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This manuscript presents an experimental and modeling approach in order to characterize the stiffness loss of bioabsorbable polymer filaments due to hydrolysis. In this regard, bioabsorbable suture yarns (poly(lactic-co-glycolic) acid—PLGA) were chosen as a representative material for the present investigation. The observed mechanical response was characterized by means of a thermodynamically consistent constitutive variational framework. Usually, two different damage variables are assumed to take place in this class of materials: a hydrolytic damage (long-term degradation) and a strain-driven damage (short-term degradation). This work concerns the proposition of a constitutive model that only considers the hydrolytic damage, in which a specific strain energy and a proper dissipation damage potential were tailored to model the tested material. A nonlinear curve fitting procedure based on Particle Swarm Optimization was performed to identify the constitutive parameters. A set of numerical simulations demonstrates the effectiveness of the proposed constitutive model to predict damage-induced creep and damage-induced stress relaxation, behaviors that can be used as design criteria in absorbable implants. The main achieved results show that the proposed constitutive approach leads to a simple but effective model capable to drive the first steps in the design of absorbable biomedical devices. The present variational framework can be extended to study the constitutive response of other bioabsorbable polymers, accounting for viscous and/or plastic behaviors.

Congenital myasthenic syndromes are disorders of the neuromuscular junction resulting from genetic defects in its components. Clinical presentations are diverse and virtually always of early onset. We herein report a 67-year-old female patient first presenting with episodes of sudden respiratory failure. A diagnosis of seronegative myasthenia gravis was put forward based on the presence of a limb-girdle pattern of muscle weakness with pathological decremental responses on repetitive nerve stimulation. Lack of response to steroids, intravenous human immunoglobulin and acetylcholinesterase inhibitors lead us to test for classical congenital myasthenic syndrome genes. A c.1378dup heterozygotic mutation in DOK7 was found, classically (albeit not exclusively) described as pathogenic only when inherited in a homozygotic fashion. Patients with such a single, heterozygous mutation have been previously described, but these have been left unexplained. Thus, under certain still poorly understood circumstances, an heterozygotic state may allow for disease manifestation. These patients may benefit from tailored therapies akin to those normally reserved to homozygotic/compound heterozygotic patients. Awareness for and recognition of such conditions are expected to allow for better provided care and improved quality of life.

Sydenham's chorea is an autoimmune chorea emerging after a group A beta-hemolytic streptococcal (GABHS) infection, i.e. a rheumatic chorea with or without the presence of carditis or arthritis. The disorder, defined by the presence of chorea, is also associated with cognitive and behavioral symptoms, including emotional lability, anxiety, depressive and obsessive-compulsive symptoms. The authors review the pathophysiology, clinical characteristics, and available evidence on therapeutic strategies, the latter including the secondary prevention of GABHS infections, reduction of chorea, and immune modulation. Sydenham's chorea has been regarded as a model for pediatric autoimmune neuropsychiatric disorders, however, the field is marked by conflicting results and controversies. Regarding therapeutics, there are limited high-quality interventional studies and the selection of treatment strategy often relies on the clinician's experience. A serial treatment algorithm is presented based upon the severity of clinical presentation and response to symptomatic pharmacotherapy.

ObjectiveIschaemic stroke is a severe complication of rheumatic heart disease (RHD), which may result in permanent disability and death. This study aimed to assess the incidence and predictors of stroke in patients with RHD in the current era of evidence-based recommendations for prevention.MethodsConsecutive patients with RHD diagnosed by clinical and echocardiographic criteria were selected. A structured clinical and neurological assessment was performed to determine the aetiology and classification of stroke at enrolment. The primary endpoint was an ischaemic cerebrovascular event, which included fatal or non-fatal stroke. Risk of stroke was estimated accounting for competing risks.ResultsA total of 515 patients were enrolled, 438 women (85%), 46±12 years of age. The most frequent valve lesion was mixed mitral (80%). At the time of enrolment, 92 patients (18%) had a prior stroke, with anterior circulation infarction being the most frequent topography (72%). During the mean follow-up of 3.9 years, 27 patients (5.2%) had stroke with the overall incidence of 1.47 strokes per 100 patient-years. Predictors of stroke by the Cox model were prior stroke (adjusted HR 5.395, 95% CI 2.272 to 12.811), age (HR 1.591, 95% CI 1.116 to 2.269) and atrial fibrillation (AF) at baseline (HR 2.945, 95% CI 1.083 to 8.007). By considering death as a competing risk, the effect of AF on stroke risk was attenuated (HR 2.287, 95% CI 0.962 to 5.441).ConclusionsIn this large cohort of patients with RHD, stroke occurred in 5.2% of the patients, which was predicted by age, AF and prior stroke. The effect of AF on stroke risk estimation was influenced by death as competing risk.

