Study protocol: improving response to malaria in the Amazon through identification of inter-community networks and human mobility in border regions of Ecuador, Peru and Brazil.

INTRODUCTION: Understanding human mobility's role in malaria transmission is critical to successful control and elimination. However, common approaches to measuring mobility are ill-equipped for remote regions such as the Amazon. This study develops a network survey to quantify the effect of community connectivity and mobility on malaria transmission. METHODS: We measure community connectivity across the study area using a respondent driven sampling design among key informants who are at least 18 years of age. 45 initial communities will be selected: 10 in Brazil, 10 in Ecuador and 25 in Peru. Participants will be recruited in each initial node and administered a survey to obtain data on each community's mobility patterns. Survey responses will be ranked and the 2-3 most connected communities will then be selected and surveyed. This process will be repeated for a third round of data collection. Community network matrices will be linked with each country's malaria surveillance system to test the effects of mobility on disease risk. ETHICS AND DISSEMINATION: This study protocol has been approved by the institutional review boards of Duke University (USA), Universidad San Francisco de Quito (Ecuador), Universidad Peruana Cayetano Heredia (Peru) and Universidade Federal Minas Gerais (Brazil). Results will be disseminated in communities by the end of the study.

Network Profile: Improving Response to Malaria in the Amazon through Identification of Inter-Community Networks and Human Mobility in Border Regions of Ecuador, Peru, and Brazil.

Objectives: Understanding human mobility's role on malaria transmission is critical to successful control and elimination. However, common approaches to measuring mobility are ill-equipped for remote regions such as the Amazon. This study develops a network survey to quantify the effect of community connectivity and mobility on malaria transmission. Design: A community-level network survey. Setting: We collect data on community connectivity along three river systems in the Amazon basin: the Pastaza river corridor spanning the Ecuador-Peru border; and the Amazon and Javari river corridors spanning the Brazil-Peru border. Participants: We interviewed key informants in Brazil, Ecuador, and Peru, including from indigenous communities: Shuar, Achuar, Shiwiar, Kichwa, Ticuna, and Yagua. Key informants are at least 18 years of age and are considered community leaders. Primary outcome: Weekly, community-level malaria incidence during the study period. Methods: We measure community connectivity across the study area using a respondent driven sampling design. Forty-five communities were initially selected: 10 in Brazil, 10 in Ecuador, and 25 in Peru. Participants were recruited in each initial node and administered a survey to obtain data on each community's mobility patterns. Survey responses were ranked and the 2-3 most connected communities were then selected and surveyed. This process was repeated for a third round of data collection. Community network matrices will be linked with eadch country's malaria surveillance system to test the effects of mobility on disease risk. Findings: To date, 586 key informants were surveyed from 126 communities along the Pastaza river corridor. Data collection along the Amazon and Javari river corridors is ongoing. Initial results indicate that network sampling is a superior method to delineate migration flows between communities. Conclusions: Our study provides measures of mobility and connectivity in rural settings where traditional approaches are insufficient, and will allow us to understand mobility's effect on malaria transmission.

Gait speed according to cognitive status in older adults: a cross-sectional study in a resource-limited country.

OBJECTIVE: We aimed to investigate the association between gait speed and cognitive status in outpatient older adults from a resource-limited setting in Peru. METHODS: We performed a cross-sectional study including older adults aged ≥60 years attending a geriatrics outpatient clinic between July 2017 and February 2020. Gait speed was measured over a 10-meters distance without considering the first and last meter traveled. Cognitive status was assessed through the Short Portable Mental Status Questionnaire (SPMSQ) and the Mini-Mental State Examination (MMSE). We used a multivariate binomial logistic regression to conduct both an epidemiological and fully adjusted models. RESULTS: We included 519 older adults (mean age: 75 years; IQR = 10), of whom 95 (18.3%) and 151 (31.5%) were cognitively impaired according to the SPMSQ and MMSE, respectively. Gait speed was slower among patients with poorer cognitive status as assessed by both tools (p < 0.001). Malnutrition (PR: 1.74; CI: 1.45-2.08) and functional dependency (PR: 4.35; CI: 2.68-7.08) were associated with a greater prevalence of cognitive impairment according to the SPMSQ, whereas a faster gait speed (PR: 0.27, CI: 0.14-0.52) and longer years of education (PR: 0.83, CI: 0.77-0.88) were associated with a less prevalence. CONCLUSIONS: Slower gait speed was associated with poorer cognitive status in outpatient older adults. Gait speed may be a complementary tool in the cognitive assessment of older adults from resource-limited settings.

