Contrasting Disease Progression, Microglia Reactivity, Tolerance, and Resistance to Toxoplasma gondii Infection in Two Mouse Strains.

Our study investigated the innate immune response to Toxoplasma gondii infection by assessing microglial phenotypic changes and sickness behavior as inflammatory response markers post-ocular tachyzoite instillation. Disease progression in Swiss albino mice was compared with the previously documented outcomes in BALB/c mice using an identical ocular route and parasite burden (2 × 105 tachyzoites), with saline as the control. Contrary to expectations, the Swiss albino mice displayed rapid, lethal disease progression, marked by pronounced sickness behaviors and mortality within 11-12 days post-infection, while the survivors exhibited no apparent signs of infection. Comparative analysis revealed the T. gondii-infected BALB/c mice exhibited reduced avoidance of feline odors, while the infected Swiss albino mice showed enhanced avoidance responses. There was an important increase in microglial cells in the dentate gyrus molecular layer of the infected Swiss albino mice compared to the BALB/c mice and their respective controls. Hierarchical cluster and discriminant analyses identified three microglial morphological clusters, differentially affected by T. gondii infection across strains. The BALB/c mice exhibited increased microglial branching and complexity, while the Swiss albino mice showed reduced shrunken microglial arbors, diminishing their morphological complexity. These findings highlight strain-specific differences in disease progression and inflammatory regulation, indicating lineage-specific mechanisms in inflammatory responses, tolerance, and resistance. Understanding these elements is critical in devising control measures for toxoplasmosis.

Topical delivery of seriniquinone for treatment of skin cancer and fungal infections is enabled by a liquid crystalline lamellar phase.

Seriniquinone (SQ) was initially described by our group as an antimelanoma drug candidate and now also as an antifungal drug candidate. Despite its promising in vitro effects, SQ translation has been hindered by poor water-solubility. In this paper, we described the challenging nanoformulation process of SQ, which culminated in the selection of a phosphatidylcholine-based lamellar phase (PLP1). Liposomes and nanostructured lipid carriers were also evaluated but failed to encapsulate the compound. SQ-loaded PLP1 (PLP1-SQ) was characterized for the presence of sedimented or non-dissolved SQ, rheological and thermal behavior, and irritation potential with hen's egg test on the chorioallantoic membrane (HET-CAM). PLP1 influence on transepidermal water loss (TEWL) and skin penetration of SQ was assessed in a porcine ear skin model, while biological activity was evaluated against melanoma cell lines (SK-MEL-28 and SK-MEL-147) and C. albicans SC5314. Despite the presence of few particles of non-dissolved SQ (observed under the microscope 2 days after formulation obtainment), PLP1 tripled SQ retention in viable skin layers compared to SQ solution at 12 h. This effect did not seem to relate to formulation-induced changes on the barrier function, as no increases in TEWL were observed. No sign of vascular toxicity in the HET-CAM model was observed after cutaneous treatment with PLP1. SQ activity was maintained on melanoma cells after 48 h-treatment (IC50 values of 0.59-0.98 µM) whereas the minimum inhibitory concentration (MIC) against C. albicans after 24 h-treatment was 32-fold higher. These results suggest that a safe formulation for SQ topical administration was developed, enabling further in vivo studies.

Beyond Formulation: Contributions of Nanotechnology for Translation of Anticancer Natural Products into New Drugs.

Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, which is quite curious since the research and development (R&D) course of nanoformulations are even more expensive and prone to failure than the conventional ones. Nonetheless, nanosystems are cost-effective and represent both novel and safer dosage forms with fewer side effects due to modification of pharmacokinetic properties and tissue targeting. In addition, nanotechnology-based drugs can contribute to dose modulation, reversion of multidrug resistance, and protection from degradation and early clearance; can influence the mechanism of action; and can enable drug administration by alternative routes and co-encapsulation of multiple active agents for combined chemotherapy. In this review, we discuss the contribution of nanotechnology as an enabling technology taking the clinical use of DOX and PTX as examples. We also present other nanoformulations approved for clinical practice containing different anticancer natural-product-derived drugs.

