Multitarget anti-parasitic activities of isoquinoline alkaloids isolated from Hippeastrum aulicum (Amaryllidaceae).

BACKGROUND: Chagas disease and leishmaniasis affect a significant portion of the Latin American population and still lack efficient treatments. In this context, natural products emerge as promising compounds for developing more effective therapies, aiming to mitigate side effects and drug resistance. Notably, species from the Amaryllidaceae family emerge as potential reservoirs of antiparasitic agents due to the presence of diverse biologically active alkaloids. PURPOSE: To assess the anti-Trypanosoma cruzi and anti-Leishmania infantum activity of five isolated alkaloids from Hippeastrum aulicum Herb. (Amaryllidaceae) against different life stages of the parasites using in silico and in vitro assays. Furthermore, molecular docking was employed to evaluate the interaction of the most active alkaloids. METHODS: Five natural isoquinoline alkaloids isolated in suitable quantities for in vitro testing underwent preliminary in silico analysis to predict their potential efficacy against Trypanosoma cruzi (amastigote and trypomastigote forms) and Leishmania infantum (amastigote and promastigote forms). The in vitro antiparasitic activity and mammalian cytotoxicity were investigated with a subsequent comparison of both analysis (in silico and in vitro) findings. Additionally, this study employed the molecular docking technique, utilizing cruzain (T. cruzi) and sterol 14α-demethylase (CYP51, L. infantum) as crucial biological targets for parasite survival, specifically focusing on compounds that exhibited promising activities against both parasites. RESULTS: Through computational techniques, it was identified that the alkaloids haemanthamine (1) and lycorine (8) were the most active against T. cruzi (amastigote and trypomastigote) and L. infantum (amastigote and promastigote), while also revealing unprecedented activity of alkaloid 7­methoxy-O-methyllycorenine (6). The in vitro analysis confirmed the in silico tests, in which compound 1 presented the best activities against the promastigote and amastigote forms of L. infantum with half-maximal inhibitory concentration (IC50) 0.6 µM and 1.78 µM, respectively. Compound 8 exhibited significant activity against the amastigote form of T. cruzi (IC50 7.70 µM), and compound 6 demonstrated activity against the trypomastigote forms of T. cruzi and amastigote of L. infantum, with IC50 values of 89.55 and 86.12 µM, respectively. Molecular docking analyses indicated that alkaloids 1 and 8 exhibited superior interaction energies compared to the inhibitors. CONCLUSION: The hitherto unreported potential of compound 6 against T. cruzi trypomastigotes and L. infantum amastigotes is now brought to the forefront. Furthermore, the acquired dataset signifies that the isolated alkaloids 1 and 8 from H. aulicum might serve as prototypes for subsequent structural refinements aimed at the exploration of novel leads against both T. cruzi and L. infantum parasites.

Multitarget anti-parasitic activities of isoquinoline alkaloids isolated from Hippeastrum aulicum (Amaryllidaceae)

Background Chagas disease and leishmaniasis affect a significant portion of the Latin American population and still lack efficient treatments. In this context, natural products emerge as promising compounds for developing more effective therapies, aiming to mitigate side effects and drug resistance. Notably, species from the Amaryllidaceae family emerge as potential reservoirs of antiparasitic agents due to the presence of diverse biologically active alkaloids. Purpose To assess the anti-Trypanosoma cruzi and anti-Leishmania infantum activity of five isolated alkaloids from Hippeastrum aulicum Herb. (Amaryllidaceae) against different life stages of the parasites using in silico and in vitro assays. Furthermore, molecular docking was employed to evaluate the interaction of the most active alkaloids. Methods Five natural isoquinoline alkaloids isolated in suitable quantities for in vitro testing underwent preliminary in silico analysis to predict their potential efficacy against Trypanosoma cruzi (amastigote and trypomastigote forms) and Leishmania infantum (amastigote and promastigote forms). The in vitro antiparasitic activity and mammalian cytotoxicity were investigated with a subsequent comparison of both analysis (in silico and in vitro) findings. Additionally, this study employed the molecular docking technique, utilizing cruzain (T. cruzi) and sterol 14α-demethylase (CYP51, L. infantum) as crucial biological targets for parasite survival, specifically focusing on compounds that exhibited promising activities against both parasites. Results Through computational techniques, it was identified that the alkaloids haemanthamine (1) and lycorine (8) were the most active against T. cruzi (amastigote and trypomastigote) and L. infantum (amastigote and promastigote), while also revealing unprecedented activity of alkaloid 7‑methoxy-O-methyllycorenine (6). The in vitro analysis confirmed the in silico tests, in which compound 1 presented the best activities against the promastigote and amastigote forms of L. infantum with half-maximal inhibitory concentration (IC50) 0.6 µM and 1.78 µM, respectively. Compound 8 exhibited significant activity against the amastigote form of T. cruzi (IC50 7.70 µM), and compound 6 demonstrated activity against the trypomastigote forms of T. cruzi and amastigote of L. infantum, with IC50 values of 89.55 and 86.12 µM, respectively. Molecular docking analyses indicated that alkaloids 1 and 8 exhibited superior interaction energies compared to the inhibitors. Conclusion The hitherto unreported potential of compound 6 against T. cruzi trypomastigotes and L. infantum amastigotes is now brought to the forefront. Furthermore, the acquired dataset signifies that the isolated alkaloids 1 and 8 from H. aulicum might serve as prototypes for subsequent structural refinements aimed at the exploration of novel leads against both T. cruzi and L. infantum parasites.

