach was associated with a greater rise in both cardiac biomarkers (p < 0.001 for both), and a lesser improvement in left ventricular ejection fraction (p = 0.058) and global longitudinal strain (p = 0.039) at 6- to 12-month follow-up. Greater increases of cardiac troponin T levels were independently associated with 30-day and 1-year overall and cardiovascular mortality (p < 0.001 for all). A 15-fold rise in cardiac troponin T levels was the optimal threshold for determining poorer outcomes (p < 0.001)., Conclusions: Periprocedural TAVR-related myocardial injury in nontransfemoral candidates was demonstrated in all patients, but the transapical approach was associated with significantly greater myocardial injury compared with the transaortic approach. A higher degree of myocardial injury translated into reduced left ventricular function improvement and lower early and midterm survival rates., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Spinal cord injury (SCI) has been associated with a marked increase in bone loss and bone remodeling, especially short-term after injury. The absence of mechanical load, mediated by osteocyte mechanosensory function, seems to be a causative factor related to bone loss in this condition. However, the pathogenesis and clinical management of this process remain unclear. Therefore, the aim of the study was to analyze the effect of recent SCI on the Wnt pathway antagonists, sclerostin and Dickkopf (Dkk-1), and their relationship with bone turnover and bone mineral density (BMD) evolution. Forty-two patients (aged 35 ± 14yrs) with a recent (<6months) complete SCI were prospectively included. Sclerostin and Dkk-1, bone turnover markers (bone formation: PINP, bone ALP; resorption: sCTx) and BMD (lumbar spine, proximal femur, total body and lower extremities [DXA]) were assessed at baseline and at 6 and 12 months. The results were compared with a healthy control group. 22/42 patients completed the 12-month follow-up. At baseline, SCI patients showed a marked increase in bone markers (PINP and sCTx), remaining significantly increased at up to 6 months of follow-up. Additionally, they presented significantly increased Dkk-1 values throughout the study, whereas sclerostin values did not significantly change. BMD markedly decreased at the proximal femur (-20.2 ± 5.4%, p < 0.01), total body (-5.7 ± 2.2%, p = 0.02) and lower extremities (-13.1 ± 4.5%, p = 0.01) at 12 months. Consequently, 59% of patients developed densitometric osteoporosis at 12 months. Patients with higher Dkk-1 values (>58 pmol/L) at baseline showed higher sublesional BMD loss. In conclusion, this study shows that short-term after SCI there is a marked increase in bone turnover and bone loss, the latter associated with an increase in Dkk-1 serum levels. The persistence of increased levels of this Wnt antagonist throughout the study and their relationship with the magnitude of bone loss suggests a contributory role of this mediator in this process., (© 2015 American Society for Bone and Mineral Research.)

Fibromyalgia is a chronic pain syndrome associated with numerous somatic symptoms including gastrointestinal manifestations of nonspecific nature. Celiac disease and nongluten sensitivity frequently evolve in adults with gastrointestinal and extraintestinal symptoms similar to those found among patients with fibromyalgia. The objective of the present study was to evaluate the presence of celiac-type symptoms among patients with fibromyalgia in comparison with healthy subjects and with those experienced by adult celiac patients and subjects with gluten sensitivity. A list of typical celiac-type symptoms was developed, comparing the frequency of presentation of these symptoms between patients with fibromyalgia (N = 178) and healthy subjects (N = 131), in addition to those of celiac patients and gluten-sensitive patients reported in the literature. The frequency of presentation of every celiac-type symptom, excepting anemia, was significantly higher among patients with fibromyalgia compared to controls (p < 0.0001). Regarding the existing data in the literature, the prevalence of fatigue, depression, cognitive symptoms and cutaneous lesions predominated among patients with fibromyalgia, whereas the prevalence of gastrointestinal symptoms was higher among patients with fibromyalgia compared to gluten-sensitive patients and was similar among patients with fibromyalgia and celiac disease patient. The symptomatological similarity of both pathologies, especially gastrointestinal symptoms, suggests that at least a subgroup of patients with fibromyalgia could experience subclinical celiac disease or nonceliac gluten intolerance.

