Idiopathic collapsing glomerulopathy is associated with APOL1 high-risk genotypes or Mendelian variants in most affected individuals in a highly admixed population.

Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.

Food web structure of fish communities of Doce River, 5 years after the Fundão dam failure.

The rupture of the Fundão dam is considered the largest mining failure in history, which had a particularly detrimental impact on fish populations, as the mud from the ore tailings significantly altered the water quality and habitat of Doce River basin. This study aimed to assess the trophic structure of fish communities in areas impacted and not impacted by the dam rupture in the Doce River basin. To evaluate the food web structure, community-wide trophic niche, and trophic positions of fish, stable isotopes of carbon (δ13C) and nitrogen (δ15N) were utilized across ten sites (seven impacted and three control). In general, fish appeared to assimilate resources such as invertebrates, algae, and periphyton, although the importance of each resource varied among sites. The site closest to the dam rupture exhibited a more simplified trophic structure compared to the control sites and those nearer the river mouth. In this site, most fish species occupied a similar trophic position. Trophic niches also exhibited the greatest dissimilarity between the site closest to the dam failure and those farther away from it, with an expansion of trophic niche breadth observed with an increase in the distance from the dam rupture. Our study provided valuable insights into the trophic structure of fish communities within the Doce River basin, shedding light on the trophic ecology of the 59 fish species investigated. We also emphasize the importance of our study for future assessments of ore tailings dam failure disasters and evaluating the effectiveness of mitigation measures for Doce River basin recovery.

Assessing the impact of center volume on the cost-effectiveness of centralizing ERCP.

BACKGROUND AND AIMS: ERCP is a complex endoscopic procedure in which the center's procedure volume influences outcomes. With the increasing healthcare expenses and limited resources, promoting cost-effective care becomes essential for healthcare provision. This study performed a cost-effectiveness analysis to evaluate the hypothesis that high-volume (HV) centers perform ERCP with higher quality at lower costs than low-volume (LV) centers. METHODS: A baseline case compared the current distribution of ERCPs among HV and LV centers with a hypothetical scenario in which all ERCPs are performed at HV centers. A cost-effectiveness analysis was constructed, followed by one-way and two-way sensitivity analyses and probabilistic sensitivity analysis (PSA) using Monte Carlo simulations. RESULTS: In the baseline case, the ICER was -141,017€/year, due to the hypothetical scenario's lower costs and slightly higher QALYs. The model was most sensitive to changes in the transportation costs (109.34%), probability of significant adverse events (AEs) after successful ERCP at LV centers (42.12%), utility after ERCP with significant AEs (30.10%), and probability of significant AEs after successful ERCP at HV centers (23.53%) but only transportation cost above 3,407€ changed the study outcome. The current ERCP distribution would only be cost-effective if LV centers achieved higher success (≥ 92.4% vs. 89.3%) with much lower significant AEs (≤ 0.5% vs 6.7%). The study's main findings remained unchanged while combining all model parameters in the PSA. CONCLUSIONS: Our findings show that HV centers have high-performance rates at lower costs, raising the need to consider the principle of centralization of ERCPs into HV centers to improve the quality of care.

Electroresponsive and pH-Sensitive Hydrogel as Carrier for Controlled Chloramphenicol Release.

Multiresponsive hydrogels, which are smart soft materials that respond to more than one external stimulus, have emerged as powerful tools for biomedical applications, such as drug delivery. Within this context and with the aim of eliminating the systematic administration of antibiotics, special attention is being paid to the development of systems for controlled delivery of antibiotic for topical treatment of bacterial infections. In this work, an electro-chemo responsive hydrogel able to release chloramphenicol (CAM), a broad spectrum antibiotic also used for anticancer therapy, is proposed. This has been prepared by grafting poly(acrylic acid) (PAA) to sodium alginate (Alg) and in situ encapsulation of poly(3,4-ethylenedioxythiophene) nanoparticles loaded with CAM (PEDOT/CAM NPs), which were obtained by emulsion polymerization. Although the response to electrical stimuli of PEDOT was the main control for the release of CAM from PEDOT/CAM NPs, the release by passive diffusion had a relatively important contribution. Conversely, the passive release of antibiotic from the whole engineered hydrogel system, Alg-g-PAA/PEDOT/CAM, was negligible, whereas significant release was achieved under electrostimulation in an acid environment. Bacterial tests and assays with cancer cells demonstrated that the biological activity of CAM remained after release by electrical stimulation. Notably, the successful dual-response of the developed hydrogel to electrical stimuli and pH changes evidence the great prospect of this smart material in the biomedical field, as a tool to fight against bacterial infections and to provide local cancer treatment.