Seguridad de las drogas biológicas y sintéticas dirigidas utilizadas en pacientes con enfermedades reumáticas inmunomediadas. Datos del registro BIOBADASAR 3.0 / Safety of biological and targeted synthetic drugs in patients with immune-mediated rheumatic diseases. Data from the BIOBADASAR 3.0 registry

Introducción: conocer la seguridad de las drogas actualmente disponibles para el tratamiento de las enfermedades reumáticas es muy importante al momento de tomar decisiones terapéuticas objetivas e individualizadas en la consulta médica diaria. Asimismo, datos de la vida real amplían el conocimiento revelado por los ensayos clínicos. Objetivos: describir los eventos adversos (EA) reportados, estimar su frecuencia e identificar los factores relacionados con su desarrollo. Materiales y métodos: se utilizaron datos BIOBADASAR, un registro voluntario y prospectivo de seguimiento de EA de tratamientos biológicos y sintéticos dirigidos en pacientes con enfermedades reumáticas inmunomediadas. Los pacientes son seguidos hasta la muerte, pérdida de seguimiento o retiro del consentimiento informado. Para este análisis se extrajeron datos recopilados hasta el 31 de enero de 2023. Resultados: se incluyó un total de 6253 pacientes, los cuales aportaron 9533 ciclos de tratamiento, incluyendo 3647 (38,3%) ciclos sin drogas modificadoras de la enfermedad biológicas y sintéticas dirigidas (DME-b/sd) y 5886 (61,7%) con DME-b/sd. Dentro de estos últimos, los más utilizados fueron los inhibidores de TNF y abatacept. Se reportaron 5890 EA en un total de 2701 tratamientos (844 y 1857 sin y con DME-b/sd, respectivamente), con una incidencia de 53,9 eventos cada 1000 pacientes/año (IC 95% 51,9-55,9). La misma fue mayor en los ciclos con DME-b/sd (71,1 eventos cada 1000 pacientes/año, IC 95% 70,7-77,5 versus 33,7, IC 95% 31,5-36,1; p<0,001). Las infecciones, particularmente las de la vía aérea superior, fueron los EA más frecuentes en ambos grupos. El 10,9% fue serio y el 1,1% provocó la muerte del paciente. El 18,7% de los ciclos con DME-b/sd fue discontinuado a causa de un EA significativamente mayor a lo reportado en el otro grupo (11,5%; p<0,001). En el análisis ajustado, las DME-b/sd se asociaron a mayor riesgo de presentar al menos un EA (HR 1,82, IC 95% 1,64-1,96). De igual manera, la mayor edad, el mayor tiempo de evolución, el antecedente de enfermedad pulmonar obstructiva crónica, el diagnóstico de lupus eritematoso sistémico y el uso de corticoides se asociaron a mayor riesgo de EA. Conclusiones: la incidencia de EA fue significativamente superior durante los ciclos de tratamientos que incluían DME-b/sd.