In a recent randomized controlled trial comparing vertebroplasty (VP) versus conservative treatment (CT) in patients with symptomatic vertebral fractures (VF), we observed the development of chronic back pain (CBP) in nearly one-quarter of patients. The aim of this study was to identify the risk factors related to the development of severe CBP in these subjects. We evaluated risk factors including visual analog scale (VAS) at baseline and during the 1-year follow-up, age, gender, symptom onset time, number, type and severity of VF at baseline, number of vertebral bodies treated, incident VF, and antiosteoporotic treatment, among others. CBP was considered in patients with VAS ≥ 7 at 12 months. 91/125 patients completed the 12-months follow-up. CBP was observed in 23% of VP-treated patients versus 23% receiving CT. Patients developing CBP after VP showed a longer symptom onset time (82% ≥ 4 months in VP vs. 40% in CT, P = 0.03). On univariate analysis, female gender (OR 1.52; 95% CI 1.47-1.57, P < 0.0001), multiple acute VF (OR 1.79; 95% CI 1.71-1.87, P < 0.0001), VAS ≥ 7 two months after treatment (OR 11.04; 95% CI 6.71-18.17, P < 0.0001), and type of antiosteoporotic drug (teriparatide) (OR 0.12; 95% CI 0.03-0.60, P = 0.0236) were risk factors of CBP development in both groups. In the multivariate analysis, the main risk factors were baseline and post-treatment VAS ≥ 7, longer symptom onset time, and type of antiosteoporotic treatment. In conclusion, 23% of patients with symptomatic osteoporotic VF developed severe CBP independently of the type of treatment. Symptom onset time before VP and persistence of severe CBP after treatment were the main factors related to CBP with teriparatide treatment decreasing the risk of this complication.

Background: This study is done to compare the effect of adjunctive therapy with pregabalin versus usual care (UC) on health-care costs and clinical and patients consequences in generalized anxiety disorder (GAD) subjects with partial response (PR) to a previous selective serotonin reuptake inhibitor (SSRI) course in medical practice in Spain., Methods: Post hoc analysis of patients with PR to SSRI monotherapy enrolled in a prospective 6-month naturalistic study was done. PR was defined as a Clinical Global Impression (CGI) scale score ≥3 and insufficient response with persistence of anxiety symptoms ≥16 in the Hamilton Anxiety Rating Scale (HAM-A). Two groups were analyzed: 1) adjunctive therapy (AT) with pregabalin (150-600 mg/day) to existing therapy and 2) UC (switching to a different SSRI or adding another anxiolytic different than pregabalin). Costs included GAD-related health-care resources utilization. Consequences were a combination of psychiatrist-based measurements [HAM-A, CGI, and Montgomery-Asberg Depression Rating Scale (MADRS)] and patient-reported outcomes [Medical Outcomes Study Sleep (MOS-sleep) scale, disability (World Health Organization Disability Assessment Schedule II (WHO-DAS II) and quality-of-life (Euro Qol-5D (EQ-5D)]. Changes in both health-care costs and scale scores were compared separately at end-of-trial visit by a general linear model with covariates., Results: Four hundred eighty-six newly prescribed pregabalin and 239 UC GAD patients [mean (SD) HAM-A 26.7 (6.9) and CGI 4.1 (0.5)] were analyzed. Adding pregabalin was associated with significantly higher mean (95% CI) score reductions vs. UC in HAM-A [-14.9 (-15.6; -14.2) vs. -11.2 (-12.2; -10.2), p < 0.001] and MADRS [-11.6 (-12.2; -10.9) vs. -7.8 (-8.7; -6.8), p < 0.001]. Changes in all patient-reported outcomes favored significantly patients receiving pregabalin, including quality-of-life gain; 26.4 (24.7; 28.1) vs. 19.4 (17.1; 21.6) in the EQ-VAS, p < 0.001. Health-care costs were significantly reduced in both cohorts yielding similar 6-month costs; €1,565 (1,426; 1,703) pregabalin and €1,406 (1,200; 1,611) UC, p = 0.777. The effect of sex on costs and consequences were negligible., Conclusion: In medical practice, GAD patients with PR to SSRI experienced greater consequence improvements with adjunctive therapy with pregabalin versus UC, without increasing health-care cost. The effect of pregabalin was independent of patient gender.

