Structural Characterization and Rat Aortic Vascular Reactivity of Bradykinin-Potentiating Peptides (BPPs) from the Snake Venom of Bothrops moojeni from Delta do Parnaíba Region, Brazil.

Snake venoms contain various bradykinin-potentiating peptides (BPPs). First studied for their vasorelaxant properties due to angiotensin converting enzyme (ACE) inhibition, these molecules present a range of binding partners, among them the argininosuccinate synthase (AsS) enzyme. This has renewed interest in their characterization from biological sources and the evaluation of their pharmacological activities. In the present work, the low molecular weight fraction of Bothrops moojeni venom was obtained and BPPs were characterized by mass spectrometry. Eleven BPPs or related peptides were sequenced, and one of them, BPP-Bm01, was new. Interestingly, some oxidized BPPs were detected. The three most abundant peptides were BPP-Bm01, BPP-Bax12, and BPP-13a, and their putative interactions with the AsS enzyme were investigated in silico. A binding cavity for these molecules was predicted, and docking studies allowed their ranking. Three peptides were synthesized and submitted to vasorelaxation assays using rat aortic rings. While all BPPs were active, BPP-Bm01 showed the highest potency in this assay. This work adds further diversity to BPPs from snake venoms and suggests, for the first time, a putative binding pocket for these molecules in the AsS enzyme. This can guide the design of new and more potent AsS activators.

Pseudobombax parvifolium Hydroalcoholic Bark Extract: Chemical Characterisation and Cytotoxic, Mutagenic, and Preclinical Aspects Associated with a Protective Effect on Oxidative Stress.

Plants have long been used in traditional medicine to treat illnesses. Nevertheless, their chemical diversity requires studies to establish the extract dosage and its safe use. Pseudobombax parvifolium, an endemic species of the Brazilian Caatinga biome, is commonly used in folk medicine, due to its anti-inflammatory properties related to cellular oxidative stress; however, its biological properties have scarcely been studied. In this study, we chemically characterized the P. parvifolium hydroalcoholic bark extract (EBHE) and evaluated its cytotoxic, mutagenic, and preclinical aspects, as well as its antioxidant effect. Our phytochemical analysis revealed a significative total polyphenol content and identified loliolide for the first time in this species. Cytotoxicity, mutagenicity, and acute oral and repeated dose indicated no toxic effects on cell culture, Drosophila melanogaster, and Wistar rat exposure to different EBHE concentrations, respectively. Furthermore, we observed a significant decrease in lipid peroxidation and a mild hypoglycemic and hypolipidemic effect with repeated oral dosing of EBHE. Although there were no significant changes in glutathione content, we did observe a significant increase in superoxide dismutase at a dose of 400 mg/kg and in glutathione peroxidase at doses of 100, 200, and 400 mg/kg. These findings suggest that EBHE has potential as a source of bioactive molecules, and it can be used safely in traditional medicine and in the development of herbal medicines for application in the public health system.

Cervical cancer prevention program in Mexico disrupted due to COVID-19 pandemic: Challenges and opportunities.