Introduction: knowing the efficacy and safety of the drugs currently available for the treatment of rheumatic diseases is very important when making objective and individualized therapeutic decisions in daily medical consultation. Likewise, real-life data extends the knowledge revealed by clinical trials. Objectives: to describe the reported adverse events (AEs), estimate their frequency and identify factors associated to them. Materials and methods: BIOBADASAR data were used, which is a voluntary, prospective follow-up registry of AEs of biological and synthetic treatments in patients with immune-mediated rheumatic diseases. Patients are followed until death, loss of followup, or withdrawal of informed consent. To carry out this analysis, the data collected up to January 31, 2023 was extracted. Results: a total of 6253 patients were included, who contributed with 9533 treatment periods, including 3647 (38.3%) periods without b/ts-DMARDs and 5886 (61.7%) with b/ts-DMARDs. Among the latter, the most used were TNF inhibitors and abatacept. A total of 5890 AEs were reported in a total of 2701 treatments (844 and 1857 without and with b/ts-DMARDs, respectively), with an incidence of 53.9 events per 1000 patients/ year (95% CI 51.9-55.9). It was higher during the periods with b/ts-DMARDs (71.1 events per 1000 patients/year, 95% CI 70.7-77.5 vs 33.7, 95% CI 31.5-36.1, p<0.001). Infections, particularly those of the upper respiratory tract, were the most frequent AEs in both groups. 10.9% were severe and 1.1% were associated with the death of the patient. 18.7% of the periods with b/ts-DMARDs were discontinued due to an AE, significantly higher than that reported in the other group (11.5%; p<0.001). In the adjusted analysis, b/ts-DMARDs were associated with a higher risk of presenting at least one AE (HR 1.82, 95% CI 1.64-1.96). Similarly, older age, longer evolution time, history of chronic obstructive pulmonary disease, diagnosis of systemic lupus erythematosus, and use of corticosteroids were associated with a higher risk of AE. Conclusions: the incidence of AEs was significantly higher during those treatment periods that included DME-b/sd.

Mechanical performance of original; yellowish and blueish ProFile instruments: isolating heat-treatment as a variable.

The present study aimed to perform two different heat-treatments in an austenitic NiTi ProFile instrument and to compare the mechanical performance of original and heat-treated instruments. Heat treatment of ProFile (tip size 25 and 0.06 taper) instruments were carried out in a furnace in argon atmosphere using a heating rate of 10° C/min. After reaching the programmed temperatures of 450 ºC or 500 ºC the system remained at a constant temperature for 10 minutes; followed by cooling in water at room temperature. Afterwards; the three groups (n=30 per group) of instruments were compared regarding their cyclic fatigue (n=10 per group); bending (n=10 per group); and buckling resistance (n=10 per group). After cyclic fatigue tests; a scanning electron microscope was used to analyze the fracture surfaces and observe the fracture mode. Statistical analysis was performed using One-way ANOVA and Student-Newman-Keuls test; with an alpha type error set at 0.05. Yellowish and blueish coloration was observed in the ProFile instruments after 450 ºC or 500 ºC heat treatments; respectively. Conventional ProFile instruments showed the lower cyclic fatigue; and the higher bending and buckling resistance (P<0.05). In contrast; yellowish ProFile instruments (heat treated at 500° C) showed the higher cyclic fatigue; and the lower bending and buckling resistance (P>0.05). It can be concluded that the different heat treatments performed on ProFile instruments increased its cyclic fatigue resistance and improved the flexibility and buckling resistance.

O presente estudo teve como objetivo realizar dois tratamentos térmicos diferentes em instrumentos de NiTi austenítico ProFile e comparar o desempenho mecânico de instrumentos originais e tratados termicamente. O tratamento térmico dos instrumentos ProFile (tamanho de ponta 25 e conicidade 0.06) foi realizado em um forno em atmosfera de argônio usando uma taxa de aquecimento de 10°C/min. Após atingir as temperaturas programadas de 450 ºC ou 500 ºC o sistema permaneceu em temperatura constante por 10 minutos; seguido de resfriamento em água à temperatura ambiente. Em seguida; os três grupos de instrumentos (n=30 por grupo) foram comparados quanto à fadiga cíclica (n=10 por grupo); flexão (n=10 por grupo) e resistência à flambagem (n=10 por grupo). Após testes de fadiga cíclica; um microscópio eletrônico de varredura foi utilizado para analisar as superfícies de fratura e observar o modo de fratura. A análise estatística foi realizada por meio dos testes de One-way ANOVA e teste de Student-Newman-Keuls; com erro de tipo alfa fixado em 0.05. Coloração amarelada e azulada foi observada nos instrumentos ProFile após tratamentos térmicos a 450 ºC ou 500 ºC; respectivamente. Os instrumentos ProFile originais apresentaram menor fadiga cíclica e maior resistência à flexão e flambagem (P<0.05). Em contraste; os instrumentos ProFile azulados (tratados termicamente a 500°C) apresentaram maior fadiga cíclica e menor resistência à flexão e flambagem (P>0.05). Pode-se concluir que os diferentes tratamentos térmicos realizados nos instrumentos ProFile aumentaram sua resistência à fadiga cíclica e melhoraram a flexibilidade e resistência à flambagem.