Background: Modeling count and binary data collected in hierarchical designs have increased the use of Generalized Linear Mixed Models (GLMMs) in medicine. This article presents a systematic review of the application and quality of results and information reported from GLMMs in the field of clinical medicine., Methods: A search using the Web of Science database was performed for published original articles in medical journals from 2000 to 2012. The search strategy included the topic "generalized linear mixed models","hierarchical generalized linear models", "multilevel generalized linear model" and as a research domain we refined by science technology. Papers reporting methodological considerations without application, and those that were not involved in clinical medicine or written in English were excluded., Results: A total of 443 articles were detected, with an increase over time in the number of articles. In total, 108 articles fit the inclusion criteria. Of these, 54.6% were declared to be longitudinal studies, whereas 58.3% and 26.9% were defined as repeated measurements and multilevel design, respectively. Twenty-two articles belonged to environmental and occupational public health, 10 articles to clinical neurology, 8 to oncology, and 7 to infectious diseases and pediatrics. The distribution of the response variable was reported in 88% of the articles, predominantly Binomial (n = 64) or Poisson (n = 22). Most of the useful information about GLMMs was not reported in most cases. Variance estimates of random effects were described in only 8 articles (9.2%). The model validation, the method of covariate selection and the method of goodness of fit were only reported in 8.0%, 36.8% and 14.9% of the articles, respectively., Conclusions: During recent years, the use of GLMMs in medical literature has increased to take into account the correlation of data when modeling qualitative data or counts. According to the current recommendations, the quality of reporting has room for improvement regarding the characteristics of the analysis, estimation method, validation, and selection of the model.

Mixed virus infections in plants are common in nature. The outcome of such virus-virus interactions ranges from cooperation and coexistence (synergism) to mutual exclusion (antagonism). A priori, the outcome of mixed infections is hard to predict. To date, the analyses of plant virus mixed infections were limited to reports of emerging symptoms and/or to qualitative, at best quantitative, descriptions of the accumulation of both viruses. Here, we show that evolutionary game theory provides an adequate theoretical framework to analyze mixed viral infections and to predict the long-term evolution of the mixed populations., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Arabidopsis thaliana DBP1 belongs to the plant-specific family of DNA-binding protein phosphatases. Although recently identified as a novel host factor mediating susceptibility to potyvirus, little is known about DBP1 targets and partners and the molecular mechanisms underlying its function. Analyzing changes in the phosphoproteome of a loss-of-function dbp1 mutant enabled the identification of 14-3-3λ isoform (GRF6), a previously reported DBP1 interactor, and MAP kinase (MAPK) MPK11 as components of a small protein network nucleated by DBP1, in which GRF6 stability is modulated by MPK11 through phosphorylation, while DBP1 in turn negatively regulates MPK11 activity. Interestingly, grf6 and mpk11 loss-of-function mutants showed altered response to infection by the potyvirus Plum pox virus (PPV), and the described molecular mechanism controlling GRF6 stability was recapitulated upon PPV infection. These results not only contribute to a better knowledge of the biology of DBP factors, but also of MAPK signalling in plants, with the identification of GRF6 as a likely MPK11 substrate and of DBP1 as a protein phosphatase regulating MPK11 activity, and unveils the implication of this protein module in the response to PPV infection in Arabidopsis.