Inflammatory bowel disease (IBD) is a multifactorial chronic disease, commonly associated with alteration in the composition and function of gut microbiota. This process can lead to a decreased production of short chain fatty acids (SCFAs) by the gut microbiota, mainly butyrate, which is an important immunomodulatory molecule in the intestine. Butyrogenic bacteria normally produces butyrate through carbohydrate fermentation or amino acids degradation pathways. This molecule plays an important protective role in intestinal homeostasis acting in both adaptive immunity and innate immunity. This review summarizes the current knowledge about the role of butyrate on the development of IBD and the protective mechanisms of this metabolite on the intestinal mucosa and the whole body, as reported by in vitro and in vivo studies. Thus, butyrate can regulate the activation of regulatory T cells, increasing the acetylation of histones and decreasing the activation of NF-κB. In addition, it can also stimulate the mucus production from epithelial cells and the rearrangement of tight junction proteins.

Cerebrospinal fluid (CSF) is an excellent source of biological information regarding the nervous system, once it is in close contact and accurately reflects alterations in this system. Several studies have analyzed differential protein profiles of CSF samples between healthy and diseased human subjects. However, the pathophysiological mechanisms and how CSF proteins relate to diseases are still poorly known. By applying bioinformatics tools, we attempted to provide new insights on the biological and functional meaning of proteomics data envisioning the identification of putative disease biomarkers. Bioinformatics analysis of data retrieved from 99 mass spectrometry (MS)-based studies on CSF profiling highlighted 1985 differentially expressed proteins across 49 diseases. A large percentage of the modulated proteins originate from exosome vesicles, and the majority are involved in either neuronal cell growth, development, maturation, migration, or neurotransmitter-mediated cellular communication. Nevertheless, some diseases present a unique CSF proteome profile, which were critically analyzed in the present study. For instance, 48 proteins were found exclusively upregulated in the CSF of patients with Alzheimer's disease and are mainly involved in steroid esterification and protein activation cascade processes. A higher number of exclusively upregulated proteins were found in the CSF of patients with multiple sclerosis (76 proteins) and with bacterial meningitis (70 proteins). Whereas in multiple sclerosis, these proteins are mostly involved in the regulation of RNA metabolism and apoptosis, in bacterial meningitis the exclusively upregulated proteins participate in inflammation and antibacterial humoral response, reflecting disease pathogenesis. The exploration of the contribution of exclusively upregulated proteins to disease pathogenesis will certainly help to envision potential biomarkers in the CSF for the clinical management of nervous system diseases.

Alternatives that alleviate stress-related responses and improve performance of the beef cattle herd are imperative and deserve further investigation. In previous trials, administration of the bovine appeasing substance (BAS) has improved performance of newly-weaned and feedlot received beef animals, as well as reduced the risk of dark, firm, and dry (DFD) cuts in carcass obtained from Bos indicus cattle. Therefore, this study was designed to evaluate the effects of BAS administration at castration on pre-conditioning performance of crossbred beef animals. On day 0, 390 crossbred Angus × Nellore animals were ranked by initial shrunk BW (255 ± 21.1 kg) and assigned to receive or not (CON) 5 mL/head of BAS (SecureCattle; Nutricorp, Araras, SP, Brazil) immediately before castration. From d 0 to 30, animals within treatments were maintained in 2 feedot pens with a minimum distance (300 m) to avoid contact between treatment groups and received a grass hay-based diet (70:30 roughage:concentrate ratio) ad libitum. On day 30, animals were individually weighed following 16 hours of feed and water restriction. Hence, a descriptive analysis was performed to evaluate pen dry matter intake (DMI) and feed efficiency (FE). Animal was considered the experimental unit and all data were analyzed using the PROC MIXED procedure of SAS (version 9.4; SAS Inst. Inc., Cary, NC). Bovine appeasing substance administration at castration improved ADG and BW change (P < 0.0001) compared with CON cohorts (0.983 vs. 1.155 kg/d and 29.5 vs. 34.6 kg for ADG and BW change, respectively). Total DMI was similar among treatments when reported as kg/d (6.70 vs. 6.75 kg) or % of BW (2.48 vs. 2.48%), whereas FE was dramatically improved in BAS-administered animals (146 vs. 172 g/kg for CON and BAS, respectively). In summary, BAS administration improved performance of crossbred beef animals for 30 days post-castration.