Mechanical performance of original; yellowish and blueish ProFile instruments: isolating heat-treatment as a variable

Resumo O presente estudo teve como objetivo realizar dois tratamentos térmicos diferentes em instrumentos de NiTi austenítico ProFile e comparar o desempenho mecânico de instrumentos originais e tratados termicamente. O tratamento térmico dos instrumentos ProFile (tamanho de ponta 25 e conicidade 0.06) foi realizado em um forno em atmosfera de argônio usando uma taxa de aquecimento de 10°C/min. Após atingir as temperaturas programadas de 450 ºC ou 500 ºC o sistema permaneceu em temperatura constante por 10 minutos; seguido de resfriamento em água à temperatura ambiente. Em seguida; os três grupos de instrumentos (n=30 por grupo) foram comparados quanto à fadiga cíclica (n=10 por grupo); flexão (n=10 por grupo) e resistência à flambagem (n=10 por grupo). Após testes de fadiga cíclica; um microscópio eletrônico de varredura foi utilizado para analisar as superfícies de fratura e observar o modo de fratura. A análise estatística foi realizada por meio dos testes de One-way ANOVA e teste de Student-Newman-Keuls; com erro de tipo alfa fixado em 0.05. Coloração amarelada e azulada foi observada nos instrumentos ProFile após tratamentos térmicos a 450 ºC ou 500 ºC; respectivamente. Os instrumentos ProFile originais apresentaram menor fadiga cíclica e maior resistência à flexão e flambagem (P<0.05). Em contraste; os instrumentos ProFile azulados (tratados termicamente a 500°C) apresentaram maior fadiga cíclica e menor resistência à flexão e flambagem (P>0.05). Pode-se concluir que os diferentes tratamentos térmicos realizados nos instrumentos ProFile aumentaram sua resistência à fadiga cíclica e melhoraram a flexibilidade e resistência à flambagem.

Abstract The present study aimed to perform two different heat-treatments in an austenitic NiTi ProFile instrument and to compare the mechanical performance of original and heat-treated instruments. Heat treatment of ProFile (tip size 25 and 0.06 taper) instruments were carried out in a furnace in argon atmosphere using a heating rate of 10° C/min. After reaching the programmed temperatures of 450 ºC or 500 ºC the system remained at a constant temperature for 10 minutes; followed by cooling in water at room temperature. Afterwards; the three groups (n=30 per group) of instruments were compared regarding their cyclic fatigue (n=10 per group); bending (n=10 per group); and buckling resistance (n=10 per group). After cyclic fatigue tests; a scanning electron microscope was used to analyze the fracture surfaces and observe the fracture mode. Statistical analysis was performed using One-way ANOVA and Student-Newman-Keuls test; with an alpha type error set at 0.05. Yellowish and blueish coloration was observed in the ProFile instruments after 450 ºC or 500 ºC heat treatments; respectively. Conventional ProFile instruments showed the lower cyclic fatigue; and the higher bending and buckling resistance (P<0.05). In contrast; yellowish ProFile instruments (heat treated at 500° C) showed the higher cyclic fatigue; and the lower bending and buckling resistance (P>0.05). It can be concluded that the different heat treatments performed on ProFile instruments increased its cyclic fatigue resistance and improved the flexibility and buckling resistance.

Cancer cell membrane-derived nanoparticles block the expression of immune checkpoint proteins on cancer cells and coordinate modulatory activity on immunosuppressive macrophages.