The COVID-19 pandemic, emergency aid and social work in Brazil.

This essay reflects on the implementation of federal government emergency aid in Brazil in the context of the COVID-19 pandemic, highlighting elements from the work of Social Workers in the context of growing demand for the supply of material provisions. Economic and social conditions in Brazil have particularities that impact the operationalisation of this benefit, which is aimed at the poor, that add complexity and impose limits. When considering the structural limits set, this context imposes challenges on the work of Social Workers. The need to reconnect and enhance the struggle for social rights is emphasised through the different strategies of the working class.

l-Hypaphorine and d-hypaphorine: Specific antiacetylcholinesterase activity in rat brain tissue.

Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzheimer's disease (AD). l-Hypaphorine (l-HYP) is a natural indole alkaloid that has been shown to have effects on the central nervous system (CNS). The goal of this research was to synthesize l-HYP and d-HYP and test their anticholinesterasic properties in rat brain regions. l-HYP suppressed acetylcholinesterase (AChE) activity only in the cerebellum, whereas d-HYP inhibited AChE activity in all CNS regions studied. No cytotoxic effect on normal human cells (HaCaT) was observed in the case of l-HYP and d-HYP although an increase in cell proliferation. Molecular modeling studies revealed that d-HYP and l-HYP have significant differences in their binding mode positions and interact stereospecifically with AChE's amino acid residues.

S-(4-Methoxyphenyl)-4-methoxybenzenesulfonothioate as a Promising Lead Compound for the Development of a Renal Carcinoma Agent.

Organosulfur compounds show cytotoxic potential towards many tumor cell lines. Disulfides and thiosulfonates act through apoptotic processes, inducing proteins associated with apoptosis, endoplasmic reticulum stress, and the unfolded protein response. Three p-substituted symmetric diaryl disulfides and three diaryl thiosulfonates were synthesized and analyzed for inhibition of tubulin polymerization and for human cancer cell cytotoxic activity against seven tumor cell lines and a non-tumor cell line. S-(4-methoxyphenyl)-4-methoxybenzenesulfonothioate (6) exhibited inhibition of tubulin polymerization and showed the best antiproliferative potential, especially against the 786-0 cell line, being six times more selective as compared with the non-tumor cell line. In addition, compound 6 was able to activate caspase-3 after 24 and 48 h treatments of the 786-0 cell line and induced cell-cycle arrest in the G2/M stage at the highest concentration evaluated at 24 and 48 h. Compound 6 was able to cause complete inhibition of proliferation, inducing the death of 786-0 cells, by increasing the number of cells at G2/M and greater activation of caspase-3.

Respostas cardiovasculares ao treino resistido com diferentes níveis de oclusão vascular / Cardiovascular responses to resistance training with different vascular oclusion levels

: O treino com oclusão vascular (OV) tem sido amplamente utilizado devido a seus benefícios. No entanto, ainda permanecem escassos os estudos em relação às respostas cardiovasculares a este tipo de treino. O objetivo deste estudo foi verificar as respostas hemodinâmicas e trabalho do miocárdio com diferentes níveis de oclusão vascular no exercício de extensão unilateral de joelho. Recrutamos 14 voluntários e estes foram submetidos a um protocolo de três séries de 15 repetições com 30% de uma repetição máxima no exercício de extensão unilateral de joelho com diferentes níveis de OV, sendo eles: sem oclusão (SO), oclusão parcial (OP) e oclusão total (OT). A pressão arterial sistólica (PAS) e frequência cardíaca (FC) foram verificadas em repouso e ao final de cada série do protocolo. A análise de variância de duas entradas com post hoc de Bonferroni foi utilizado para verificar diferença entre os tipos de oclusão, tendo nível de significância quando p<0.05. Observou-se diferença da PAS, FC e duploproduto (DP) entre as séries e o repouso (p<0,001). Independentemente do tipo de execução, a PAS, FC e DP foram maiores na 2ª e 3ª séries comparadas à 1ª. A OP e OT proporcionaram maiores valores de PAS na 3ª série comparada à 2ª série (p= 0,036; p=0,025). Por fim, houve diferença na 3ª série entre a OT e SO (p= 0,01). O presente estudo conclui que a sobrecarga cardiovascular tem relação direta com o volume de exercício e o nível de oclusão....(AU)