Petiveria alliacea L. (Phytolaccaceae) is an Amazonian shrub used in traditional medicine for many purposes. This study investigated the genotoxicity of the hydroalcoholic extract of P. alliacea (EHPa). In addition, we conducted pharmacognostic characterization and phytochemical investigation. Phytochemical screening and thin layer chromatography (TLC) were used to determine the chemical composition of the extract. Genotoxicity was evaluated using an in vitro comet assay in human lymphocytes (50, 100, and 250 mg/ml) and an in vivo micronucleus assay in mice orally treated with the extract (50, 100, and 250 mg/kg b.w., p.o.). The phytochemical screening identified the metabolites reducing sugars, alkaloids and saponins. TLC analyses identified organosulfur compounds in EHPa. Comet assay data showed that EHPa induced exacerbated DNA damage at 100 mg/ml treatments (EHPa 100 mg/ml: TL 219.13 ± 48.38 mm, % DNA-t 59.33 ± 18.98%, TM 134.99 ± 61.34, OM 87.48 ± 32.98) as compared with negative control (Roswell Park Memorial Institute (RPMI): TL 37.79 ± 24.79 mm, % DNA-t 9.73 ± 6.56%, TM 4.86 ± 5.79, OM 6.90 ± 5.80; p

Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence ofβ-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβpeptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aβpeptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.

The human gut barrier is the tissue exposed to the highest load of microorganisms, harbouring 100 trillion bacteria. In addition, the gut's renewal rate outruns that of any other human tissue. Antimicrobial peptides (AMPs) are highly optimized defense molecules in the intestinal barrier optimized to maintain gastrointestinal homeostasis. Alterations in AMPs activity can lead to or result from human gastrointestinal diseases. In this review, unique, conserved, or otherwise regular alterations in the expression patterns of human AMPs across gastrointestinal inflammatory and infectious diseases were analyzed for pattern elucidation. Human gastrointestinal diseases are associated with alterations in gut AMPs' expression patterns in a peptide-specific, disease-specific, and pathogen-specific way, modulating human gastrointestinal functioning. Across diseases, there is a (i) marked reduction in otherwise constitutively expressed AMPs, leading to increased disease susceptibility, and a (ii) significant increase in the expression of inducible AMPs, leading to tissue damage and disease severity. Infections and inflammatory conditions are associated with altered gene expression in the gut, whose patterns may favour cellular metaplasia, mucosal dysfunction, and disease states. Altered expression of AMPs can thus thrive disease severity and evolution since its early stages. Nevertheless, the modulation of AMP expression patterns unveils promising therapeutic targets.

The ageing phenomenon is intrinsically responsible for diseases and lifestyle-associated conditions afflicting the ageing male. In particular, male infertility seems to result from deleterious lifestyle choices. However, the ageing effect at the individual gene/protein level is poorly discussed and valuable information is certainly missing. We have thus used an omics approach to identify differentially expressed proteins and genes from spermatozoa and seminal plasma samples across several conditions affecting adult male fertility. Our search resulted in 400 differentially expressed proteins in seminal plasma and 409 differentially expressed proteins in spermatozoa as well as, almost 6,000 differentially expressed spermatozoa mRNAs. We have functionally analyzed these proteins and genes to understand and discuss how biological processes and signaling pathways associated with ageing might affect male fertility. Sperm and seminal fluid proteins from infertile males display significant alterations in i) processes previously implicated in the ageing phenomena, such as mitochondrial dysfunction, DNA instability, oxidative stress, protein misfolding and intracellular mistrafficking, and ii) processes specifically involved in reproductive phenomena, such as sperm-egg recognition/acrosome reaction, embryo and morula development, blastocyst implantation and DNA methylation involved in embryo development. These proteins display a widespread distribution and seem to be significantly influenced by deleteriously lifestyle choices. Conventional assays to assess male fertility are inadequate to comprehensively reveal the broad-spectrum of alterations at the transcriptional and translational levels afflicting the infertile ageing male. In turn, proteomics and transcriptomics are suitable options for addressing these key issues that may explain many poorly understood fertility-associated phenomena resulting from the ageing process.