Cancer is the most recurrent chronic disease in the world, with human hepatocellular carcinoma (HCC) being the second leading cause of death among neoplasias. The high frequency of HCC relapse and metastasis warrants the development of new diagnostic and therapeutic procedures. In advanced stages, neoplastic cells can evade immune surveillance and express immunosuppressive proteins and cytokines at tumor sites. Nanocomposites conjugated with immunomodulatory agents can increase the main mechanisms of cellular immunity. In this study, we used nanocarriers to transport oligonucleotide sequences (siRNAs) into cancer cells and leukocytes to modulate the activity of tumor microenvironment cells in vitro. Cell membrane-derived nanoparticles (MNPs) were synthesized with lipids and proteins from the plasma membrane of hepatic tumor cells to deliver a large amount of antigenic material to professional antigen-presenting cells (APCs), following their exposure to HCC and immunosuppressive macrophages. To establish a pro-inflammatory response, pure lipid MNPs were incorporated with monophosphoryl lipid A and siRNA to silence the c-MYC (myelocytomatosis) oncogene. Nanocarriers were tested for the following: (a) NP internalization into cancer and immunocompetent cells; (b) immunomodulatory activity by observing the expression of cell surface markers; and (c) in vitro cytotoxicity. The adsorption of plasma proteins on the MNPs surface and their effects on cellular uptake were also investigated. Our results indicate that the nanostructures are stable in biological suspensions, and can reduce CD47 and PD-L1 expression on cancer cells and simultaneously switch APC activity for an anti-tumor response.

Systematic review of diagnostic and prognostic models of chronic kidney disease in low-income and middle-income countries.

OBJECTIVE: To summarise available chronic kidney disease (CKD) diagnostic and prognostic models in low-income and middle-income countries (LMICs). METHOD: Systematic review (Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines). We searched Medline, EMBASE, Global Health (these three through OVID), Scopus and Web of Science from inception to 9 April 2021, 17 April 2021 and 18 April 2021, respectively. We first screened titles and abstracts, and then studied in detail the selected reports; both phases were conducted by two reviewers independently. We followed the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies recommendations and used the Prediction model Risk Of Bias ASsessment Tool for risk of bias assessment. RESULTS: The search retrieved 14 845 results, 11 reports were studied in detail and 9 (n=61 134) were included in the qualitative analysis. The proportion of women in the study population varied between 24.5% and 76.6%, and the mean age ranged between 41.8 and 57.7 years. Prevalence of undiagnosed CKD ranged between 1.1% and 29.7%. Age, diabetes mellitus and sex were the most common predictors in the diagnostic and prognostic models. Outcome definition varied greatly, mostly consisting of urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. The highest performance metric was the negative predictive value. All studies exhibited high risk of bias, and some had methodological limitations. CONCLUSION: There is no strong evidence to support the use of a CKD diagnostic or prognostic model throughout LMIC. The development, validation and implementation of risk scores must be a research and public health priority in LMIC to enhance CKD screening to improve timely diagnosis.

Immunomodulatory properties of nanostructured systems for cancer therapy.

Based on statistical data reported in 2020, cancer was responsible for approximately 10 million deaths. Furthermore, 17 million new cases were diagnosed worldwide. Nanomedicine and immunotherapy have shown satisfactory clinical results among all scientific and technological alternatives for the treatment of cancer patients. Immunotherapy-based treatments comprise the consideration of new alternatives to hinder neoplastic proliferation and to reduce adverse events in the body, thereby promoting immune destruction of diseased cells. Additionally, nanostructured systems have been proven to elicit specific immune responses that may enhance anti-tumor activity. A new generation of nanomedicines, based on biomimetic and bioinspired systems, has been proposed to target tumors by providing immunomodulatory features and by enabling recovery of human immune destruction capacity against cancer cells. This review provides an overview of the aspects and the mechanisms by which nanomedicines can be used to enhance clinical procedures using the immune modulatory responses of nanoparticles (NPs) in the host defense system. We initially outline the cancer statistics for conventional and new treatment approaches providing a brief description of the human host defense system and basic principles of NP interactions with monocytes, leukocytes, and dendritic cells for the modulation of antitumor immune responses. A report on different biomimetic and bioinspired systems is also presented here and their particularities in cancer treatments are addressed, highlighting their immunomodulatory properties. Finally, we propose future perspectives regarding this new therapeutic strategy, highlighting the main challenges for future use in clinical practice.