Background: The development of renal fibrosis is a consequence of arterial hypertension. L-carnitine plays an essential role in the β-oxidation of fatty acids, and we have previously demonstrated hypotensive, antioxidant, and anti-inflammatory effects of L-carnitine in arterial hypertension. This work aims to analyze the effect of L-carnitine on renal fibrosis and to explore the participation of peroxisome-proliferator activated receptor (PPAR)-γ in this effect., Methods: Four groups or rats were used: control, treated with L-carnitine, treated with L-NAME, and treated with L-carnitine + L-NAME. Cultured rat kidney cells were also used to examine the role of PPAR-γ in L-carnitine effect., Results: An increase in the expression of collagen, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), Nox2, and Nox4 was found in the kidney of L-NAME-treated rats. Hypertensive rats presented with an expansion of renal fibrotic areas, which was also accompanied by overexpression of proinflammatory cytokines, interleukin (IL)-1β, and IL-6. A reduction in the expression of PPAR-γ and in that of anti-inflammatory IL-10 was found in the kidney of these rats. Simultaneous treatment with L-carnitine attenuated the renal fibrosis (which correlated with a reduction of plasma TGF-β1 levels) and the pro-oxidative and proinflammatory status reported in L-NAME groups, with a concomitant increase in the expression of PPAR-γ. Furthermore, the antifibrotic effect of L-carnitine could be blocked by PPAR-γ inhibition., Conclusions: This study confirms the efficacy of L-carnitine against hypertension-associated renal fibrosis from in vivo and in vitro studies and suggests that the L-carnitine effect occurs in a PPAR-γ-dependent manner.

Transcription factors (TFs) regulate gene expression through binding to cis-regulatory specific sequences in the promoters of their target genes. In contrast to the genetic code, the transcriptional regulatory code is far from being deciphered and is determined by sequence specificity of TFs, combinatorial cooperation between TFs and chromatin competence. Here we addressed one of these determinants by characterizing the target sequence specificity of 63 plant TFs representing 25 families, using protein-binding microarrays. Remarkably, almost half of these TFs recognized secondary motifs, which in some cases were completely unrelated to the primary element. Analyses of coregulated genes and transcriptomic data from TFs mutants showed the functional significance of over 80% of all identified sequences and of at least one target sequence per TF. Moreover, combining the target sequence information with coexpression analysis we could predict the function of a TF as activator or repressor through a particular DNA sequence. Our data support the correlation between cis-regulatory elements and the sequence determined in vitro using the protein-binding microarray and provides a framework to explore regulatory networks in plants.

Grit blasting is used as a cost-effective method to increase the surface roughness of metallic biomaterials, as Ti6Al4V and 316 LVM, to enhance the osteointegration, fixation and stability of implants. Samples of these two alloys were blasted by using alumina and zirconia particles, yielding rough (up to Ra~8μm) and nearly smooth (up to Ra~1μm) surfaces, respectively. In this work, we investigate the sub-surface induced microstructural effects and its correlation with the mechanical properties, with special emphasis in the fatigue behavior. Blasting with zirconia particles increases the fatigue resistance whereas the opposite effect is observed using alumina ones. As in a conventional shot penning process, the use of rounded zirconia particles for blasting led to the development of residual compressive stresses at the surface layer, without zones of stress concentrators. Alumina particles are harder and have an angular shape, which confers a higher capability to abrade the surface, but also a high rate of breaking down on impact. The higher roughness and the presence of a high amount of embedded alumina particles make the blasted alloy prone to crack nucleation. Interestingly, the beneficial or detrimental role of blasting is more intense for the Ti6Al4V alloy than for the 316 steel. It is proposed that this behavior is related to their different strain hardening exponents and the higher mass fraction of particles contaminating the surface. The low value of this exponent for the Ti6Al4V alloy justifies the expected low sub-surface hardening during the severe plastic deformation, enhancing its capability to soft during cyclic loading., (© 2013 Published by Elsevier Ltd.)

