Non-collagen genes role in digenic Alport syndrome.

BACKGROUND: Alport syndrome is a clinically heterogeneous nephropathy characterized by severe symptomatology at kidney level due to ultrastructural lesions of the glomerular basement membrane (GBM) as consequence of mutations in COL4 genes. The disease has been linked to COL4A3/COL4A4/COL4A5 mutations, which impair GBM functionality and can be inherited in a dominant, recessive or X-linked transmission. Although a targeted Next Generation Sequencing approach has allowed identifying families with pathogenic mutations in more than one COL4 α3-α4-α5 heterotrimer encoding genes, leading to conclude for a digenic pattern of inheritance, the role of non-collagen genes in digenic Alport syndrome has not yet been established. METHODS: We employed a whole-exome sequencing approach on three families in whom a digenic pattern of transmission could be suspected because of a likely biparental contribution or an unexplained phenotype in the proband. RESULTS: We identified in the three probands hypomorphic LAMA5 mutations co-inherited with pathogenic COL4 α4-α5 chains mutations. Segregation analysis revealed that the combination of LAMA5/COL4 variants co-segregate with a fully penetrant phenotype in line with a digenic inheritance. In one of the three probands an hypomorphic variant in NPHS2 was also found, suggesting that role of other kidney disease related-genes as modifiers. CONCLUSION: These findings validate the impact of LAMA5 mutations in digenic ATS and highlight the role of extracellular matrix's genes, basement membrane, slit diaphragm and podocyte cytoskeleton in ATS. This underline the need for a more extensive panel approach in the presence of a digenic ATS, in order to better define clinical severity and recurrence risk for family members.

Individual trajectories of cognitive performance in first episode psychosis: a 2-year follow-up study.

Individual changes over time in cognition in patients with psychotic disorders have been studied very little, especially in the case of first episode psychosis (FEP). We aimed to establish whether change in individual trajectories in cognition over 2 years of a sample of 159 FEP patients was reliable and clinically significant, using the reliable change index (RCI) and clinically significant change (CSC) methods. We also studied a sample of 151 matched healthy controls. Patients and controls were assessed with a set of neuropsychological tests, as well as premorbid, clinical and functionality measures. We analysed the course of cognitive measures over time, using analysis of variance, and the individual trajectories in the cognitive measures with the regression-based RCI (RCISRB) and the CSC. The RCISRB showed that between 5.4 and 31.2% of the patients showed deterioration patterns, and between 0.6 and 8.8% showed improvement patterns in these tests over time. Patients showing better cognitive profiles according to RCISRB (worsening in zero to two cognitive measures) showed better premorbid, clinical and functional profiles than patients showing deterioration patterns in more than three tests. When combining RCISRB and CSC values, we found that less than 10% of patients showed improvement or deterioration patterns in executive function and attention measures. These results support the view that cognitive impairments are stable over the first 2 years of illness, but also that the analysis of individual trajectories could help to identify a subgroup of patients with particular phenotypes, who may require specific interventions.

Alport syndrome: impact of digenic inheritance in patients management.

Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members.

Effect of artificial aging and surface treatment on bond strengths to dental zirconia.

The objective of this project was to study the influence of artificial aging and surface treatment on the microtensile bond strengths (µTBS) between zirconia and a phosphate monomer-based self-adhesive cement. Thirty zirconia disks (IPS e.max ZirCAD, Ivoclar Vivadent) were randomly assigned to two aging regimens: AR, used as received, which served as a control, and AG, artificial aging to simulate low-temperature degradation. Subsequently, the disks of each aging regimen were assigned to three surface treatments: NT, no surface treatment; CO, surface silicatization with CoJet sand (3M ESPE); and ZP, zirconia surface treated with Z-Prime Plus (Bisco Inc). Thirty discs were made of Filtek Z250 (3M ESPE) composite resin and luted to the zirconia discs using RelyX Unicem (3M ESPE). The specimens were sectioned with a diamond blade in X and Y directions to obtain bonded beams with a cross-section of 1.0 ± 0.2 mm. The beams were tested in tensile mode in a universal testing machine at a speed of 0.5 mm/min to measure µTBS. Selected beams were selected for fractographic analysis under the SEM. Statistical analysis was carried out with two-way analysis of variance and Dunnett T3 post hoc test at a significance level of 95%. The mean µTBS for the three AR subgroups (AR-NT, AR-CO, and AR-ZP) were significantly higher than those of the corresponding AG groups (p<0.0001). Both AR-CO and AR-ZP resulted in statistically significant higher mean bond strengths than the group AR-NT (p<0.006 and p<0.0001, respectively). Both AG-CO and AG-ZP resulted in statistically significant higher mean bond strengths than the group AG-NT (both at p<0.0001). Overall, AG decreased mean µTBS. Under the SEM, mixed failures showed residual cement attached to the zirconia side of the beams. CO resulted in a characteristic roughness of the zirconia surface. AR-ZP was the only group for which the amount of residual cement occupied at least 50% of the interface in mixed failures.