Timed up and go test predicts mortality in older adults in Peru: a population-based cohort study.

BACKGROUND: While there is evidence about stablished risk factors (e.g., raised blood pressure) and higher mortality risk in older population, less has been explored about other functional parameters like the Timed Up and Go test and the Gait Speed in older people at low- and middle-income countries. We aimed to study these mobility tests as predictors of mortality in a population of older people in Peru. METHODS: Population-based prospective cohort study (2013-2020). Random sampling of people aged 60+ years in a community of Lima, Peru. Geriatricians conducted all clinical evaluations and laboratory tests were conducted in the local hospital. Participants were sought in the national vital registration system, and we collated cause (ICD-10) and date of death. We conducted a nested forward multivariate Cox proportional hazard model to identify all potential predictors of all-cause, communicable and non-communicable diseases mortality. RESULTS: At baseline, there were 501 older people (mean age 70.6 and 62.8% were women), complete follow-up information was available from 427 people. Mean follow-up time was 46.5 months (SD = 25.3). In multivariate models, the Timed Up and Go test was associated with higher risk of all-cause mortality (HR = 1.05; 95% CI: 1.02-1.09). For cause-specific mortality, history of heart disease (HR = 2.25; 95% CI: 1.07-4.76) and age in years (HR = 1.05; 95% CI: 1.01-1.09) were predictors of non-communicable diseases mortality. CONCLUSIONS: In addition to established risk factors for mortality in older population, the Timed Up and Go test, a functional parameter, raised as a relevant predictor of all-cause mortality.

Provision of a protein-rich supplement for grazing suckling female beef calves to improve productive performance and metabolic response.

OBJECTIVE: This study was conducted to evaluate the effects of the provision of a protein-rich supplement on productive performance, and metabolic profile on grazing suckling female beef calves in tropical conditions during 150 d of experimentation. METHODS: Fifty-six Nellore suckling female calves, and their respective dams were distributed in a completely randomised design and made to undergo two treatments as follows: UNS (without supplementation), and SUP (supplementation with 5 g/kg body weight [BW] of a protein supplement). Throughout the experiment, animal performance and metabolic profile were evaluated. Also, ureagenesis and gluconeogenesis were assessed for gene expression. RESULTS: SUP female calves showed a higher voluntary intake (p≤0.03) of the diet components evaluated, digestibility of organic matter (p≤0.02) and microbial nitrogen production (MICN; p≤0.02) compared to UNS female calves. In its turn, serum urea nitrogen (p≤0.01) and insulin-like growth factor-1 (p≤0.03) levels and ureagenesis (p≤0.04) increased in SUP female calves compared to UNS female calves. Blood glucose and triglyceride levels were not affected by supplementation. The average daily gain (ADG) from SUP female calves was higher (p≤0.02) compared with UNS female calves. However, supplementation did not affect the body measures of the animals. CONCLUSION: In summary, provision of a protein-rich supplement improves the intake and nutrients digestibility, ADG and final BW and increases metabolic indicators of the protein status in grazing suckling female beef calves in tropical conditions.

Morphological characterization of blue-and-yellow macaw (Ara ararauna) seasonal testicular variations in captivity.