Redesign of radiotherapy for prostate cancer: a proposal for universal healthcare systems.

Aim: This study was designed to recommend strategies to improve prostate patients' access to radiotherapy treatment in the Brazilian Unified Health System, along with a cost-tool to support radiotherapy care pathways' lead times and costs. Methods: Data was collected prospectively from patients with prostate cancer receiving radiotherapy in two Brazilian centers to provide data to apply design thinking and process reengineering techniques. The current status of the radiotherapy pathway was determined and the length of time taken for in-hospital activities was measured using data exported from ARIA®. Interviews with patients were used to estimate their waiting periods. This provided the data used to provide recommended strategies and the cost tool based on time-driven activity-based costing. The strategies were classified according to priority. Results: Data from 47 patients were analyzed. The mean interval from diagnosis to start of radiotherapy was 349 days (SD581), and the mean interval from seeking medical attention to starting treatment was 635 days (SD629). Twelve strategies affecting in-hospital processes and 11 impacting patients' care pathways and experiences are recommended, mostly focused on system improvement opportunities. A time-driven activity-based costing monitoring using data extracted from ARIA was coded and can be used by centers as a cost assessment guide. Conclusion: This study uses reengineering and design techniques to introduce priority strategies to allow more efficient and patient-centered radiotherapy.

High prevalence of burnout syndrome among medical and nonmedical residents during the COVID-19 pandemic.

BACKGROUND: Since the beginning of the COVID-19 pandemic, health professionals have been working under extreme conditions, increasing the risk of physical and mental illness. We evaluated the prevalence of burnout and its associated factors among postgraduate student residents in health professions during the global health crisis. METHODS: Healthcare residents were recruited from all across Brazil between July and September 2020 through digital forms containing instruments for assessing burnout (Oldenburg Burnout Inventory (OLBI)), resilience (brief resilient coping scale (BRCS)) and anxiety, stress and depression (depression, anxiety and stress scale (DASS-21) and Patient Health Questionnaire (PHQ-9)). Additionally, the relationships between burnout and chronic diseases, autonomy and educational adequacy in the residency programme, personal protective equipment (PPE), workload and care for patients with COVID-19 were evaluated. The chi-square test, Student's t test, Pearson's correlation test and logistic regression were performed. RESULTS: A total of 1,313 participants were included: mean (standard deviation) age, 27.8 (4.4) years; female gender, 78.1%; white race, 59.3%; and physicians, 51.3%. The overall prevalence of burnout was 33.4%. The odds (odds ratio [95% confidence interval]) of burnout were higher in the presence of pre-existing diseases (1.76 [1.26-2.47]) and weekly work > 60 h (1.36 [1.03-1.79]) and were lower in the presence of high resilience (0.84 [0.81-0.88]), autonomy (0.87 [0.81-0.93]), and educational structure (0.77 [0.73-0.82]), adequate availability of PPE (0.72 [0.63-0.83]) and non-white race (0.63 [0.47-0.83]). Burnout was correlated with anxiety (r = 0.47; p < 0.05), stress (r: 0.58; p < 0.05) and depression (r: 0.65; p < 0.05). CONCLUSIONS: We observed a high prevalence of burnout among residents during the COVID-19 pandemic. Individual characteristics and conditions related to the work environment were associated with a higher or lower occurrence of the syndrome.