Modified triple Kessler with least risk of elongation among Achilles tendon repair techniques: a systematic review and network meta-analysis of human cadaveric studies.

PURPOSE: Current treatment recommendations emphasize early loading, with preservation of tendon length and physiologic tension. The objective of this systematic review and network meta-analysis was to compare failure load and elongation after cyclic loading of Achilles tendon repair techniques at time-zero. METHODS: The databases PubMed, CENTRAL and Web of Science were searched for all published in-vitro studies comparing Achilles tendon repair techniques, or augmentation with autografts/biomaterials, and reports of failure load or elongation after cyclic loading. Only studies using human cadaveric Achilles tendons and matched pairs, or randomized specimen allocation, were selected for quantitative synthesis. A network meta-analysis per primary outcome was performed. Results were summarized as P score rankings and their validity was assessed using statistical methods. RESULTS: Sixteen studies, comprising 367 tendon repairs, were included. The following repair techniques were used (n = number of studies): Krackow (n = 8), Achillon (n = 4), double Krackow (n = 3), Bunnell (n = 3), Percutaneous Achilles Repair System (n = 3), Percutaneous Achilles Repair System Midsubstance (n = 2), Kessler (n = 3), double Kessler (n = 1), modified triple Kessler (n = 1), triple bundle (n = 1), a multifilament stainless steel cable-crimp technique (n = 1) and a double loop knot stitch (n = 1). Five studies assessed augmentation with autografts/biomaterials. Regarding the failure load, biomaterial augmented Krackow repairs occupied the first four positions in the ranking, followed by the multifilament stainless steel cable-crimp and Percutaneous Achilles Repair System Midsubstance techniques. Concerning elongation after cyclic loading, the triple Kessler was ranked first, followed by the Achillon and Percutaneous Achilles Repair System Midsubstance techniques. A negligible correlation between ranks was found (rs = 0.11; p = 0.75n.s.), meaning that a higher repair tensile strength is not necessarily related to improved performance in regard to avoidance of elongation. CONCLUSION: In the failure load network meta-analysis, biomaterial augmented Krackow repairs ranked highest, but noticeable statistical heterogeneity was found. Regarding elongation with cyclic loading, the modified triple Kessler stitch showed the highest probability of ranking first. LEVEL OF EVIDENCE: Level IV.

Return-to-performance in elite soccer players after Achilles tendon ruptures: a study using a weighted plus/minus metric and matched-control analysis.

PURPOSE: Studies have shown decreased match participation and shortened careers in athletes suffering Achilles tendon ruptures (ATRs), but assessment using a true performance metric is lacking. Plus/minus (PM) metrics provide a practical and objective approach to player performance assessment and are commonly used in other sports. This study aimed to quantify and compare individual player performance variations in elite football league players who sustained ATRs and returned to play within 1 year compared to those without ATRs, using a PM metric. METHODS: Player and team data were sourced from Transfermarkt.com. Male players sustaining ATRs between 2007 and 2018 were identified through injury reports. A control group (CTRL) was matched by position, age, height, and league, with a 6:1 ratio of controls to ATR subjects. The day of injury was considered "time zero". Year -1 corresponds to the 360 days preceding injury, and Year 1 to the interval between 360 and 720 days after. Performance in the player's main team was evaluated using a previously validated weighted PM metric. Only data from Year -1 and Year 1 were used for ATR versus CTRL group comparisons. Statistical significance was set at p < 0.05. RESULTS: The ATR group included 125 athletes. Data from more than 76,000 matches were analyzed. No statistically significant differences in net weighted PM metric between Year -1 and Year 1 were found. CONCLUSION: No differences were found between athletes suffering from ATRs and controls regarding the weighted PM metric. LEVEL OF EVIDENCE: III.

Early analysis shows that endoscopic flexor hallucis longus transfer has a promising cost-effectiveness profile in the treatment of acute Achilles tendon ruptures.