High precision micro-displacement fiber sensor through a suspended-core Sagnac interferometer.

A sensing system for micro-displacement measurement based in a suspended-core fiber Sagnac interferometer is presented. The suspended-core fiber characterization was made through the use of an optical backscatter reflectometer, screening its multimodal and birefringent behavior. Its sensitivity to displacement measurements is shown to be due only to birefringence, being that core-cladding mode coupling is negligible. High precision (~0.45 µm) was obtained using three different measurement instruments, showing an extremely high stability and high insensitivity to temperature, demonstrating that the sensing system has the ability for low cost applications.

Suspended-core fiber Sagnac combined dual-random mirror Raman fiber laser.

In the present work, a multiwavelength fiber laser based in the combination of a double-random mirror and a suspended-core Sagnac interferometer is presented. The double-random mirror acts by itself as a random laser, presenting a 30dB SNR, as result of multiple Rayleigh scattering events produced in the dispersion compensating fibers by the Raman amplification. The suspended-core fiber Sagnac interferometer provides the multi peak channeled spectrum, which can be tuned by changing the length of the fiber. The result of this combination is a stable multiwavelength peak laser with a minimum of ~25dB SNR, which is highly sensitive to polarization induced variations.

TiO2 bioactive implant surfaces doped with specific amount of Sr modulate mineralization.

One of the main problems that remain in the implant industry is poor osseointegration due to bioinertness of implants. In order to promote bioactivity, calcium (Ca), phosphorus (P) and strontium (Sr) were incorporated into a TiO2 porous layer produced by micro-arc oxidation. Ca and P as bioactive elements are already well reported in the literature, however, the knowledge of the effect of Sr is still limited. In the present work, the effect of various amounts of Sr was evaluated and the morphology, chemical composition and crystal structure of the oxide layer were investigated. Furthermore, in vitro studies were carried out using human osteoblast-like cells. The oxide layer formed showed a triplex structure, where higher incorporation of Sr increased Ca/P ratio, amount of rutile and promoted the formation of SrTiO3 compound. Biological tests revealed that lower concentrations of Sr did not compromise initial cell adhesion neither viability and interestingly improved mineralization. However, higher concentration of Sr (and consequent higher amount of rutile) showed to induce collagen secretion but with compromised mineralization, possibly due to a delayed mineralization process or induced precipitation of deficient hydroxyapatite. Ca-P-TiO2 porous layer with less concentration of Sr seems to be an ideal candidate for bone implants.

Systolic dysfunction by two-dimensional speckle tracking echocardiography in dogs with parvoviral enteritis.

INTRODUCTION/OBJECTIVES: Parvoviral enteritis (PVE) can cause either primary or secondary myocardial injury; the latter is associated with systemic inflammatory response syndrome and sepsis. Strain (St) and strain rate (SR) are relatively new speckle tracking echocardiographic (STE) variables used to assess myocardial function and are less influenced by preload and volume status than are conventional variables. The aim of this study was to evaluate systolic function in dogs with PVE using two-dimensional STE. ANIMALS: Forty-five client-owned dogs were included. MATERIALS AND METHODS: Dogs were classified into four groups: healthy (n = 9), PVE-mild (n = 15), PVE-severe (n = 13) and PVE-died (n = 8). Left ventricular global and segmental myocardial St and SR were assessed in radial, circumferential and longitudinal axes in the right parasternal transverse and apical 4-chamber views. In the circumferential and longitudinal axes, the value of each segment was determined separately at the endocardial and epicardial levels. RESULTS: Compared to healthy animals, all dogs with PVE showed significantly impaired St and SR values, mainly for PVE-severe and PVE-died groups. Moreover, the lowest SR value was observed in the circumferential axis at the mid-septal epicardial segment in the PVE-died group. For this variable, a cut-off value of 0.95 s-1 demonstrated 100% sensitivity and specificity for distinguishing between PVE-severe and PVE-died groups. CONCLUSIONS: In the present study, all dogs with PVE developed systolic dysfunction, which was more severe in non-survivors. Assessment of St and SR in dogs with PVE might be clinically useful for evaluating haemodynamic status and developing suitable therapeutic strategies to improve prognosis.