Introduction: The COVID-19 pandemic disrupted the preventive services for cervical cancer (CC) control programs in Mexico, which will result in increased mortality. This study aims to assess the impact of the pandemic on the interruption of three preventive actions in the CC prevention program in Mexico. Methods: This study is a retrospective time series analysis based on administrative records for the uninsured population served by the Mexican Ministry of Health. Patient data were retrieved from the outpatient service information system and the hospital discharge database for the period 2017-2021. Data were aggregated by month, distinguishing a pre-pandemic and a pandemic period, considering April 2020 as the start date of the pandemic. A Poisson time series analysis was used to model seasonal and secular trends. Five process indicators were selected to assess the disruption of the CC program, these were analyzed as monthly data (N=39 pre-pandemic, N=21 during the pandemic). HPV vaccination indicators (number of doses and coverage) and diagnostic characteristics of CC cases were analyzed descriptively. The time elapsed between diagnosis and treatment initiation in CC cases was modeled using restricted cubic splines from robust regression. Results: Annual HPV vaccination coverage declined dramatically after 2019 and was almost null in 2021. The number of positive Papanicolaou smears decreased by 67.8% (90%CI: -72.3, -61.7) in April-December 2020, compared to their expected values without the pandemic. The immediate pandemic shock (April 2020) in the number of first-time and recurrent colposcopies was -80.5% (95%CI:-83.5, -77.0) and -77.9% (95%CI: -81.0, -74.4), respectively. An increasing trend was observed in the proportion of advanced stage and metastatic CC cases. The fraction of CC cases that did not receive medical treatment or surgery increased, as well as CC cases that received late treatment after diagnosis. Conclusions: Our analyses show significant impact of the COVID-19 pandemic with declines at all levels of CC prevention and increasing inequalities. The restarting of the preventive programs against CC in Mexico offers an opportunity to put in place actions to reduce the disparities in the burden of disease between socioeconomic levels.

The health system and access to treatment in patients with cervical cancer in Mexico.

Cervical cancer (CC) is tightly related to a low Human Development Index. Mexico is an upper-middle-income country with 126 million inhabitants, and its public health system aims to provide universal health coverage. Currently, employment-based social insurance covers approximately 60% of the population, and the scope of the remaining 40% is on course via the "IMSS-Bienestar" Institute. However, the annual government spending on health remains at 3% of the Gross Domestic Product, which is well below the 6% recommended by the Organization for Economic Cooperation and Development. CC is the second in incidence and mortality among women. Regarding primary prevention with the Human Papilloma Virus-vaccine, the current coverage for girls aged 9 to 14 years is only around 7%. Among secondary prevention with screening, the program is yet to cover the total number of women at risk; nevertheless, the age-standardized CC mortality rate has decreased from 12 per 100,000 women in 1979 to 5.7 per 100,000 women in 2020 due in part to increased screening coverage. Still, around two-thirds of patients present with locally advanced disease at diagnosis. Data from our country demonstrate that even socially disadvantaged CC patients achieve "standard" survival outcomes if treatment is granted. Nevertheless, there is a shortage in almost every aspect regarding CC treatment, including oncologists, chemotherapy units, medical physicists, radiation technicians, and both teletherapy and brachytherapy facilities. In conclusion, advances in the public health system in Mexico are urgently required to achieve CC control and reduce the mortality from this neoplasia that mainly targets socially disadvantaged women.

Análisis de costos de la atención hospitalaria en un paciente con fibrilación auricular no valvular y accidente cerebrovascular a repetición / Cost analysis of in hospital attention in a non-valvular atrial fibrillation patient and recurrent stroke

RESUMEN INTRODUCCIÓN: Paciente de 71 años con diagnóstico de fibrilación auricular y ataques cerebrovasculares recurrentes, tratada con varios anticoagulantes. El costo del tratamiento del ictus en Colombia para el año 2008 fue de $450.000 millones de pesos colombianos. OBJETIVO: Estimar el costo hospitalario de la atención de un paciente con ictus a repetición secundario a fibrilación auricular. MÉTODOS: Estudio económico parcial de microcosteo de la atención intrahospitalaria para un caso de espectro severo recurrente, que no necesariamente refleja el caso promedio. El consumo de recursos se valoró mediante el uso de tarifas de referencia nacionales. Los resultados se presentan en precios actuales del 2019 (peso colombiano y dólar americano). RESULTADOS: Paciente con 3 eventos hospitalarios, que estuvo 31 días hospitalizada. Las hospitalizaciones tuvieron unos costos de: $53.883.490 (USD 16.141,1), $6.343.096 (USD 1.900,1) y $15.719.443 (USD 4.708,9) respectivamente, con un precio promedio por cada hospitalización de $25.315.343 (USD 7.583,4), costo total de $75.946.029 (USD 22.750,1) costo día de $2.449.872 (USD 729,5). El rubro que aumentó consistentemente los costos fueron los procedimientos (35,7 %). CONCLUSIONES: El ictus recurrente causado por fibrilación auricular no valvular se asocia con un incremento significativo de los costos directos, con un impacto de casi dos veces el PIB per cápita. Un diagnóstico oportuno y una selección adecuada pueden reducirlo.