Effects of Exercise Training on Left Ventricular Diastolic Function Markers in Patients with Obstructive Sleep Apnea: A Randomized Study

Abstract Background Exercise training (ET) is an adjunctive treatment for obstructive sleep apnea (OSA) and its consequences. However, the effects of exercise on heart remodeling are unknown in the population with OSA. Objective We investigated the effect of ET on markers of diastolic function, sleep parameters, and functional capacity in patients with OSA. Methods Sedentary patients with OSA (apnea-hypopnea index, AHI ≥15 events/hr) were randomly assigned to untrained (n=18) and trained (n=20) strategies. Polysomnography, cardiopulmonary exercise test, and echocardiography were evaluated at the beginning and end of the study. ET consisted of 3 weekly sessions of aerobic exercise, resistance exercises, and flexibility training (72 sessions, completed in 11.65±0.86 months). A two-way analysis of variance (ANOVA) was used, followed by Tukey's post-hoc test. The level of statistical significance was set at p<0.05 for all analyses. Result Thirty-eight patients were included (AHI:45±29 events/hr, age:52±7 y, body mass index: 30±4 kg/m2). They had similar baseline parameters. ET caused a significant change in OSA severity (AHI:4.5±18 versus -5.7±13 events/hr; arousal index:1.5±8 versus -6.1±13 events/hr, in untrained and trained groups respectively, p<0.05). The trained patients had an increase in functional capacity after intervention. ET improved isovolumetric relaxation time (IVRT, untrained=6.5±17.3 versus trained=-5.1±17.1 msec, p<0.05). There was a significant correlation between changes in IVRT and arousal index in the trained group (r =-0.54, p<0.05). No difference occurred in the other diastolic function parameters evaluated. Conclusion ET promotes modest but significant improvement in AHI, functional capacity, and cardiac IVRT, a validated parameter of diastolic function.

Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis.

Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy.

Impact of COVID-19 on the mental health of public university hospital workers in Brazil: A cohort-based analysis of 32,691 workers.

BACKGROUND: In early 2020, the COVID-19 pandemic paralyzed the world and exposed the fragility of health systems in the face of mass illness. Health professionals became protagonists, fulfilling their mission at the risk of physical and mental illness. The study aimed to evaluate absenteeism indirectly related to SARS-CoV-2 infection in a large population of health care professionals. METHODS: An observational longitudinal repeated measures study was performed, including workers linked to 40 public university hospitals in Brazil. All causes of absenteeism were analyzed, focusing on those not directly attributed to COVID-19. Results for the same population were compared over two equivalent time intervals: prepandemic and during the pandemic. FINDINGS: A total of 32,691 workers were included in the study, with health professionals comprising 82.5% of the sample. Comparison of the periods before and during the pandemic showed a 26.6% reduction in work absence for all causes, except for COVID-19 and mental health-related absence. Concerning work absence related to mental health, the odds ratio was 39.0% higher during the pandemic. At the onset of the pandemic, there was an increase in absenteeism (all causes), followed by a progressive reduction until the end of the observation period. INTERPRETATION: Work absence related to mental illness among health care professionals increased during the COVID-19 pandemic, highlighting the need for health care managers to prioritize and implement support strategies to minimize absenteeism.

Disturbed Blood Flow Acutely Increases Endothelial Microparticles and Decreases Flow Mediated Dilation in Patients With Heart Failure With Reduced Ejection Fraction.

INTRODUCTION: Disturbed blood flow, characterized by high retrograde and oscillatory shear rate (SR), is associated with a proatherogenic phenotype. The impact of disturbed blood flow in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. We tested the hypothesis that acute elevation to retrograde and oscillatory SR provoked by local circulatory occlusion would increase endothelial microparticles (EMPs) and decrease brachial artery flow-mediated dilation (FMD) in patients with HFrEF. METHODS: Eighteen patients with HFrEF aged 55 ± 2 years, with left ventricular ejection fraction (LVEF) 26 ± 1%, and 14 control subjects aged 49 ± 2 years with LVEF 65 ± 1 randomly underwent experimental and control sessions. Brachial artery FMD (Doppler) was evaluated before and after 30 min of disturbed forearm blood flow provoked by pneumatic cuff (Hokanson) inflation to 75 mm Hg. Venous blood samples were collected at rest, after 15 and 30 min of disturbed blood flow to assess circulating EMP levels (CD42b-/CD31+; flow cytometry). RESULTS: At rest, FMD was lower in patients with HFrEF compared with control subjects (P < 0.001), but blood flow patterns and EMPs had no differences (P > 0.05). The cuff inflation provoked a greater retrograde SR both groups (P < 0.0001). EMPs responses to disturbed blood flow significantly increased in patients with HFrEF (P = 0.03). No changes in EMPs were found in control subjects (P > 0.05). Disturbed blood flow decreased FMD both groups. No changes occurred in control condition. CONCLUSION: Collectively, our findings suggest that disturbed blood flow acutely decreases FMD and increases EMP levels in patients with HFrEF, which may indicate that this set of patients are vulnerable to blood flow disturbances.