The reproduction of monogamous wild birds in captivity it`s difficult and the apparent low fertility in males requires more investigations. The objective of the study was to test the hypothesis that wild bird species in captivity would present low reproductive potential, through the analysis of the morphological characteristics of Ara ararauna testicles, maintained in captivity, correlating them with the climate variations in the Cerrado Biome. For that, testicles were captured in April (dry) and October (rainy). The right and left testicles showed mean weight, gonadosomatic index, longer axis, and volume similar between the dry and rainy season. Only the shorter axis demonstrated higher values during the rainy season. The morphometric variables of the seminiferous tubules have also higher values during the rainy season. By these histological and morphometric characteristics of the seminiferous epithelium we can conclude that, during the rainy season, the testicles were in gonadal recrudescence, which precedes the reproduction phase. During the dry season, the testicles were in the rest phase of the seminiferous epithelium. Therefore, we concluded that the species in captivity, under Cerrado environmental conditions, have kept their reproductive potential, presenting a complete spermatogenic cycle during the rainy season, which can guarantee the species perpetuation.

Histological, histochemical and energy disorders caused by R-limonene on Aedes aegypti L. larvae (Diptera: Culicidae).

The study evaluated the effects of R-limonene, in sublethal concentration, on the histology, histochemistry, biochemistry, and carbohydrates and proteins levels in the third instar Aedes aegypti larvae. The R-limonene (LC50 of 27 ppm) and control groups were analyzed 12 and 24 h after the beginning of treatments. The midgut of the control larvae was composed of cylindrical and elongated cells with a spherical and central nucleus and regenerative cells with a pyramidal shape. After 12 h of treatment, columnar cells, protuberances, and cytoplasmic vacuolization were found. However, 24 h after treatment, complete disorganization of the epithelium was observed. There was a positive reaction in all treatments for the presence of glycogen. However, the midgut of larvae treated with R-limonene showed higher levels. For the total protein, positive marking occurred in all groups evaluated, with higher levels in treatments and the lowest in control 12 h. The levels of total protein and glycogen increased in the treated larvae compared to the 12 h control. Besides, a reduction in total sugar levels was observed in the treated larvae compared to controls 12 and 24 h, being more evident in the last one. Therefore, these results demonstrate that R-Limonene caused pathological changes in the epithelium of the A. aegypti midgut at histophysiological and biochemical levels.

Prenylated 4-phenylcoumarins and 4-alkylcoumarins from Kielmeyera argentea and their cytotoxic activity.

Two new prenylated 4-phenylcoumarins, named kielcoumarin A (1) and kielcoumarin B (2) together with three known compounds, mammea B/BA (3), mammea B/BA cyclo F (4) and ferruol A (5), were obtained from stems and roots of Kielmeyera argentea (Calophyllaceae). Their structures were elucidated based on spectroscopic data. Cytotoxic activity of the 4-alkylcoumarins 3-5 was evaluated in vitro against human U251 glioblastoma cell line. Compound 3 showed significative activity with EC50 value of 6.6 µM while compounds 4 and 5 showed respective EC50 values of 52.0 and 37.0 µM.

Logic of Selecting Suitable Dissolution Parameters in New Drug Formulations Based on A BCS Approach.

Since the biopharmaceutical quality of generic drug formulations depends on the quality of the reference products and also information about the in-vitro release performance of drugs under different conditions is scarce in the literature, a dissolution study of four reference tablets was performed. Each drug was representative of one Class of the Biopharmaceutical Classification System. The in-vitro release performance of propranolol-HCl, carbamazepine, ranitidine-HCl, and metronidazole was evaluated using a USP basket and paddle apparatus at different agitation rates (50, 75, and 100 rpm) with two doses of each drug. In all experiments, pharmacopeial dissolution media was used and the samples were taken with automatic equipment at specific times up to 60 min, except for propranolol-HCl, for which the samples were taken up to 30 min. The dissolution profiles were compared by model-independent, model-dependent, and ANOVA-based comparisons. The three methods of data comparison showed that low vs. high doses were significantly different (P < 0.05), which may influence cases in which biowaivers of propranolol-HCl and ranitidine-HCl are requested. Additionally, the results showed that despite different hydrodynamic environments produced by the basket and paddle apparatus, under certain conditions, both types of equipment generated comparable in-vitro results. Variables such as the dose, agitation rate, and type of dissolution apparatus are important factors to consider in designing dissolution tests for drug products. This information can be used to test a new dosage when there is no pharmacopeial method available to perform a dissolution study. Further researches on the in-vitro release performance of reference drug products are required.