ABSTRACT INTRODUCTION: A 71-year-old patient with a diagnosis of atrial fibrillation and recurrent strokes, treated with various anticoagulants, the stroke treatment in Colombia for 2008 was $ 450 billion Colombian pesos. OBJECTIVE: To estimate the hospital cost of caring for a patient with recurrent stroke secondary to atrial fibrillation. METHODS: Partial economic study of micro costing of in-hospital care for a case of recurrent severe spectrum stroke, which does not necessarily reflect the average case. Resource consumption was valued using national reference rates. The results are presented in current 2019 prices (Colombian pesos and US dollars). RESULTS: Patient with 3 hospital events, who was hospitalized for 31 days. Hospitalizations had costs of $ 53,883,490 (USD 16,141.1), $ 6,343,096 (USD 1,900.1) and $ 15,719,443 (USD 4,708.9) respectively, with an average price for each hospitalization of $ 25,315,343 (USD 7,583.4), total cost of $ 75,946,029 (USD 22,750.1) daily cost of $ 2,449,872 (USD 729.5). The item that consistently increased costs was procedures (35.7 %). CONCLUSIONS: Recurrent stroke caused by nonvalvular atrial fibrillation is associated with a significant increase in direct costs, with an impact of almost twice the GDP per capita. A timely diagnosis and proper selection can reduce it.

Chemical Characterization of Flowers and Leaf Extracts Obtained from Turnera subulata and Their Immunomodulatory Effect on LPS-Activated RAW 264.7 Macrophages.

The anti-inflammatory properties of Turnera subulata have been evaluated as an alternative drug approach to treating several inflammatory processes. Accordingly, in this study, aqueous and hydroalcoholic extracts of T. subulata flowers and leaves were analyzed regarding their phytocomposition by ultrafast liquid chromatography coupled to mass spectrometry, and their anti-inflammatory properties were assessed by an in vitro inflammation model, using LPS-stimulated RAW-264.7 macrophages. The phytochemical profile indicated vitexin-2-O-rhamnoside as an important constituent in both extracts, while methoxyisoflavones, some bulky amino acids (e.g., tryptophan, tyrosine, phenylalanine), pheophorbides, and octadecatrienoic, stearidonic, and ferulic acids were detected in hydroalcoholic extracts. The extracts displayed the ability to modulate the in vitro inflammatory response by altering the secretion of proinflammatory (TNF-α, IL-1ß, and IL-6) and anti-inflammatory (IL-10) cytokines and inhibiting the PGE-2 and NO production. Overall, for the first time, putative compounds from T. subulata flowers and leaves were characterized, which can modulate the inflammatory process. Therefore, the data highlight this plant as an option to obtain extracts for phytotherapic formulations to treat and/or prevent chronic diseases.

Novel disintegrin-like peptides derived from an amphibian skin cDNA sequence of Hypsiboas punctatus.

Disintegrins comprise a family of small proteins that bind to and alter the physiological function of integrins, especially integrins that mediate platelet aggregation in blood. Here, we report a lysine-glycine-aspartic acid (KGD) disintegrin-like motif present in a 15-amino acid residue peptide identified in a cDNA library of the amphibian Hypsiboas punctatus skin. The original peptide sequence was used as a template from which five new analogs were designed, chemically synthesized by solid phase, and tested for disintegrin activity and tridimensional structural studies using NMR spectroscopy. The original amphibian peptide had no effect on integrin-mediated responses. Nevertheless, derived peptide analogs inhibited integrin-mediated platelet function, including platelet spreading on fibrinogen.