Recommendations for assessing patient-reported outcomes and health-related quality of life in clinical trials on allergy: a GA(2)LEN taskforce position paper.

The aim of this Global Allergy and Asthma European Network (GA(2)LEN) consensus report is to provide recommendations for patient-reported outcomes (PROs) evaluation in clinical trials for allergic diseases, which constitute a global health problem in terms of physical, psychological economic and social impact. During the last 40 years, PROs have gained large consideration and use in the scientific community, to gain a better understanding of patients' subjective assessment with respect to elements concerning their health condition. They include all health-related reports coming from the patient, without involvement or interpretation by physician or others. PROs assessment should be performed by validated tools (disease-specific tools when available or generic ones) selected taking into account the aim of the study, the expected intervention effects and the determinant and confounding factors or patient-related factors which could influence PROs. Moreover, each tool should be used exclusively in the patient population following the authors' indications without modification and performing a cross-cultural validation if the tool must be used in a language that differs from the original. The result analysis also suggests that the relevance of PROs results in any interventional study should include a pre-post assessment providing information concerning statistical differences within or among groups, rates of response for the PROs and a minimal important difference for the population. The report underlines the importance of further investigation on some topics, such as the quality assessment of existing PROs tools, the definition of inclusion and exclusion criteria and a more extensive evaluation of the correlation between PROs, besides health-related quality of life, and clinical data.

Specific recommendations for PROs and HRQoL assessment in allergic rhinitis and/or asthma: a GA(2)LEN taskforce position paper.

The GA(2)LEN taskforce on Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQoL) published in 2009 a position paper concerning PROS and HRQoL assessment in clinical trials on allergy. Because of the specificity of this topic in asthma and rhinitis, specific recommendations are needed. The aim of this position paper is to define PROs and their meaning in asthma and rhinitis research, explore the available tools to provide criteria for a proper choice, identify patient-related factor which could influence PROs assessment, define specific recommendations for assessment, analysis and results spreading, underline the unexplored areas and unmet needs. PROs assessment is gaining increasing importance, and it must be performed with a rigorous methodological procedure and using validated tools. This approach enables to better understand patient-related factors influencing clinical trials and real-life management outcomes, identify patients subgroups that can benefit from specific treatment and management plan and tailor treatment to address PROs (not only physician-defined targets) to improve asthma and rhinitis management.

Influence of macroporosity on NIH/3T3 adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 over bio-functionalized highly porous titanium implant material.

Highly porous Ti implant materials are being used in order to overcome the stress shielding effect on orthopedic implants. However, the lack of bioactivity on Ti surfaces is still a major concern regarding the osseointegration process. It is known that the rapid recruitment of osteoblasts in bone defects is an essential prerequisite for efficient bone repair. Conventionally, osteoblast recruitment to bone defects and subsequent bone repair has been achieved using growth factors. Thus, in this study highly porous Ti samples were processed by powder metallurgy using space holder technique followed by the bio-functionalization through microarc oxidation using a Ca- and P-rich electrolyte. The biological response in terms of early cell response, namely, adhesion, spreading, viability, and proliferation of the novel biofunctionalized highly porous Ti was carried out with NIH/3T3 fibroblasts and MC3T3-E1 preosteoblasts in terms of viability, adhesion, proliferation, and alkaline phosphatase activity. Results showed that bio-functionalization did not affect the cell viability. However, bio-functionalized highly porous Ti (22% porosity) enhanced the cell proliferation and activity. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 73-85, 2019.