PURPOSE: Current options for treating an Achilles tendon rupture (ATR) include conservative and surgical approaches. Endoscopic flexor hallucis longus (FHL) transfer has been recently proposed to treat acute ruptures, but its cost-effectiveness potential remains to be evaluated. Therefore, the objective of this study was to perform an early cost-effectiveness analysis of endoscopic FHL transfer for acute ATRs, comparing the costs and benefits of current treatments from a societal perspective. METHODS: A conceptual model was created, with a decision tree, to outline the main health events during the treatment of an acute ATR. The model was parameterized using secondary data. A systematic review of the literature was conducted to gather information on the outcomes of current treatments. Data related to outcomes of endoscopic FHL transfers in acute Achilles ruptures was obtained from a single prospective study. Analysis was limited to the two first years. The incremental cost-effectiveness ratio was the main outcome used to determine the preferred strategy. A willingness-to-pay threshold of $100,000 per quality-adjusted life-year was used. Sensitivity analyses were performed to determine whether changes in input parameters would cause significant deviation from the reference case results. Specifically, a probability sensitivity analysis was conducted using Monte Carlo simulations, and a one-way sensitivity analysis was conducted by sequentially varying each model parameter within a given range. RESULTS: For the reference case, incremental cost-effectiveness ratios exceeded the willingness-to-pay threshold for all the surgical approaches. Overall, primary treatment was the main cost driver. Conservative treatment showed the highest direct costs related to the treatment of complications. In the probabilistic sensitivity analysis, at a willingness-to-pay threshold of $100,000, open surgery was cost-effective in 50.9%, minimally invasive surgery in 55.8%, and endoscopic FHL transfer in 72% of the iterations. The model was most sensitive to parameters related to treatment utilities, followed by the costs of primary treatments. CONCLUSION: Surgical treatments have a moderate likelihood of being cost-effective at a willingness-to-pay threshold of $100,000, with endoscopic FHL transfer showing the highest likelihood. Following injury, interventions to improve health-related quality of life may be better suited for improved cost-effectiveness. LEVEL OF EVIDENCE: Level III.

Hydroxyapatite-filled osteoinductive and piezoelectric nanofibers for bone tissue engineering.

Osteoporotic-related fractures are among the leading causes of chronic disease morbidity in Europe and in the US. While a significant percentage of fractures can be repaired naturally, in delayed-union and non-union fractures surgical intervention is necessary for proper bone regeneration. Given the current lack of optimized clinical techniques to adequately address this issue, bone tissue engineering (BTE) strategies focusing on the development of scaffolds for temporarily replacing damaged bone and supporting its regeneration process have been gaining interest. The piezoelectric properties of bone, which have an important role in tissue homeostasis and regeneration, have been frequently neglected in the design of BTE scaffolds. Therefore, in this study, we developed novel hydroxyapatite (HAp)-filled osteoinductive and piezoelectric poly(vinylidene fluoride-co-tetrafluoroethylene) (PVDF-TrFE) nanofibers via electrospinning capable of replicating the tissue's fibrous extracellular matrix (ECM) composition and native piezoelectric properties. The developed PVDF-TrFE/HAp nanofibers had biomimetic collagen fibril-like diameters, as well as enhanced piezoelectric and surface properties, which translated into a better capacity to assist the mineralization process and cell proliferation. The biological cues provided by the HAp nanoparticles enhanced the osteogenic differentiation of seeded human mesenchymal stem/stromal cells (MSCs) as observed by the increased ALP activity, cell-secreted calcium deposition and osteogenic gene expression levels observed for the HAp-containing fibers. Overall, our findings describe the potential of combining PVDF-TrFE and HAp for developing electroactive and osteoinductive nanofibers capable of supporting bone tissue regeneration.

Novel Electroactive Mineralized Polyacrylonitrile/PEDOT:PSS Electrospun Nanofibers for Bone Repair Applications.