Nonproportional hazards model with a frailty term for modeling subgroups with evidence of long-term survivors: Application to a lung cancer dataset.

With advancements in medical treatments for cancer, an increase in the life expectancy of patients undergoing new treatments is expected. Consequently, the field of statistics has evolved to present increasingly flexible models to explain such results better. In this paper, we present a lung cancer dataset with some covariates that exhibit nonproportional hazards (NPHs). Besides, the presence of long-term survivors is observed in subgroups. The proposed modeling is based on the generalized time-dependent logistic model with each subgroup's effect time and a random term effect (frailty). In practice, essential covariates are not observed for several reasons. In this context, frailty models are useful in modeling to quantify the amount of unobservable heterogeneity. The frailty distribution adopted was the weighted Lindley distribution, which has several interesting properties, such as the Laplace transform function on closed form, flexibility in the probability density function, among others. The proposed model allows for NPHs and long-term survivors in subgroups. Parameter estimation was performed using the maximum likelihood method, and Monte Carlo simulation studies were conducted to evaluate the estimators' performance. We exemplify this model's use by applying data of patients diagnosed with lung cancer in the state of São Paulo, Brazil.

Weighted Lindley frailty model: estimation and application to lung cancer data.

In this paper, we propose a novel frailty model for modeling unobserved heterogeneity present in survival data. Our model is derived by using a weighted Lindley distribution as the frailty distribution. The respective frailty distribution has a simple Laplace transform function which is useful to obtain marginal survival and hazard functions. We assume hazard functions of the Weibull and Gompertz distributions as the baseline hazard functions. A classical inference procedure based on the maximum likelihood method is presented. Extensive simulation studies are further performed to verify the behavior of maximum likelihood estimators under different proportions of right-censoring and to assess the performance of the likelihood ratio test to detect unobserved heterogeneity in different sample sizes. Finally, to demonstrate the applicability of the proposed model, we use it to analyze a medical dataset from a population-based study of incident cases of lung cancer diagnosed in the state of São Paulo, Brazil.

Survival models induced by zero-modified power series discrete frailty: Application with a melanoma data set.

Survival models with a frailty term are presented as an extension of Cox's proportional hazard model, in which a random effect is introduced in the hazard function in a multiplicative form with the aim of modeling the unobserved heterogeneity in the population. Candidates for the frailty distribution are assumed to be continuous and non-negative. However, this assumption may not be true in some situations. In this paper, we consider a discretely distributed frailty model that allows units with zero frailty, that is, it can be interpreted as having long-term survivors. We propose a new discrete frailty-induced survival model with a zero-modified power series family, which can be zero-inflated or zero-deflated depending on the parameter value. Parameter estimation was obtained using the maximum likelihood method, and the performance of the proposed models was performed by Monte Carlo simulation studies. Finally, the applicability of the proposed models was illustrated with a real melanoma cancer data set.

Identification of Differential N-Glycan Compositions in the Serum and Tissue of Colon Cancer Patients by Mass Spectrometry.

Colorectal cancer (CRC) ranks second as the leading cause of cancer-related deaths worldwide. N-glycosylation is one of the most common posttranslational protein modifications. Therefore, we studied the total serum N-glycome (TSNG) of 13 colon cancer patients compared to healthy controls using MALDI-TOF/MS and LC-MS. N-glycosylation of cancer tumor samples from the same cohort were further quantified using a similar methodology. In total, 23 N-glycan compositions were down-regulated in the serum of colon cancer patients, mostly galactosylated forms whilst the mannose-rich HexNAc2Hex7, the fucosylated bi-antennary glycan HexNAc4Hex5Fuc1NeuAc2, and the tetra-antennary HexNAc6Hex7NeuAc3 were up-regulated in serum. Hierarchical clustering analysis of TSNG correctly singled out 85% of the patients from controls. Albeit heterogenous, N-glycosylation of tumor samples showed overrepresented oligomannosidic, bi-antennary hypogalactosylated, and branched compositions related to normal colonic tissue, in both MALDI-TOF/MS and LC-MS analysis. Moreover, compositions found upregulated in tumor tissue were mostly uncorrelated to compositions in serum of cancer patients. Mass spectrometry-based N-glycan profiling in serum shows potential in the discrimination of patients from healthy controls. However, the compositions profile in serum showed no parallel with N-glycans in tumor microenvironment, which suggests a different origin of compositions found in serum of cancer patients.