The analysis of concordance among repeated measures has received a huge amount of attention in the statistical literature leading to a range of different approaches. However, because all the approaches are able to assess the closeness among the readings taken on the same subject, the conclusions about the degree of concordance should be similar regardless the approach applied. Here, two indices to assess the concordance among continuous repeated measures, the intraclass correlation coefficient and the total deviation index, are applied and compared in two case examples. The first example concerns the repeatability of individual nutrient allocation strategy assessed by stable isotope analysis. The second example dealt with the assessment of the concordance of functional magnetic resonance imaging data that shows spatial correlation. The results differ depending upon the approach applied leading to contradictory conclusions about the degree of concordance. The reason behind these results is discussed reaching the conclusion that the total deviation index is just assessing agreement among repeated measurements, whereas the intraclass correlation coefficient assesses the concept of distinguishability among subjects that involves agreement among repeated measurements and spread of subjects at once. Therefore, the best way to select the right approach is to understand the right question behind the research hypothesis., (Copyright © 2013 John Wiley & Sons, Ltd.)

Aims: The NADPH oxidases constitute a major source of superoxide anion (·O2(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by transforming growth factor-β₁ (TGF-β₁). We investigated whether a chronic treatment with P144, a peptide synthesized from type III TGF-β₁ receptor, inhibited NADPH oxidases in the renal cortex of spontaneously hypertensive rats (SHR)., Results: Here, we show that chronic administration of P144 significantly reduced the NADPH oxidase expression and activity as well as the oxidative stress observed in control vehicle-treated SHR (V-SHR). In addition, P144 was also able to reduce the significant increase in the renal fibrosis and in mRNA expression of different components of collagen metabolism, as well as in the levels of connective tissue growth factor observed in V-SHR. Finally, TGF-β₁-stimulated NRK52E exhibited a significant increase in NADPH oxidase expression and activity as well as a TGF-β₁-dependent intracellular pathway that were inhibited in the presence of P144., Innovation: Our experimental evidence suggests that reversing oxidative stress may be therapeutically useful in preventing fibrosis-associated renal damage. We show here that (i) the TGF-β₁-NADPH oxidases axis is crucial in the development of fibrosis in an experimental hypertensive renal disease animal model, and (ii) the use of P144 reverses TGF-β₁-dependent NADPH oxidase activity; thus, P144 may be considered a novel therapeutic tool in kidney disease associated with hypertension., Conclusion: We demonstrate that P144 inhibits NADPH oxidases and prevents oxidative stress in kidneys from hypertensive rats. Our data also suggest that these effects are associated with the renal antifibrotic effect of P144.

Background and Aims: The juvenile to adult transition (JAT) in higher plants is required for them to reach reproductive competence. However, it is a poorly understood process in woody plants, where only a few genes have been definitely identified as being involved in this transition. This work aims at increasing our understanding of the mechanisms regulating the JAT in citrus., Methods: Juvenile and adult plants from Pineapple sweet orange (Citrus sinensis) and Rough lemon (C. jambhiri) were used to screen for differentially expressed transcription factors (TFs) using a 1·15K microarray developed on the basis of the CitrusTF database. Murcott tangor (C. reticulata × C. sinensis) and Duncan grapefruit (C. paradisi) were incorporated into the quantitative real-time reverse transcription-PCR validation in order to select those genes whose phase-specific regulation was common to the four species., Key Results: A browsable web database has been created with information about the structural and functional annotation related to 1152 unigenes of putative citrus TFs (CTFs). This database constitutes a valuable resource for research on transcriptional regulation and comparative genomics. Moreover, a microarray has been developed and used that contains these putative CTFs, in order to identify eight genes that showed differential expression in juvenile and adult meristems of four different species of citrus. Those genes have been characterized, and their expression pattern in vegetative and reproductive tissues has been analysed. Four of them are MADS-box genes, a family of TFs involved in developmental processes, whereas another one resembles MADS-box genes but lacks the MADS box itself. The other three showed high partial sequence similarity restricted to specific Arabidopsis protein domains but negligible outside those domains., Conclusions: The work presented here indicates that the JAT in citrus could be controlled by mechanisms that are in part common to those of Arabidopsis, but also somehow different, since specific factors without Arabidopsis orthologues have also been characterized. The potential involvement of the genes in the JAT is discussed.