Bone defect repair remains a critical challenge in current orthopedic clinical practice, as the available therapeutic strategies only offer suboptimal outcomes. Therefore, bone tissue engineering (BTE) approaches, involving the development of biomimetic implantable scaffolds combined with osteoprogenitor cells and native-like physical stimuli, are gaining widespread interest. Electrical stimulation (ES)-based therapies have been found to actively promote bone growth and osteogenesis in both in vivo and in vitro settings. Thus, the combination of electroactive scaffolds comprising conductive biomaterials and ES holds significant promise in improving the effectiveness of BTE for clinical applications. The aim of this study was to develop electroconductive polyacrylonitrile/poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PAN/PEDOT:PSS) nanofibers via electrospinning, which are capable of emulating the native tissue's fibrous extracellular matrix (ECM) and providing a platform for the delivery of exogenous ES. The resulting nanofibers were successfully functionalized with apatite-like structures to mimic the inorganic phase of the bone ECM. The conductive electrospun scaffolds presented nanoscale fiber diameters akin to those of collagen fibrils and displayed bone-like conductivity. PEDOT:PSS incorporation was shown to significantly promote scaffold mineralization in vitro. The mineralized electroconductive nanofibers demonstrated improved biological performance as observed by the significantly enhanced proliferation of both human osteoblast-like MG-63 cells and human bone marrow-derived mesenchymal stem/stromal cells (hBM-MSCs). Moreover, mineralized PAN/PEDOT:PSS nanofibers up-regulated bone marker genes expression levels of hBM-MSCs undergoing osteogenic differentiation, highlighting their potential as electroactive biomimetic BTE scaffolds for innovative bone defect repair strategies.

Imbalanced IL-1B and IL-18 Expression in Sézary Syndrome.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.

Dendritic Self-assembled Structures from Therapeutic Charged Pentapeptides.

CRENKA [Cys-Arg-(NMe)Glu-Lys-Ala, where (NMe)Glu refers to N-methyl-Glu], an anti-cancer pentapeptide that induces prostate tumor necrosis and significant reduction in tumor growth, was engineered to increase the resistance to endogenous proteases of its parent peptide, CREKA (Cys-Arg-Glu-Lys-Ala). Considering their high tendency to aggregate, the self-assembly of CRENKA and CREKA into well-defined and ordered structures has been examined as a function of peptide concentration and pH. Spectroscopic studies and atomistic molecular dynamics simulations reveal significant differences between the secondary structures of CREKA and CRENKA. Thus, the restrictions imposed by the (NMe)Glu residue reduce the conformational variability of CRENKA with respect to CREKA, which significantly affects the formation of well-defined and ordered self-assembly morphologies. Aggregates with poorly defined morphology are obtained from solutions with low and moderate CREKA concentrations at pH 4, whereas well-defined dendritic microstructures with fractal geometry are obtained from CRENKA solutions with similar peptide concentrations at pH 4 and 7. The formation of dendritic structures is proposed to follow a two-step mechanism: (1) pseudo-spherical particles are pre-nucleated through a diffusion-limited aggregation process, pre-defining the dendritic geometry, and (2) such pre-nucleated structures coalesce by incorporating conformationally restrained CRENKA molecules from the solution to their surfaces, forming a continuous dendritic structure. Instead, no regular assembly is obtained from solutions with high peptide concentrations, as their dynamics is dominated by strong repulsive peptide-peptide electrostatic interactions, and from solutions at pH 10, in which the total peptide charge is zero. Overall, results demonstrate that dendritic structures are only obtained when the molecular charge of CRENKA, which is controlled through the pH, favors kinetics over thermodynamics during the self-assembly process.

Pre-injury performance is most important for predicting the level of match participation after Achilles tendon ruptures in elite soccer players: a study using a machine learning classifier.