Upper extremity deep venous thrombosis and pulmonary embolism after transvenous lead replacement or upgrade procedures.

BACKGROUND: Venous obstructions are frequent in patients with transvenous leads, although related clinical findings are rarely reported. After lead replacement or upgrade procedures, these lesions are even more frequent, but there is still no evidence to support this observation. AIM: To investigate the incidence and possible risk factors for upper extremity deep venous thrombosis (UEDVT) and pulmonary embolism (PE) after lead replacement or upgrade procedures. METHODS: Prospective cohort carried out between April 2013 and July 2016. Preoperative evaluation included venous ultrasound and pulmonary angiotomography. Diagnostic exams were repeated postoperatively to detect the study outcomes. Multivariate logistic regression models were used to identify prognostic factors. RESULTS: Among the 84 patients included, 44 (52.4%) were female and mean age was 59.3 ± 15.2 years. Lead malfunctioning (75.0%) was the main surgical procedure indication. Lead removal was performed in 44 (52.4%) cases. The rate of postoperative combined events was 32.6%, with 24 (28.6%) cases of UEDVT and six (7.1%) cases of PE. Clinical manifestations of deep venous thrombosis occurred in 10 (11.9%) patients. Independent prognostic factors for UEDVT were severe collateral circulation in the preoperative venography (odds ratio [OR] 4.7; 95% confidence interval [CI] 1.1-19.8; P = .037) and transvenous lead extraction (OR 27.4; 95% CI 5.8-128.8; P < .0001). CONCLUSION: Reoperations involving previously implanted transvenous leads present high rates of thromboembolic complications. Transvenous lead extraction had a significant impact on the development of UEDVT. These results show the need of further studies to evaluate the role of preventive strategies for this subgroup of patients.

Shock-Wave Therapy Improves Myocardial Blood Flow Reserve in Patients with Refractory Angina: Evaluation by Real-Time Myocardial Perfusion Echocardiography.

BACKGROUND: Cardiac shock-wave therapy (CSWT) has been demonstrated as an option for the treatment of patients with refractory angina (RA), promoting immediate vasodilatory effects and, in the long-term, neoangiogenic effects that would be responsible for reducing the myocardial ischemic load. The aim of this study was to determine the effects of CSWT on myocardial blood flow reserve (MBFR) assessed by quantitative real-time myocardial perfusion echocardiography in patients with RA. METHODS: Fifteen patients (mean age 61.5 ± 12.8 years) with RA who underwent CSWT during nine sessions, over 3 months of treatment, were prospectively studied. A total of 32 myocardial segments with ischemia were treated, while another 31 did not receive therapy because of technical limitations. Myocardial perfusion was evaluated at rest and after dipyridamole stress (0.84 mg/kg) before and 6 months after CSWT, using quantitative real-time myocardial perfusion echocardiography. Clinical effects were evaluated using Canadian Cardiovascular Society grading of angina and the Seattle Angina Questionnaire. RESULTS: The ischemic segments treated with CSWT had increased MBFR (from 1.33 ± 0.22 to 1.74 ± 0.29, P < .001), a benefit that was not observed in untreated ischemic segments (1.51 ± 0.29 vs 1.54 ± 0.28, P = .47). Patients demonstrated increased global MBFR (from 1.78 ± 0.54 to 1.89 ± 0.49, P = .017). Semiquantitative single-photon emission computed tomographic analysis of the treated ischemic segments revealed a score reduction from 2.10 ± 0.87 to 1.68 ± 1.19 (P = .024). There was improvement in Canadian Cardiovascular Society score (from 3.20 ± 0.56 to 1.93 ± 0.70, P < .05) and in Seattle Angina Questionnaire score (from 42.3 ± 12.99 to 71.2 ± 14.29, P < .05). No major cardiovascular events were recorded during follow-up. CONCLUSIONS: CSWT improved MBFR in ischemic segments, as demonstrated by quantitative real-time myocardial perfusion echocardiography. These results suggest that CSWT has the potential to increase myocardial blood flow, with an impact on symptoms and quality of life in patients with RA.

Antitrypanosomal activity of isololiolide isolated from the marine hydroid Macrorhynchia philippina (Cnidaria, Hydrozoa).