Purpose: Arterial hypertension is associated with a high production of reactive oxygen species and a decrease in the antioxidant defense systems. Based on the lack of toxicity of L-carnitine (LC) and previous studies reporting beneficial effects of this compound in experimental models of hypertension, the aim of this work was to test the hypothesis that LC might protect the kidney against hypertension-induced oxidative damage, as well as to investigate the mechanisms involved in this effect. To this end, specific activities and protein/mRNA expression of the antioxidant enzymes (glutathione peroxidase, glutathione reductase, and superoxide dismutase), and those of NADPH oxidase (the main responsible for superoxide anion production in renal tissue) have been measured in renal cortex homogenates from NG-nitro-L-arginine methyl ester (L-NAME)-treated rats and control normotensive rats. In addition, components of the renin-angiotensin system (RAS) and redox-sensitive transcription factors (NF-κB, Nrf2, and PPARα) have also been evaluated., Methods: Male Wistar rats aged 6-8 weeks were divided into four groups of six animals each: (1) control, normotensive Wistar rats (with free access to tap water); (2) Wistar rats subjected to treatment with 25 mg of L-NAME/kg body weight/day dissolved in the drinking water, in order to develop L-NAME-induced hypertension; (3) Wistar rats subjected to treatment with 400 mg of LC/kg body weight/day (also dissolved in the drinking water); and (4) L-NAME-treated rats subjected to simultaneous treatment with LC at the indicated doses., Results: The beneficial effect of LC supplementation on oxidative damage in the renal cortex of hypertensive rats reversed hypertension-associated renal function damage and produced an upregulation of both antioxidant enzymes and eNOS, and with a downregulation of both NADPH oxidase and RAS components. LC improves the oxidative stress response through a specific modulation of NF-κB, Nrf2, and PPARα transcription factors. Thus, the low production of superoxide anions, subsequent to NADPH oxidase inhibition, might act by increasing the expression of Nrf2 and PPARα and by decreasing that of NF-κB, which, in turn, would enhance the antioxidant defense systems., Conclusions: Our results might support the use of LC to prevent hypertension-induced renal damage.

Dysfunctional serotoninergic regulation and hypothalamic-pituitary-adrenal (HPA) axis overreactivity have been consistently reported in research studies with eating disorders (ED). In addition, the links between stress response, serotonin function, HPA axis and inflammatory mechanisms in ED have also been suggested in a number of studies. In our study, inflammatory parameters in white blood cells were investigated in 26 female patients with ED and 25 healthy control subjects matched for sex, age and ethnicity. Patients were free of medication for at least two weeks at the time of the study. Results showed a significant increase in plasma levels of the proinflammatory cytokine IL1β and the protein expression of cyclooxygenase 2 (COX2) in peripheral mononuclear blood cells (PMBCs) in ED patients compared with controls. As well as a significant increase of the oxidative-nitrosative marker TBARS (Thiobarbituric Acid Reactive Substances) in plasma. These findings were associated with increased expression of the alpha7 subunit of the nicotinic receptor (α7nAChR) in PMBC in ED patients independent of plasma cotinine levels. These results suggest that a pro-inflammatory and oxidant phenotype might be present in ED patients. Further research on cellular inflammatory and anti-inflammatory pathways might be oriented to investigate differences between ED subtypes and to search for new potential targets for pharmacological treatment., (Copyright © 2013. Published by Elsevier Inc.)