PURPOSE: Achilles tendon ruptures (ATR) are career-threatening injuries in elite soccer players due to the decreased sports performance they commonly inflict. This study presents an exploratory data analysis of match participation before and after ATRs and an evaluation of the performance of a machine learning (ML) model based on pre-injury features to predict whether a player will return to a previous level of match participation. METHODS: The website transfermarkt.com was mined, between January and March of 2021, for relevant entries regarding soccer players who suffered an ATR while playing in first or second leagues. The difference between average minutes played per match (MPM) 1 year before injury and between 1 and 2 years after the injury was used to identify patterns in match participation after injury. Clustering analysis was performed using k-means clustering. Predictions of post-injury match participation were made using the XGBoost classification algorithm. The performance of this model was evaluated using the area under the receiver operating characteristic curve (AUROC) and Brier score loss (BSL). RESULTS: Two hundred and nine players were included in the study. Data from 32,853 matches was analysed. Exploratory data analysis revealed that forwards, midfielders and defenders increased match participation during the first year after injury, with goalkeepers still improving at 2 years. Players were grouped into four clusters regarding the difference between MPMs 1 year before injury and between 1 and 2 years after the injury. These groups ranged between a severe decrease (n = 34; - 59 ± 13 MPM), moderate decrease (n = 75; - 25 ± 8 MPM), maintenance (n = 70; 0 ± 8 MPM), or increase (n = 30; 32 ± 13 MPM). Regarding the predictive model, the average AUROC after cross-validation was 0.81 ± 0.10, and the BSL was 0.12, with the most important features relating to pre-injury match participation. CONCLUSION: Most players take 1 year to reach peak match participation after an ATR. Good performance was attained using a ML classifier to predict the level of match participation following an ATR, with features related to pre-injury match participation displaying the highest importance. LEVEL OF EVIDENCE: I.

Piezoelectric Electrospun Fibrous Scaffolds for Bone, Articular Cartilage and Osteochondral Tissue Engineering.

Osteochondral tissue (OCT) related diseases, particularly osteoarthritis, number among the most prevalent in the adult population worldwide. However, no satisfactory clinical treatments have been developed to date to resolve this unmet medical issue. Osteochondral tissue engineering (OCTE) strategies involving the fabrication of OCT-mimicking scaffold structures capable of replacing damaged tissue and promoting its regeneration are currently under development. While the piezoelectric properties of the OCT have been extensively reported in different studies, they keep being neglected in the design of novel OCT scaffolds, which focus primarily on the tissue's structural and mechanical properties. Given the promising potential of piezoelectric electrospun scaffolds capable of both recapitulating the piezoelectric nature of the tissue's fibrous ECM and of providing a platform for electrical and mechanical stimulation to promote the regeneration of damaged OCT, the present review aims to examine the current state of the art of these electroactive smart scaffolds in OCTE strategies. A summary of the piezoelectric properties of the different regions of the OCT and an overview of the main piezoelectric biomaterials applied in OCTE applications are presented. Some recent examples of piezoelectric electrospun scaffolds developed for potentially replacing damaged OCT as well as for the bone or articular cartilage segments of this interfacial tissue are summarized. Finally, the current challenges and future perspectives concerning the use of piezoelectric electrospun scaffolds in OCT regeneration are discussed.

Maternal Immune Activation with H1N1 or Toxoplasma gondii Antigens Induces Behavioral Impairments Associated with Mood Disorders in Rodents.

INTRODUCTION: Epidemiological studies revealed that maternal exposure to influenza A (H1N1) and Toxoplasma gondii (T. gondii) infection during pregnancy may increase the risk for mood disorders of the offspring. However, the impact of maternal infections in different stages of neural development and the nature of antigens remain to be elucidated. OBJECTIVE: This study investigated behavioral impairments induced by maternal immune activation (MIA) due to H1N1 or T. gondii infection during preborn neurodevelopment. METHODS: Maternal infection with influenza or toxoplasma was mimicked by administration of influenza vaccine antigens or suspension of soluble T. gondii antigen (STAg) in pregnant Balb/c mice at E6 or E16. Adult male offspring were evaluated for anxiety-like and depressive-like behavior in elevated plus maze (EPM) and forced swimming test (FST). RESULTS: In FST, immobility time at E6 and E16 increased when the mothers were treated with both antigen solutions. There was increased immobility in the pups whose mothers were treated with STAg at E16. MIA with influenza antigens reduced the exploration of the open arms of EPM for the pups whose progenitors received treatment at E6 and E16. The animals at E6 exhibited a greater number of stretch-attend postures compared with the saline group. STAg at E6 reduced the time of exploration in the open arms and increased the number of stretch-attend postures compared with the saline group. CONCLUSION: These results suggest that immunological responses to H1N1 or T. gondii during pregnancy may impact differently the susceptibility of adult offspring to mood disorder.

Magnetic stimulation of the angiogenic potential of mesenchymal stromal cells in vascular tissue engineering.