Efeitos do Exercício Aeróbico Tardio na Remodelação Cardíaca de Ratos com Infarto do Miocárdio Pequeno / Effects of Late Aerobic Exercise on Cardiac Remodeling of Rats with Small-Sized Myocardial Infarction

Resumo Fundamento: O exercício físico tem sido considerado uma importante terapia não farmacológica para a prevenção e tratamento das doenças cardiovasculares. No entanto, seus efeitos na remodelação cardíaca leve não são claros. Objetivo: Avaliar a influência do exercício aeróbico sobre a capacidade funcional, estrutura cardíaca, função ventricular esquerda (VE) e expressão gênica das subunidades da NADPH oxidase em ratos com infarto do miocárdio pequeno (IM). Métodos: Três meses após a indução do IM, ratos Wistar foram divididos em três grupos: Sham; IM sedentário (IM-SED); e IM exercício aeróbico (IM-EA). Os ratos se exercitaram em uma esteira três vezes por semana durante 12 semanas. Um ecocardiograma foi realizado antes e após o treinamento. O tamanho do infarto foi avaliado por histologia e a expressão gênica por RT-PCR. O nível de significância para análise estatística foi estabelecido em 5%. Resultados: Ratos com IM menor que 30% da área total do VE foram incluídos no estudo. A capacidade funcional foi maior no IM-EA do que nos ratos Sham e IM-SED. O tamanho do infarto não diferiu entre os grupos. Ratos infartados apresentaram aumento do diâmetro diastólico e sistólico do VE, diâmetro do átrio esquerdo e massa do VE, com disfunção sistólica. A espessura relativa da parede foi menor no grupo IM-SED do que nos grupos IM-EA e Sham. A expressão gênica das subunidades NADPH oxidase NOX2, NOX4, p22phox e p47phox não diferiu entre os grupos. Conclusão: Infarto do miocárdio pequeno altera a estrutura cardíaca e a função sistólica do VE. O exercício aeróbico tardio pode melhorar a capacidade funcional e a remodelação cardíaca por meio da preservação da geometria ventricular esquerda. A expressão gênica das subunidades da NADPH oxidase não está envolvida na remodelação cardíaca, nem é modulada pelo exercício aeróbico em ratos com infarto do miocárdio pequeno.

Abstract Background: Physical exercise has been considered an important non-pharmacological therapy for the prevention and treatment of cardiovascular diseases. However, its effects on minor cardiac remodeling are not clear. Objective: To evaluate the influence of aerobic exercise on the functional capacity, cardiac structure, left ventricular (LV) function, and gene expression of NADPH oxidase subunits in rats with small-sized myocardial infarction (MI). Methods: Three months after MI induction, Wistar rats were divided into three groups: Sham; sedentary MI (MI-SED); and aerobic exercised MI (MI-AE). The rats exercised on a treadmill three times a week for 12 weeks. An echocardiogram was performed before and after training. The infarction size was evaluated by histology, and gene expression was assessed by RT-PCR. The significance level for statistical analysis was set at 5%. Results: Rats with MI lower than 30% of the LV total area were included in the study. Functional capacity was higher in MI-AE than in Sham and MI-SED rats. The infarction size did not differ between groups. Infarcted rats had increased LV diastolic and systolic diameter, left atrial diameter, and LV mass, with systolic dysfunction. Relative wall thickness was lower in MI-SED than in the MI-AE and Sham groups. Gene expression of the NADPH oxidase subunits NOX2, NOX4, p22phox, and p47phox did not differ between groups. Conclusion: Small-sized MI changes cardiac structure and LV systolic function. Late aerobic exercise is able to improve functional capacity and cardiac remodeling by preserving the left ventricular geometry. NADPH oxidase subunits gene expression is not involved in cardiac remodeling or modulated by aerobic exercise in rats with small-sized MI.