Marine invertebrates are a rich source of small antiparasitic compounds. Among them, Macrorhynchia philippina is a chemically underexplored marine cnidarian. In the search for candidates against the neglected protozoan Chagas disease, we performed a bio-guided fractionation to obtain active compounds. The structural characterization of the active compound was determined using NMR analysis and MS and resulted in the isololiolide, a compound described for the first time in this species. It showed in vitro activity against both trypomastigote and intracellular amastigotes of Trypanosoma cruzi, with IC50 values of 32 µM and 40 µM, respectively, with no mammalian cytotoxicity (>200 µM). The lethal action was investigated in T. cruzi using different fluorophores to study: (i) mitochondrial membrane potential; (ii) plasma membrane potential and (iii) plasma membrane permeability. Our results demonstrated that isololiolide caused disruption of the plasma membrane integrity and a strong depolarization of the mitochondrial membrane potential, rapidly leading the parasite to death. Despite being considered a possible covalent inhibitor, safety in silico studies of isololiolide also considered neither mutagenic nor genotoxic potential. Additionally, isololiolide showed no resemblance to interference compounds (PAINS), and it succeeded in most filters for drug-likeness. Isololiolide is a promising candidate for future optimization against Chagas disease.

Antitrypanosomal Activity of Acetogenins Isolated from the Seeds of Porcelia macrocarpa Is Associated with Alterations in Both Plasma Membrane Electric Potential and Mitochondrial Membrane Potential.

As part of a drug discovery program aimed at the identification of anti- Trypanosoma cruzi metabolites from Brazilian flora, four acetogenins (1-4) were isolated from the seeds of Porcelia macrocarpa and were identified by NMR spectroscopy and HRESIMS. The new compounds 1 and 2 displayed activity against the trypomastigote (IC50 = 0.4 and 3.6 µM) and amastigote (IC50 = 23.0 and 27.7 µM) forms. The structurally related known compound 3 showed less potency to the amastigotes, with an IC50 value of 58 µM, while the known compound 4 was inactive. To evaluate the potential mechanisms for parasite death, parameters were evaluated by fluorometric assays: (i) plasma membrane permeability, (ii) plasma membrane electric potential (ΔΨp), (iii) reactive oxygen species production, and (iv) mitochondrial membrane potential (ΔΨm). The results obtained indicated that compounds 1 and 2 depolarize plasma membranes, affecting ΔΨp and ΔΨm and contributing to the observed cellular damage and disturbing the bioenergetic system. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were nonmutagenic, noncarcinogenic, nongenotoxic, and weak hERG blockers. Additionally, none of the isolated acetogenins 1-4 were predicted as pan-assay interference compounds.

Exercise Training Increases Metaboreflex Control in Patients with Obstructive Sleep Apnea.

INTRODUCTION/PURPOSE: We demonstrated that patients with obstructive sleep apnea (OSA) have reduced muscle metaboreflex control of muscle sympathetic nerve activity (MSNA). In addition, exercise training increased muscle metaboreflex control in heart failure patients. OBJECTIVE: We tested the hypothesis that exercise training would increase muscle metaboreflex control of MSNA in patients with OSA. METHODS: Forty-one patients with OSA were randomized into the following two groups: 1) nontrained (OSANT, n = 21) and 2) trained (OSAT, n = 20). Muscle sympathetic nerve activity was assessed by microneurography technique, muscle blood flow (FBF) by venous occlusion plethysmography, heart rate by electrocardiography, and blood pressure with an automated oscillometric device. All physiological variables were simultaneously assessed at rest, during isometric handgrip exercise at 30% of the maximal voluntary contraction, and during posthandgrip muscle ischemia (PHMI). Muscle metaboreflex sensitivity was calculated as the difference in MSNA between PHMI and the rest period. Patients in the OSAT group underwent 72 sessions of moderate exercise training, whereas patients in the OSANT group were clinical follow-up for 6 months. RESULTS: The OSANT and OSAT groups were similar in anthropometric, neurovascular, hemodynamic and sleep parameters. Exercise training reduced the baseline MSNA (34 ± 2 bursts per minute vs 25 ± 2 bursts per minute; P < 0.05) and increased the baseline FBF (2.1 ± 0.2 mL·min per 100 g vs 2.4 ± 0.2 mL·min per 100 g; P < 0.05). Exercise training significantly reduced MSNA levels and increased FBF responses during isometric exercise. Exercise training significantly increased MSNA responses during PHMI (Δ6.5 ± 1 vs -1.7 ± 1 bursts per minute, P < 0.01). No significant changes in FBF or hemodynamic parameters in OSANT patients were found. CONCLUSIONS: Exercise training increases muscle metaboreflex sensitivity in patients with OSA. This autonomic change associated with increased muscle blood flow may contribute to the increase in exercise performance in this set of patients.