Bladder cancer (BCa) is one of the most prevalent malignancies worldwide. Risk factors for BCa are well established and include smoking and infections, which can lead to immune system activation, altered gene expression patterns, proteolytic activity, tissue damage, and, ultimately, cancer development. Urine has become one of the most attractive diagnosis samples, and, notably, urine profiling by mass spectrometry allows the simultaneously analysis of multiple enzymes and their interactors, substrates, inhibitors, and regulators, providing an integrative view of enzymatic dynamics. Most BCa-associated enzymatic alterations take place at the level of proteases, being MMP-9, MMP-2, urokinase-type plasminogen activator, cathepsin D, and cathepsin G already related to BCa development and progression. Herein, we overview the role of proteases and the classes more studied in BCa pathogenesis, as well as the methodologies used for assessing protease amount and activity in urine samples, highlighting its advantages and limitations, and the value of urinary proteases as disease biomarkers.

Purpose The pharmaceutical industry is one of the most tightly regulated sectors, and it is essential to know each country׳s legal framework to understand the regulation, approval, and marketing of medicinal products for human use. This article describes the main statutes and procedures governing medicinal products for human use in Portugal and the role of the country׳s National Medicines and Health Products Authority ( Autoridade Nacional do Medicamento e Produtos de Saude, I.P. ; INFARMED). Methods From the most recently available data, an update of requests and approvals concerning marketing authorizations, variations, pricing, and reimbursements is provided. Data were sourced from the INFARMED website, Infomed (database of medicinal products for human use), and periodic reports issued by national authorities. Organic laws, acts, and law decrees published in the government gazette ( Diario da Republica ) are cited and reproduced as required. Findings In 2015 Portugal ranked fifth in the European System of Medicines Evaluation in terms of the number of completed procedures as a reference member state. Approximately 80% of all approved drug applications in Portugal in 2015 were for generic drugs, mostly pertaining to the nervous system. In Portugal, INFARMED monitors drug quality, safety profile, and efficacy in all stages of the drug life cycle, ensuring patients' safety. Implications The Portuguese market for medicinal products for human use has been appreciably changed by the advent of generic drugs. There is an increased trend for new request applications for biological and biotechnological substances.

Antimicrobial peptides (AMPs) are an integral part of the innate immune defense mechanism of many organisms. Due to the alarming increase of resistance to antimicrobial therapeutics, a growing interest in alternative antimicrobial agents has led to the exploitation of AMPs, both synthetic and isolated from natural sources. Thus, many peptide‐based drugs have been the focus of increasing attention by many researchers not only in identifying novel AMPs, but in defining mechanisms of antimicrobial peptide activity as well. Herein, we review the available strategies for the identification of AMPs in human body fluids and their mechanism(s) of action. In addition, an overview of the distribution of AMPs across different human body fluids is provided, as well as its relation with microorganisms and infectious conditions.

Evidence on the impacts of a large-scale expansion in preprimary education is limited and mostly circumscribed to high- and middle-income nations. This study estimates the effects of such an expansion on progression in primary school in rural communities in Guatemala, where the number of pre-primary schools increased from about 5,300 to 11,500 between 1998 and 2005. Combining administrative and population census data in a difference-in-differences framework, the analysis finds that access to pre-primary education increased by 2.4 percentage points the proportion of students that progress adequately and attend sixth grade by age 12. These positive although limited effects suggest the need for complementary actions to produce substantial improvements in adequate progression.

Petiveria alliacea is a perennial Amazonian shrub used in traditional medicine for many purposes worldwide, including as antirheumatic, antispasmodic, antifungal, and analgesic for pain relief. Herein, this review aimed to provide a concise overview of the phytochemistry and antimicrobial, anticancer, and immunomodulatory properties reported in the literature for P. alliacea. The herb is rich in sulfur-containing compounds that possess a broad-spectrum of in vitro antimicrobial activity against pathogenic fungi and bacteria at low concentrations. P. alliacea also showed cytotoxicity and antiproliferative activity against cancer cell lines through sophisticated machinery of cellular damage in vitro. Other compounds such as flavonoids, terpenoids, and benzenoids are commonly identified in P. alliacea extracts, and they may also justify these activities. Despite the great pharmacological potential, clinical trials are required to ensure its effectiveness and safety. This review may raise new trends on the studies as well as contribute to the community by offering data for decision-making with regard to its use in treating diseases.