Ischemic stroke: A paradoxical manifestation of cancer.

INTRODUCTION: Approximately 5-10 % of the patients with cryptogenic stroke have an underlying malignancy. Stroke as a complication of cancer increases the morbidity and mortality among cancer patients, leading to increased disability and healthcare costs. OBJECTIVE: To provide elements to guide physicians for when to suspect and evaluate for cancer in stroke patients. DEVELOPMENT: We performed a narrative review, portrayed in a question-answer format, to report relevant aspects of cancer stroke patients in the clinical practice and provide a guide based on the state-of-the-art literature. Conventional stroke mechanisms are only found in a fraction of patients with cancer. Although cardiovascular risk factors play an important role in both cancer and stroke pathogenesis, the recognition of more specific cancer-associated risk factors raises clinical suspicion for occult malignancy. We also expose the main type location and histology of tumors that are most commonly associated with stroke as well as potential blood biomarkers and current treatment considerations in the scenario of cancer associated stroke. CONCLUSION: Subjects with active cancer are a patient population at increased risk for developing an ischemic stroke. Cryptogenic stroke patients have a higher risk of cancer diagnosis in the following 6-12 months. We recommend a multidisciplinary approach considering the high probability of a hidden malignancy and running a comprehensive evaluation including neurologic imaging, serological biomarkers and tight follow up.

Mandibular Angle Contouring Using Porous Polyethylene Stock or PEEK-based Patient Specific Implants. A Critical Analysis.

ABSTRACT: Contour augmentation and mandibular angle modification surgery is becoming increasingly. The aim of this research is to compare technique and outcomes in augmentations done with standard implants or PEEK-based patient specific implants (PSI) in mandibular angle. Data from surgical planning, operative and post-operative of 6 months follow-up were revised for 21 patients who were submitted to facial surgery using a stock implant obtained from companies currently on the market or 3D implants created with CAD/CAM technology using PEEK 3D printing. Surgical time, intra-operative and post-operative complications were compared, analyzing the advantages and disadvantage of each technique. Statistical analyses using t-test and chi-squared were performed considering P value< 0.05 for statistical differences. Twelve patients were operated on with stock implants and nine patients with PSI. The surgical time was 15 minutes less for the 3D implant surgeries (P = 0.021) and intraoperatively only the stock implants needed modifications with wear and adaptation methods; post-operative infections were observed in both groups with no significant differences (P > 0.05). The 3D implants had greater levels of facial symmetry than the stock implants, although they did not present significant differences.Considering the limitations of this study, mandibular angle implants with a PEEK-based 3D CAD/CAM are efficient, stable and have a low complication rate; the CAD/CAM strategy is useful in facial surgery and can be integrated as a standard for surgical planning in facial makeover surgery.

COVID-19 pandemic accelerated virtual transformation in dental education: a multicenter review of remote teaching and teledentistry / Transformação virtual acelerada pela pandemia de COVID-19 na educação odontológica: uma revisão multicêntrica do ensino à distância e da teleodontologia

ABSTRACT Although prior to the pandemic there was some resistance to the virtualization of dental education, the COVID-19 pandemic is providing us a unique opportunity to overcome several barriers that previously blocked the adoption of remote teaching and teledentistry. Thanks to the extended availability of telecommunications, digital technologies, and platforms, remote education and teledentistry appear to be the preferred choice to maintain dental education and patient care active under this pandemic, without contamination risks. In this paper, we review valid remote education strategies and possible alternatives useful in virtual transformation in dental education. Furthermore, the role of teledentistry and its advantages and challenges are also revised. Under the current pandemic context, as dental educators, we are called to be creative and flexible. Every dental school should adapt and use remote education as much as possible until clinical attention can be readopted. The evidence presented in this review supports our position that under this pandemic, remote education and telemedicine/teledentistry may be "the virtual convenient solution", to adapt and improve the hitherto classic way of teaching dentistry through tele-education.