Optimization of a single chamber microbial fuel cell using Lactobacillus pentosus: Influence of design and operating parameters.

Microbial fuel cells (MFCs) have been receiving an increased attention over the last years due to their potential to combat two global problems: waste pollution and energy demand. Additionally, when a wastewater is used, MFCs can perform its treatment while recovering energy, leading to the possibility of energy-producing wastewater treatment plants, offsetting their operational costs. However, to overcome their current limitations (lower power outputs and higher costs), a clear understanding of the effect of operation and design parameters on its overall performance is mandatory. Therefore, the goal of this work was to evaluate the effect of operating conditions - batch cycle and yeast extract concentration, and design parameters - anode electrode area, membrane thickness and active area, on the overall performance of a single chamber MFC. The MFC operated with a pure culture of Lactobacillus pentosus and a synthetic wastewater based on a real dairy industry effluent. The overall performance was evaluated through the power output and the COD removal rate. Additionally, the biofilm formed at the anode electrode was characterized in terms of biomass, proteins and polysaccharides content. For the conditions used in this work, a maximum power density of 5.04 ±â€¯0.39 mW/m2 was achieved with an anode electrode area of 61 cm2, a batch cycle of 48 h, 50 mg/L of yeast extract and a Nafion 212 membrane with an active area of 25 cm2. The different conditions tested had a clear effect on the MFC energy production and biofilm characteristics, but not on the ability of L. pentosus to treat the dairy wastewater. The COD removal rates were in the range between 42% and 58%, for all the conditions tested.

Resilience dimensions and mental health outcomes in bipolar disorder in a follow-up study.

The individual process of resilience has been related to positive outcomes in mental disorders. We aimed (a) to identify the resilience domains from the Resilience Questionnaire for Bipolar Disorder that are associated cross sectionally and longitudinally with mental health outcomes in bipolar disorder (BD) and (b) to explore cross-lagged associations among resilience factors. A clinical adult sample of 125 patients diagnosed with BD (62.10% female, mean age = 46.13, SD = 10.89) gave their informed consent and completed a battery of disease-specific tools on resilience, personal recovery, symptomatology, psychosocial functioning, and quality of life, at baseline and at follow-up (n = 63, 58.10% female, mean age = 45.13, SD = 11.06, participation rate = 50.40%). Resilience domains of self-management of BD, turning point, self-care, and self-confidence were significantly associated with mental health indicators at baseline. In addition, self-confidence at baseline directly predicted an increase in personal recovery at follow-up, and self-confidence improvement mediated the relationship between interpersonal support and self-care at baseline and personal recovery at follow-up. These findings highlight that resilience domains are significantly associated with positive mental health outcomes in BD and that some predict personal recovery at follow-up. Moreover, some resilience factors improve other resilience factors over time.

Corrosion and tribocorrosion behavior of Ti-TiB-TiNx in-situ hybrid composite synthesized by reactive hot pressing.

Ti and its alloys are attractive materials for variety of fields, including biomedical implants, however, the wear behavior is yet to be improved. In the present work, Ti-TiB-TiNx in-situ metal matrix composites were synthesized by reactive hot pressing using a Ti-BN powder blend. Corrosion behavior was investigated in 9g/L NaCl solution at 37°C by performing potentiodynamic polarization and electrochemical impedance spectroscopy. Tribocorrosion behavior was investigated using reciprocating tribometer, against an alumina ball, under 1 and 10N normal load, 1 and 2Hz frequency, in 9g/L NaCl solution at 37°C. Results suggested that TiB and TiNx in-situ phases did not deteriorate the corrosion behavior of Ti but significantly improved the tribocorrosion behavior under 1N.

Tribocorrosion behavior of bio-functionalized highly porous titanium.

Titanium and its alloys are widely used in orthopedic and dental implants, however, some major clinical concerns such as poor wear resistance, lack of bioactivity, and bone resorption due to stress shielding are yet to be overcome. In order to improve these drawbacks, highly porous Ti samples having functionalized surfaces were developed by powder metallurgy with space holder technique followed by anodic treatment. Tribocorrosion tests were performed in 9g/L NaCl solution using a unidirectional pin-on-disc tribometer under 3N normal load, 1Hz frequency and 4mm track diameter. Open circuit potential (OCP) was measured before, during and after sliding. Worn surfaces investigated by field emission gun scanning electron microscope (FEG-SEM) equipped with energy dispersive X-ray spectroscopy (EDS). Results suggested bio-functionalized highly porous samples presented lower tendency to corrosion under sliding against zirconia pin, mainly due to the load carrying effect given by the hard protruded oxide surfaces formed by the anodic treatment.