The growing prevalence of vascular diseases worldwide has emphasized the need for novel tissue-engineered options concerning the development of vascularized 3D constructs. This study reports, for the first time, the use of external magnetic fields to stimulate mesenchymal stromal cells (MSCs) to increase the production of vascular endothelial growth factor-A (VEGF-A). Polyvinylalcohol and gelatin-based scaffolds, containing iron oxide nanoparticles, were designed for optimal cell magnetic stimulation. While the application of static magnetic fields over 24 h did not impact on MSCs proliferation, viability and phenotypic identity, it significantly increased the production of VEGF-A and guided MSCs morphology and alignment. The ability to enhance MSCs angiogenic potential was demonstrated by the increase in the number of new vessels formed in the presence of MSCs conditioned media through in vitro and in vivo models. Ultimately, this study uncovers the potential to manipulate cellular processes through short-term magnetic stimulation.

Glycosaminoglycan remodeling during chondrogenic differentiation of human bone marrow-/synovial-derived mesenchymal stem/stromal cells under normoxia and hypoxia.

Glycosaminoglycans (GAGs) are major components of cartilage extracellular matrix (ECM), which play an important role in tissue homeostasis not only by providing mechanical load resistance, but also as signaling mediators of key cellular processes such as adhesion, migration, proliferation and differentiation. Specific GAG types as well as their disaccharide sulfation patterns can be predictive of the tissue maturation level but also of disease states such as osteoarthritis. In this work, we used a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to perform a comparative study in terms of temporal changes in GAG and disaccharide composition between tissues generated from human bone marrow- and synovial-derived mesenchymal stem/stromal cells (hBMSC/hSMSC) after chondrogenic differentiation under normoxic (21% O2) and hypoxic (5% O2) micromass cultures. The chondrogenic differentiation of hBMSC/hSMSC cultured under different oxygen tensions was assessed through aggregate size measurement, chondrogenic gene expression analysis and histological/immunofluorescence staining in comparison to human chondrocytes. For all the studied conditions, the compositional analysis demonstrated a notable increase in the average relative percentage of chondroitin sulfate (CS), the main GAG in cartilage composition, throughout MSC chondrogenic differentiation. Additionally, hypoxic culture conditions resulted in significantly different average GAG and CS disaccharide percentage compositions compared to the normoxic ones. However, such effect was considerably more evident for hBMSC-derived chondrogenic aggregates. In summary, the GAG profiles described here may provide new insights for the prediction of cartilage tissue differentiation/disease states and to characterize the quality of MSC-generated chondrocytes obtained under different oxygen tension culture conditions.

Resolution of alkaloid racemate: a novel microbial approach for the production of enantiopure lupanine via industrial wastewater valorization.

BACKGROUND: Lupanine is a plant toxin contained in the wastewater of lupine bean processing industries, which could be used for semi-synthesis of various novel high added-value compounds. This paper introduces an environmental friendly process for microbial production of enantiopure lupanine. RESULTS: Previously isolated P. putida LPK411, R. rhodochrous LPK211 and Rhodococcus sp. LPK311, holding the capacity to utilize lupanine as single carbon source, were employed as biocatalysts for resolution of racemic lupanine. All strains achieved high enantiomeric excess (ee) of L-(-)-lupanine (> 95%), while with the use of LPK411 53% of the initial racemate content was not removed. LPK411 fed with lupanine enantiomers as single substrates achieved 92% of D-(+)-lupanine biodegradation, whereas L-(-)-lupanine was not metabolized. Monitoring the transcriptional kinetics of the luh gene in cultures supplemented with the racemate as well as each of the enantiomers supported the enantioselectivity of LPK411 for D-(+)-lupanine biotransformation, while (trans)-6-oxooctahydro-1H-quinolizine-3-carboxylic acid was detected as final biodegradation product from D-(+)-lupanine use. Ecotoxicological assessment demonstrated that lupanine enantiomers were less toxic to A. fischeri compared to the racemate exhibiting synergistic interaction. CONCLUSIONS: The biological chiral separation process of lupanine presented here constitutes an eco-friendly and low-cost alternative to widely used chemical methods for chiral separation.

Impact of Season of Birth on Psychiatric Disorder Susceptibility and Drug Abuse Incidence in a Population from the Köppen Tropical Savanna Region of Brazil.