RESUMO Embora antes da pandemia houvesse alguma resistência à virtualização da educação odontológica, a pandemia COVID-19 está nos fornecendo uma oportunidade única de superar várias barreiras que anteriormente bloqueavam a adoção do ensino à distância e teledontologia. Graças à ampla disponibilidade de telecomunicações, tecnologias digitais e plataformas, a educação à distância e a teledontologia parecem ser a escolha preferida para manter a educação odontológica e o atendimento ativo aos pacientes durante a pandemia, sem riscos de contaminação. Neste artigo, revisamos estratégias válidas de educação a distância e possíveis alternativas úteis na transformação virtual na educação odontológica. Além disso, o papel do teleodontologia e suas vantagens, assim como também os desafios. No atual contexto pandêmico, como educadores odontológicos, somos chamados a ser criativos e flexíveis. Cada escola de odontologia deve se adaptar e usar a educação à distância, tanto quanto possível, até que a atenção clínica possa ser readotada. As evidências apresentadas nesta revisão corroboram nossa posição de que, sob esta pandemia, a educação a distância e a telemedicina / teleodontologia podem ser "a solução virtual conveniente", para adaptar e aprimorar a forma até então clássica de ensino de odontologia, agora por meio da teleducação.

The Antioxidant Peptide Salamandrin-I: First Bioactive Peptide Identified from Skin Secretion of Salamandra Genus (Salamandra salamandra).

Amphibian skin is a multifunctional organ that plays key roles in defense, breathing, and water balance. In this study, skin secretion samples of the fire salamander (Salamandra salamandra) were separated using RP-HPLC and de novo sequenced using MALDI-TOF MS/MS. Next, we used an in silico platform to screen antioxidant molecules in the framework of density functional theory. One of the identified peptides, salamandrin-I, [M + H]+ = 1406.6 Da, was selected for solid-phase synthesis; it showed free radical scavenging activity against DPPH and ABTS radicals. Salamandrin-I did not show antimicrobial activity against Gram-positive and -negative bacteria. In vitro assays using human microglia and red blood cells showed that salamandrin-I has no cytotoxicity up to the concentration of 100 µM. In addition, in vivo toxicity tests on Galleria mellonella larvae resulted in no mortality at 20 and 40 mg/kg. Antioxidant peptides derived from natural sources are increasingly attracting interest. Among several applications, these peptides, such as salamandrin-I, can be used as templates in the design of novel antioxidant molecules that may contribute to devising strategies for more effective control of neurological disease.

Long-term frailty modeling using a non-proportional hazards model: Application with a melanoma dataset.

The semiparametric Cox regression model is often fitted in the modeling of survival data. One of its main advantages is the ease of interpretation, as long as the hazards rates for two individuals do not vary over time. In practice the proportionality assumption of the hazards may not be true in some situations. In addition, in several survival data is common a proportion of units not susceptible to the event of interest, even if, accompanied by a sufficiently large time, which is so-called immune, "cured," or not susceptible to the event of interest. In this context, several cure rate models are available to deal with in the long term. Here, we consider the generalized time-dependent logistic (GTDL) model with a power variance function (PVF) frailty term introduced in the hazard function to control for unobservable heterogeneity in patient populations. It allows for non-proportional hazards, as well as survival data with long-term survivors. Parameter estimation was performed using the maximum likelihood method, and Monte Carlo simulation was conducted to evaluate the performance of the models. Its practice relevance is illustrated in a real medical dataset from a population-based study of incident cases of melanoma diagnosed in the state of São Paulo, Brazil.