A vitamin A-free diet results in impairment of the rat hippocampal somatostatinergic system.

Previous studies have revealed the presence of retinoid specific receptors in the hippocampus and have demonstrated that vitamin A deficiency produces a severe deficit in spatial learning and memory which are linked to a proper hippocampal functioning. It is also well known that the tetradecapeptide somatostatin binds to specific receptors in the hippocampus and, when injected into this brain area, facilitates the acquisition of spatial tasks. In addition, depletion of somatostatin by cysteamine impairs acquisition of these tasks. Taken together, these studies support the idea that the hippocampal somatostatinergic system might be regulated by vitamin A. Hence, we evaluated the effects of vitamin A deprivation and subsequent administration of vitamin A on the rat hippocampal somatostatinergic system. Rats fed a vitamin A-free diet exhibited a significant reduction of somatostatin-like immunoreactivity content in the hippocampus whereas the somatostatin mRNA levels were unaltered. Vitamin A deficiency increased the somatostatin receptor density and its dissociation constant. Functional Gi activity as well as the capacity of somatostatin to inhibit basal and forskolin-stimulated adenylyl cyclase activity was decreased in vitamin A deficiency rats as compared with the control animals. All these parameters were fully restored when vitamin A was replaced in the diet. Furthermore, we found that the Gialpha1, Gialpha2 and Gialpha3 protein levels were unaltered in hippocampal membranes from rats fed a vitamin A-free diet whereas subsequent vitamin A administration to these rats caused a significant increase in the levels of Gialpha1 and Gialpha2. Altogether, the present findings suggest that dietary vitamin A levels modulate the somatostatinergic system in the rat hippocampus.

Psychometric properties of the Revised Fibromyalgia Impact Questionnaire (FIQR) - a contribution to the Portuguese validation of the scale.

BACKGROUND: Fibromyalgia (FM) remains a relatively misunderstood and clinically challenging condition that impact significantly in the individual´s life, impairing global functioning and diminishing quality of life. Management is complex and frequently unsatisfactory, requiring personal tailoring and adaptation of interventions according to the fluctuations of the disease manifestations and their response to therapy. The use of comprehensive and quantified assessment tools constitutes, therefore, an essential component of the management of patients with FM. The Revised Fibromyalgia Impact Questionnaire (FIQR) is currently one of the most used and well validated instruments to assess functional (in)capacity and global impact of FM and associated symptoms. OBJECTIVES: To translate to Portuguese the FIQR and to study its psychometric properties. MATERIAL AND METHODS: The total sample comprised 103 women with fibromyalgia, defined according to the established criteria for FM. A self-report battery composed by the Revised Fibromyalgia Impact Questionnaire (FIQR), the Portuguese version of Beck Depression Inventory-II (BDI-II) and the Profile of Mood States (PoMS) was administered. The FIQR was re-administered to twenty-four participants, six weeks after the first evaluation. Internal reliability was assessed through Cronbach's alpha, corrected item-total score correlations and alpha if item deleted. Spearman and Pearson correlations along with repeated measures tests were computed to assess the temporal stability of the scale. Convergent and divergent validity were assessed via Spearman and Pearson correlations. RESULTS: The FIQR demonstrated a good to very good internal consistency (from α = 0.87 to α = 0.94). All items correlated to a good degree (above 0.30) to the total score and contributed significantly to the overall reliability. Moreover, FIQR presented a good temporal stability (from r = .617 to r = .886, p ≤ .001) and favorable convergent and discriminant validity with depressive symptoms (r > .289, p ≤ .01) and positive (r > -.186, p > .05) and negative affect (r > .206, p ≤ .05). CONCLUSIONS: The Portuguese version of the FIQR demonstrated good psychometric properties, which renders it a proper and valuable tool to be used in different settings.