Activity of the hypothalamic-pituitary-adrenal axis had been studied for the past half century, when some researchers noted that some patients with Cushing's syndrome and severe mood disorders had high baseline cortisol levels, which resulted in an inhibited response in the 1mg dexamethasone suppression test. Altered dexamethasone suppression test results were subsequently found in many psychiatric diseases, including anorexia nervosa, obsessive-compulsive disorder, degenerative dementia, bipolar disorders, and schizophrenia. The relationship between high baseline cortisol levels and stress has also been studied. Some researches on the genesis of borderline personality disorder focused on traumatic childhood backgrounds. Other investigations aimed at elucidating the relationship between traumatic backgrounds and some psychiatric disorders noted that patients with post-traumatic stress disorder and borderline personality disorder showed an enhanced cortisol suppression with low cortisol doses (0.5 mg). Recent studies showed that use of an ultra-low dose of cortisol during the dexamethasone suppression test may be helpful for detecting disorders with hyperactivity of the hypothalamic-pituitary-adrenal axis. Recent advances in neuroimaging support the existence of hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with borderline personality disorder, relating a decreased pituitary gland volume to major traumatic backgrounds and suicidal attempts. The purpose of this paper is to make a narrative review of research using dexamethasone suppression test in psychiatric disorders, in order to ascertain its value as a supplemental diagnostic test or as a prognostic marker., (Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.)

We have recently observed an increased risk for vertebral fractures (VF) in a randomized controlled trial comparing the analgesic effect of vertebroplasty (VP) versus conservative treatment in symptomatic VF. The aim of the present study was to evaluate the risk factors related to the development of VF after VP in these patients. We evaluated risk factors including age, gender, bone mineral density, the number, type, and severity of vertebral deformities at baseline, the number of vertebral bodies treated, the presence and location of disk cement leakage, bone remodeling (determining bone turnover markers) and 25 hydroxyvitamin D [25(OH)D] levels at baseline in all patients. Twenty-nine radiologically new VF were observed in 17 of 57 patients undergoing VP, 72% adjacent to the VP. Patients developing VF after VP showed an increased prevalence of 25(OH)D deficiency (<20 ng/mL) and higher P1NP values. The principal factor related to the development of VF after VP in multivariate analysis was 25(OH)D levels < 20 ng/mL (RR, 15.47; 95% CI, 2.99-79.86, p < 0.0001), whereas age >80 years (RR, 3.20; 95% CI, 1.70-6.03, p = 0.0007) and glucocorticoid therapy (RR, 3.64; 95% CI, 1.61-8.26, p = 0.0055) constituted the principal factors in the overall study population. Increased risk of VF after VP was also associated with cement leakage into the inferior disk (RR, 6.14; 95% CI, 1.65-22.78, p = 0.044) and more than one vertebral body treated during VP (RR, 4.19; 95% CI, 1.03-34.3, p = 0.044). In conclusion, nearly 30% of patients with osteoporotic VF treated with VP had a new VF after the procedure. Age, especially >80 years, the presence of inferior disk cement leakage after the procedure, the number of cemented vertebrae, and low 25(OH)D serum levels were related to the development of new VF in these patients, with the latter indicating the need to correct vitamin D deficiency prior to performing VP., (Copyright © 2013 American Society for Bone and Mineral Research.)

Cohen's kappa coefficient, which was introduced in 1960, serves as the most widely employed coefficient to assess inter-observer agreement for categorical outcomes. However, the original kappa can only be applied to cross-sectional binary measurements and, therefore, cannot be applied in the practical situation when the observers evaluate the same subjects at repeated time intervals. This study summarizes six methods of assessing agreement of repeated binary outcomes under different assumptions and discusses under which condition we should use the most appropriate method in practice. These approaches are illustrated using data from the CDC anthrax vaccine adsorbed (AVA) human clinical trial comparing the agreement for two solicited adverse events after AVA between the 1-3 day in-clinic medical record and the patient's diary on the same day. We hope this article can inspire researchers to choose the most appropriate method to assess agreement for their own study with longitudinal binary data.