Coexistencia de trastornos gastrointestinales funcionales en lactantes y preescolares latinoamericanos / Coexistence of functional gastrointestinal disorders in Latin American infants and preschoolers

Resumen Introducción: se ha descrito la coexistencia de trastornos gastrointestinales funcionales (c-TGF) en lactantes y preescolares (LactPre); sin embargo, hay poca literatura sobre los principales c-TGF y sus características. Objetivo: describir la prevalencia y posibles asociaciones de c-TGF en un mismo LactPre latinoamericano. Metodología: estudio de prevalencia en LactPre de Colombia, Ecuador, Nicaragua y Panamá de consulta externa y urgencias, a quienes, según los criterios de Roma III en español, se identificaron regurgitación, síndrome de rumiación, síndrome del vómito cíclico, cólico, diarrea funcional, estreñimiento funcional y disquecia. Se tuvieron en cuenta la edad, el sexo y el origen. La estadística incluyó t de Student, chi cuadrado, prueba exacta de Fisher, análisis uni y multivariados y el cálculo de los OR e IC 95%, siendo una p <0,05 significativa. Resultados: se analizaron 2417 niños (2,4±19,8 meses de edad, 51,3% masculinos, con diagnóstico de por lo menos algún TGF del 35,7%). Se presentó c-TGF en el 3,6%, siendo el principal el síndrome de rumiación del lactante (SRL) más estreñimiento funcional (EF). Hubo predomino del género masculino en los lactantes y ser colombiano. Conclusión: la principal c-TGF en este grupo de LactPre de Latinoamérica es el SRL más EF, presentándose principalmente en el sexo masculino y en lactantes menores de 24 meses.

Abstract Introduction: Coexistence of functional gastrointestinal disorders (FGID) in infants and preschool children has been described, but there is little literature on the main types of FGID coexistence or their characteristics. Objective: This study describes the prevalence and possible associations of FGID coexistence among Latin American infants and preschool children. Methodology: This is a prevalence study of infants and preschool children conducted in Colombia, Ecuador, Nicaragua and Panama. Children included were outpatients and emergency patients who were identified according to the Rome III Criteria in Spanish as suffering from regurgitation, rumination syndrome, cyclic vomiting syndrome, colic, functional diarrhea, functional constipation and/or dyspepsia. Age, sex and origin of patients were registered. Statistical analyses included Student's T test, chi squared test, Fisher's exact test, univariate analysis, multivariate analysis and calculation of odds ratios and 95% confidence intervals with p <0.05 set as significant. Results: Two thousand four hundred and seventeen children were included. Their age range was 2.4 months to 19.8 months of age, and 51.3% were male. The proportion of patients with a diagnosis of at least one FGID was 35.7%. FGID coexistence was found in 3.6% of the patients. The most frequent combination was rumination syndrome plus functional constipation. There were predominances of males, infants and Colombian children in the total sample. Conclusion: The most commonly coexisting FGIDs in this group of Latin America infants and preschool children were infant rumination syndrome and functional constipation which were found together most frequently among boys who were under 24 months old.

Identification and characterization of phospholipases A2 from the skin secretion of Pithecopus azureus anuran.

The present work reports the isolation, characterization and the complete sequence of a phospholipase A2 (PLA2) present in the skin secretion of Pithecopus azureus. Among several peptides and small proteins previously described by our group from some species belonging to this amphibian genus (formerly named Phyllomedusa), a 15 kDa N-glycosylated protein showing PLA2 activity was purified, assayed, sequenced and named Pa-PLA2. The Pithecopus azureus skin phospholipase A2 polypeptide chain is composed by 125 amino acid residues linked by seven disulfide bonds and two N-glycosylated sites (N67 and N108). The Pa-PLA2 enzymatic activity was qualitatively evaluated and compared to classical viperid PLA2 showing that both, native and deglycosylated Pa-PLA2 forms, are catalytically functional. The tridimensional molecular model of Pa-PLA2 indicates that the observed glycan moieties are suggestively placed far from the active site of that enzyme and therefore having little or no significant role on the direct interaction of the Pa-PLA2 catalytic pocket and its substrates.