Polyprenylated benzophenone derivatives with a novel tetracyclo[8.3.1.03,11.05,10]tetradecane core skeleton from Clusia burle-marxii exhibited cytotoxicity against GL-15 glioblastoma-derived human cell line.

Three new polyprenylated benzophenone derivatives (1-3) were identified in the hexane extract of Clusia burle-marxii trunks, through the isolation and structural elucidation of their methyl derivatives, along with two known polyprenylated benzophenone derivatives sampsonine N (4) and obdeltifolione C (5). Burlemarxiones A (1) and B (2) show an unprecedent tetracyclo[8.3.1.03,11.05,10]tetradecane core skeleton. These compounds are a pair of ß-diketones in tautomeric equilibrium, whereas isonemorosonol (3) is the respective ß-diketone pair in tautomeric equilibrium with nemorosonol. Burlemarxione A methyl derivative (1a) and sampsonine N exhibited strong in vitro cytotoxic activity against GL-15 glioblastoma-derived human cell line.

Pregnancy and Parenting During Cardiology Fellowship.

Background An increasing number of residents and fellows have children during training. However, little is known about the specific experience of cardiology fellows who become parents during training. Methods and Results A 66-question Internet-based survey about experiences of pregnancy during graduate medical training was administered between May 1 and July 15, 2013, to all trainees (N=1516) in the Mayo School of Graduate Medical Education across 3 academic sites. Questions explored the experiences of new mothers, fathers, and their fellow trainees. There were 644 survey respondents overall (response rate, 42%), and of 73 cardiovascular trainees, 29 (10 women [35%]) completed the survey. Of those surveyed, 59% reported having children. All trainee mothers reported making alterations to their training schedule due to pregnancy and maternity leave. Twenty percent of trainee fathers also reported changing their training because of their partner's pregnancy. Of trainees with children, 41% reported difficulty completing research because of pregnancy and childcare obligations. Nontrainee mothers were significantly more likely to breastfeed beyond 6 months compared with trainee mothers ( P=0.018). A perceived stigma attached to pregnancy was reported by 62% of trainees. Both male and female trainees felt that their programs did not promote pregnancy-related schedule flexibility. Conclusions Our study shows that both men and women entering parenthood during cardiology training often have to change their schedule, research, and career path. Cardiology training programs should focus on curriculum design and supportive parenthood policies to both avoid negative stigma and optimize fellowship training during this time period.

Nitrogen input by bamboos in neotropical forest: a new perspective.

BACKGROUND: Nitrogen (N) is an important macronutrient that controls the productivity of ecosystems and biological nitrogen fixation (BNF) is a major source of N in terrestrial systems, particularly tropical forests. Bamboo dominates theses forests, but our knowledge regarding the role of bamboo in ecosystem functioning remains in its infancy. We investigated the importance of a native bamboo species to the N cycle of a Neotropical forest. METHODS: We selected 100 sample units (100 m2 each) in a pristine montane Atlantic Forest, in Brazil. We counted all the clumps and live culms of Merostachys neesii bamboo and calculated the specific and total leaf area, as well as litter production and respective N content. Potential N input was estimated based on available data on BNF rates for the same bamboo species, whose N input was then contextualized using information on N cycling components in the study area. RESULTS: With 4,000 live culms ha-1, the native bamboo may contribute up to 11.7 kg N ha-1 during summer (January to March) and 19.6 kg N ha-1 in winter (July to September). When extrapolated for annual values, M. neesii could contribute more than 60 kg N ha-1y-1. DISCUSSION: The bamboo species' contribution to N input may be due to its abundance (habitat availability for microbial colonization) and the composition of the free-living N fixer community on its leaves (demonstrated in previous studies). Although some N is lost during decomposition, this input could mitigate the N deficit in the Atlantic Forest studied by at least 27%. Our findings suggest that M. neesii closely regulates N input and may better explain the high diversity and carbon stocks in the area. This is the first time that a study has investigated BNF using free-living N fixers on the phyllosphere of bamboo.