Antiparasitic activity of new gibbilimbol analogues and SAR analysis through efficiency and statistical methods.

Chagas' disease and leishmaniasis are parasitic infections enrolled among the neglected tropical diseases, which urge for new treatments. In the search for new chemical entities as prototypes, gibbilimbols A/B have shown antiparasitic activity against Trypanosoma cruzi and Leishmania infantum, and then a set of analogues (LINS03 series) of this natural product were synthesized and evaluated in vitro against the parasites. In the present paper we reported five new compounds with activity against these protozoan parasites, and quite low cytotoxicity. Moreover, the interference of plasma membrane permeability of these analogues were also evaluated. We found that [(4-methoxyphenyl)methyl]octylamine (4) was noteworthy due to its high activity against the amastigote form of both parasites (IC50 1.3-5.8 µM) and good selectivity index. In order to unveil the SAR for this chemotype, we also presented a group efficiency analysis and PCA and HCA study, which indicated that the methoxyl provides good activity with lower cytotoxicity to mammalian cells. The results from SAR analyses suggest different mechanisms of action between the neutral and basic compounds. In summary, the analogues represent important activity against these parasites and must be prototypes for further exploitation.

Formação em Psicologia e oligopolização do ensino superior no Brasil / Training in psychology and the oligopolization of higher education in Brazil / Formación en psicología y oligopolización de la enseñanza superior en Brasil

Objetiva-se situar o cenário atual da organização dos cursos de Psicologia no Brasil frente ao processo de expansão e mercantilização do ensino superior. Metodologicamente realizou-se pesquisa descritiva-exploratória com base nas informações oficiais da educação superior relacionadas aos cursos de Psicologia, além de relatórios financeiros dos grupos educacionais e consultorias especializadas em fundos de investimentos das IES que ofertam cursos de Psicologia. Os resultados indicam o aprofundamento do contexto de mercantilização do ensino superior e a formação de players da educação (grandes oligopólios), que concentram significativas parcelas do mercado. A formação em Psicologia segue a mesma tendência: intensificação do caráter privado e interiorização das agências formadoras, inclusive em localidades de menor porte populacional, além de um considerável percentual (26,25%) de cursos vinculados a grandes grupos educacionais no Brasil.

This article aimed to describe the current scenario of organization of psychology courses in Brazil, considering the process of expansion and mercantilization of higher education. Methodologically, this study was of exploratory-descriptive design, based on official information related to higher education, and on financial reports of educational groups and specialized consultancies in investment funds. Results showed a deepening of the process of mercantilization of higher education and the formation of players in education (great oligopolies), which concentrate a significant share of the market. The training in psychology follows the same tendency: intensification of the private sector and interiorization of the institutions, including smaller regions, it was also observed that a significant percentage (26.25%) of courses are linked with larger educational groups in Brazil.

El objetivo es situar el escenario actual de la organización de los cursos de psicología en Brasil, a través del proceso de expansión y mercantilización de la enseñanza superior. Metodológicamente se llevó a cabo una investigación descriptiva y exploratoria basada en las informaciones oficiales de la educación superior, además de informes financieros de los grupos educacionales y consultores especializados en fondos de inversión. Los resultados indican la profundización del contexto de mercantilización de la enseñanza superior y la formación de players de la educación (grandes oligopolios), que concentran importantes cuotas del mercado. La formación en psicología sigue la misma tendencia: la intensificación del carácter privado y la interiorización de las agencias de formación, incluso en los pueblos más pequeños, además del importante porcentaje (26,25%) de cursos vinculados a los grandes grupos educacionales en Brasil.

Transnacionalização do Ensino Superior: Impactos nos Processos Formativos em Psicologia no Brasil / The Transnationalization of Higher Education: the Impacts in the Formative Process in Psychology in Brazil / Transnacionalización de la Enseñanza Superior: Impactos en los Procesos Formativos en Psicología en Brasil