BACKGROUND: Despite much evidence that season of birth (SOB) my influence the vulnerability to psychiatric disorders, divergence has been reported, in particular between populations born in the northern and southern hemispheres. We analyzed the potential modified risk by SOB to psychiatric disorder or drug addiction comorbidity in a population born in the Triângulo Mineiro region, a southern hemisphere Köppen tropical savanna region in Brazil. METHOD: We accessed the records of 98,457 of patients and healthy controls of the National Datacenter of Medical Promptuary to evaluate the influence of SOB as a modifying factor on the occurrence of mental disorders and drug abuse conditions among individuals born from the year 2000 to 2016. RESULTS: The data revealed significant modification of the relative incidence of major depressive disorder (MDD) (F11, 72 = 2.898; p = 0.003; eta-squared, ES = 0.313; ⍺ = 0.97), anxiety-related disorder (ARD) (F11, 81 =2.389; p = 0.013; ES = 0.241; ⍺ = 0.932), and schizophrenia (SZ) (F11, 83 = 2.764; p = 0.005; ES = 0.303; α = 0.963), while there was no increase in the number of healthy controls born in any month of the year (F11, 71 = 1.469; p = 0.163). Post hoc analyses indicated a significant higher vulnerability to MDD or ARD if the patient was born in August, or October to December, respectively. A relative increase in the incidence of SZ was also observed in patients born from August to October, compared to patients born from November to January. CONCLUSIONS: SOB may influence the risk for psychiatric disorders in the TMR population. Regional particularities associated with the climatic regime may account for the apparent divergence between studies.

Health-Related Quality of Life in Patients with Moderate to Severe Ulcerative Colitis: Surgical Intervention versus Immunomodulatory Therapy.

PURPOSE: Ulcerative colitis (UC) can be managed with immunomodulation or surgery. We aimed to understand whether these strategies had a different impact on patients' health-related quality of life (HRQoL). METHODS: This was a retrospective, cross-sectional study: patients who had a moderate to severe UC episode that prompted the utilization of immunomodulatory drugs or surgery were invited to complete a generic (short form [36] health survey [SF-36]) and a disease-specific (inflammatory bowel disease questionnaire [IBDQ]) survey. RESULTS: We included 157 patients, 65 (41.4%) surgically treated. The therapeutic procedure had a minimal impact on HRQoL: only the social dimension of the IBDQ and the physical function component of the SF-36 were significantly different between the study arms - lower for the surgically treated patients. The type of surgery had no impact, but the occurrence of pouchitis, namely, in a chronic form, was associated with a lower HRQoL. Regression analysis confirmed surgery as an independent predictor of lower scores in the social dimension of the IBDQ (-4.646, 95% CI -6.953 to -2.339) and in the physical functioning (-9.622, 95% CI -17.061 to -2.183) and physical role functioning (-3.669, 95% CI -7.339 to 0.001) dimensions of the SF36. CONCLUSIONS: Although usually feared by patients, surgery has a limited impact on UC patients HRQoL when compared to medical management with immunomodulatory drugs.

Evaluation of thrombocytopenia in patients with non-alcoholic fatty liver disease without cirrhosis.

INTRODUCTION AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. It is often related to metabolic syndrome, presenting an increased risk of advanced liver disease and cardiovascular-related death. In some etiologies of chronic liver disease, thrombocytopenia has been associated not only with advanced stages of fibrosis but also with autoimmune disease. In NAFLD, however, its prevalence and related factors are still unknown. The aim of this study is to evaluate the prevalence of thrombocytopenia in NAFLD patients without cirrhosis and to investigate its related risk factors. PATIENTS AND METHODS: This was a retrospective study carried out in two tertiary hospitals in the South and Southeast regions of Brazil. Patients diagnosed with NAFLD by liver biopsy were included. Those with other causes of liver disease and/or cirrhosis were excluded. For analysis, patients were divided into two groups, with and without thrombocytopenia. Data was analyzed using a significance level of 5%. RESULTS: 441 non-cirrhotic patients with NAFLD (evaluated by liver biopsy) were included in the study. The prevalence of thrombocytopenia was 3.2% (14/441 patients). In the comparative analysis between groups, thrombocytopenia was associated with male sex (p=0.007) and level of hemoglobin (p=0.023). CONCLUSION: Thrombocytopenia is an infrequent event in NAFLD patients without cirrhosis and is related with male sex and higher hemoglobin levels.