A expansão da educação superior nos últimos anos aprofundou a hegemonia do setor privado que passou a concentrar significativas fatias do mercado, inclusive com a presença de grupos internacionais operando no Brasil. Trata-se de um fenômeno resultante do alargamento da atuação de grupos financeiros em direção à esfera transnacional com a aquisição e fusão de instituições de ensino superior em todo o mundo. O presente trabalho traça um panorama histórico quanto à formação desses grupos no Brasil acompanhado da análise do impacto desse processo na formação em Psicologia e na organização dos cursos em termos do perfil do egresso, objetivos e estrutura curricular. Utilizou-se de um estudo documental, com base nas informações oficiais da educação superior e dos cursos de Psicologia no Brasil, incluindo os projetos pedagógicos de curso (fontes primárias), além de relatórios financeiros e de gestão dos grupos educacionais e consultorias especializadas em fundos de investimentos (fontes secundárias). Os resultados indicam a movimentação de pelo menos três grandes players transnacionais operando no Brasil: Laureate International Universities, DeVry University e Whitney International University System. Juntos detêm 26 instituições de ensino superior, concentrando-se nas regiões Nordeste (58%), Sudeste (25%) e Norte (12,5%). A Psicologia aparece como curso presente na maioria das IES adquiridas pelos grupos investigados (n = 21). Conclui-se que o processo em curso, ao padronizar conteúdos/currículo e homogeneizar determinados processos formativos, pode desvalorizar experiências educacionais locais e aprofundar o descompasso entre os saberes psicológicos e as necessidades sociais do país....(AU)

The spreading of higher education has enhanced the hegemony on the private sector that has concentrated significant slices of the market, including International groups in Brazil. It is a phenomenon resulting of the expansion of the actions of financial groups towards the transnational sphere with the acquisition and fusion of higher education institutions (HEI) around the world. The present work traces a historical panorama about the formation of these groups in Brazil; it is followed by the analysis of the impact of this process in the formation in Psychology and the organization of the courses in terms of alumni profile, objectives and curricular structure. This is a documental study, based on some official information on higher education and psychology courses in Brazil, including pedagogical projects of the course (Primary sources), as well as financial reports and management of educational groups and specialized consulting in funds (Secondary sources). The results indicate the movement of at least three major transnational players operating in Brazil: Laureate International Universities, DeVry University and Whitney International University System. Together they have 26 higher education institutions, concentrated in the Northeast (58%), Southeast (25%) and North (12.5%). Psychology appears as a course present in most HEI acquired by the analyzed groups (n = 21). It is concluded that the current process, by standardizing contents / curriculum and homogenizing certain formative processes, may devalue local educational experiences and deepen the gap between the psychological knowledge and the social necessities of the country....(AU)

La expansión de la educación superior en los últimos años profundizó la hegemonía del sector privado que pasó a concentrar significativas rebanadas del mercado, incluso con la presencia de grupos internacionales operando en Brasil. Este fenómeno resulta de la ampliación de la actuación de grupos financieros hacia la esfera transnacional con la adquisición y fusión de instituciones de enseñanza superior (IES) en todo el mundo. Este trabajo presenta un panorama histórico de la formación de estos grupos en Brasil, un análisis del impacto de ese proceso en la formación en Psicología y en la organización de los cursos en términos del perfil del egresado, objetivo y estructuras curriculares. Se utilizó un estudio documental, basado en las informaciones oficiales de la educación superior y de los cursos de Psicología en Brasil, incluyendo los proyectos pedagógicos (fuentes primarias), informes financieros y de gestión de los grupos educativos y consultorías especializadas en fondos de inversiones (fuentes secundarias). Los resultados indican el movimiento de por lo menos tres grandes players transnacionales operando en Brasil: Laureate International Universities, DeVry University y Whitney International University System. Estos detienen 26 instituciones de enseñanza superior, sobretodo en el Nordeste (58%), el Sudeste (25%) y el Norte (12,5%). El curso de Psicología aparece en la mayoría de las IES de los grupos investigados (n = 21). Se concluye que el proceso en curso, al estandarizar contenidos / currículos y homogeneizar determinados procesos formativos, puede devaluar experiencias educativas locales y profundizar el descompás entre los saberes psicológicos y las necesidades sociales del país....(AU)

Membrane targeting peptides toward antileishmanial activity: Design, structural determination and mechanism of interaction.

BACKGROUND: Leishmaniasis threatens poor areas population worldwide, requiring new drugs less prone to resistance development. Antimicrobial peptides with antileishmanial activity are considered among fulfilling alternatives, but not much is known about the mode of action of membrane-targeting peptides, considering promastigote and infected macrophage membranes. In a previous work, structural features of very active known peptides were prospected using molecular dynamics simulations. METHODS: Combining sequences of these peptides, analogs were designed. The structure of analog DecP-11 was validated by NMR. In vitro bioassays determined the peptide cytotoxicity toward mammalian cells, IC50 values on promastigotes and amastigotes, and membranolytic activity compared to Decoralin, one of the parent peptides. With biophysical methods, the mechanism of interaction with membrane mimetic systems was investigated. RESULTS: The designed peptide exhibits potent cytolytic and membrane permeabilizing activities, and decreased antileishmanial activity compared to the parent peptide. Interactions with lipid bilayers mimicking those of promastigotes, infected macrophage and mammalian cells showed that these peptides strongly bind to vesicles with intense lytic activity at low concentrations. Additionally, circular dichroism and light scattering experiments showed changes in the secondary structure of peptides and in vesicle size, depending on vesicles compositions. Altogether they suggest that DecP-11 antileishmanial activity is impaired by the aggregation and that aminophospholipids are probably involved. CONCLUSIONS: DecP-11 potent cytolytic and membranolytic activities with lack of selectivity toward promastigote model membranes warrant further structural studies to improve selectivity. GENERAL SIGNIFICANCE: Strong interactions of peptides with aminophospholipids, abundant in parasite membranes, potentially lead to aggregated forms impairing activity.

Global Longitudinal Strain or Left Ventricular Twist and Torsion? Which Correlates Best with Ejection Fraction?

Background: Estimative of left ventricular ejection fraction (LVEF) is a major indication for echocardiography. Speckle tracking echocardiography (STE) allows analysis of LV contraction mechanics which includes global longitudinal strain (GLS) and twist/torsion, both the most widely used. Direct comparison of correlations between these novel parameters and LVEF has never been done before. Objective: This study aims to check which one has the highest correlation with LVEF. Methods: Patients with normal LVEF (> 0,55) and systolic dysfunction (LVEF <0,55) were prospectively enrolled, and underwent echocardiogram with STE analysis. Correlation of variables was performed by linear regression analysis. In addition, correlation among levels of LV systolic impairment was also tested. Results: A total of 131 patients were included (mean age, 46 ± 14y; 43%, men). LVEF and GLS showed a strong correlation (r = 0.95; r2 = 0.89; p < 0.001), more evident in groups with LV systolic dysfunction than those with preserved LVEF. Good correlation was also found with global longitudinal strain rate (r = 0.85; r2 = 0.73; p < 0.001). Comparing to GLS, correlation of LVEF and torsional mechanics was weaker: twist (r = 0.78; r2 = 0.60; p < 0.001); torsion (r = 0.75; r2 = 0.56; p < 0.001). Conclusion: GLS of the left ventricle have highly strong positive correlation with the classical parameter of ejection fraction, especially in cases with LV systolic impairment. Longitudinal strain rate also demonstrated a good correlation. GLS increments analysis of LV systolic function. On the other hand, although being a cornerstone of LV mechanics, twist and torsion have a weaker correlation with LV ejection, comparing to GLS.

Fundamento: A estimativa da fração de ejeção do ventrículo esquerdo (FEVE) é uma das pincipais indicações para a ecocardiografia. Speckle tracking (ST) permite a análise da mecânica de contração do VE que inclui a deformação (strain) longitudinal global (SLG) e o twist / torção, sendo ambos os mais utilizados. A comparação direta de correlações entre esses novos parâmetros e a FEVE nunca foi feita antes. Objetivo: Verificar qual delas tem a maior correlação com a FEVE. Métodos: Pacientes com FEVE normal (> 0,55) e disfunção sistólica (FEVE < 0,55) foram prospectivamente inscritos e submetidos a ecocardiograma com análise do ST. A correlação das variáveis foi realizada por análise de regressão linear. Além disso, também foi testada a correlação entre os níveis de comprometimento sistólico do VE. Resultados: Foram incluídos 131 pacientes (média de idade de 46 ± 14 anos e 43% de homens). A FEVE e SLG apresentaram forte correlação (r = 0,95; r2 = 0,89; p < 0,001), mais evidente em grupos com disfunção sistólica do VE do que naqueles com FEVE preservada. Também foi encontrada boa correlação com a taxa de deformação (strain rate) longitudinal (SRL) global (r = 0,85; r2 = 0,73; p < 0,001). Comparando-a à SLG, a correlação entre FEVE e mecânica de torção foi mais fraca: twist (r = 0,78; r2 = 0,60; p < 0,001); Torção (r = 0,75, r2 = 0,56, p < 0,001). Conclusão: A SLG do ventrículo esquerdo apresenta alta correlação positiva com o parâmetro clássico de fração de ejeção, principalmente nos casos de comprometimento sistólico do VE. O SRL também demonstrou uma boa correlação. A SLG incrementa a análise da função sistólica do VE. Por outro lado, apesar de ser a pedra angular da mecânica do VE, o twist e a torção têm uma correlação mais fraca com a ejeção do VE, quando comparados ao SLG.