Vascular occlusion (VO) training has been widely used because of its benefits. However, there are still few studies regarding cardiovascular responses to this type of training. The objective of this study was to verify hemodynamics responses and myocardial workload with different occlusion levels on unilateral knee extension exercise. We recruited 14 volunteers and were submitted to a protocol of three series of 15 repetitions with 30% of a maximal repetition in the exercise of with different levels of OV, being: no occlusion (NO), partial occlusion (PO) and total occlusion (TO). Systolic blood pressure (SBP) and heart rate (HR) were checked at rest and at the end of each protocol series. Bonferroni post hoc twoway analysis of variance was used to verify the difference between occlusion types, with significance level when p <0.05. A difference of SBP, HR and double-product (DP) between series and rest was observed (p<0.001). Regardless of the type of execution, SBP, HR and DP were higher in the 2nd and 3rd grades compared to the 1st. The PO and TO provided higher SBP values in the 3rd grade compared to the 2nd grade (p = 0.036, p = 0.025). Finally, there was a difference in the 3rd grade between TO and NO (p =0.01). It's concluded that the cardiovascular overload has direct relation with exercise volume and occlusion level....(AU)

In vitro anthelmintic activity of Siparuna guianensis extract and essential oil against Strongyloides venezuelensis.

New therapeutic approaches are necessary to control strongyloidiasis due to the side effects of, and resistance to, currently available drugs thiabendazole, albendazole, and ivermectin. This study examined the anthelmintic properties of extracts and isolated compounds from Siparuna guianensis against Strongyloides venezuelensis eggs and larvae, using the egg hatching test (EHT) and larval motility test (LMT). Albendazole (0.025 mg/ml) and ivermectin (0.316 mg/ml) were used as the positive controls for the EHT and LMT assays, respectively. Strongyloides venezuelensis eggs or larvae (±50 specimens) were treated with ethanol extract (0.05-1.0 mg/ml), ethyl acetate and aqueous fractions (0.05-0.8 mg/ml), essential oil (0.2-1.0 mg/ml) and α-bisabolol (0.2-1.0 mg/ml) from S. guianensis, and analysed by optical microscopy after 48 h (EHT), or after 24, 48 and 72 h (LMT). All the tested compounds exhibited ovicidal activity equivalent to the positive control and changed the morphology of the eggs. The S. guianensis ethanol extract and aqueous fraction were as effective as the positive control. Phytochemical analysis of the ethanol extract and fractions revealed the presence of phenolic compounds, tannins and flavonoids. Therefore, S. guianensis is effective against S. venezuelensis eggs and larvae in vitro, and can be considered as a potential alternative treatment for strongyloidiasis.

Genetic differentiation in red-bellied piranha populations (Pygocentrus nattereri, Kner, 1858) from the Solimões-Amazonas River.

Red-bellied piranhas (Pygocentrus nattereri) are widely caught with different intensities throughout the region of Solimões-Amazonas River by local fishermen. Thus, the management of this resource is performed in the absence of any information on its genetic stock. P. nattereri is a voracious predator and widely distributed in the Neotropical region, and it is found in other regions of American continent. However, information about genetic variability and structure of wild populations of red-bellied piranha is unavailable. Here, we describe the levels of genetic diversity and genetic structure of red-bellied piranha populations collected at different locations of Solimões-Amazonas River system. We collected 234 red-bellied piranhas and analyzed throughout eight microsatellite markers. We identified high genetic diversity within populations, although the populations of lakes ANA, ARA, and MAR have shown some decrease in their genetic variability, indicating overfishing at these communities. Was identified the existence of two biological populations when the analysis was taken altogether at the lakes of Solimões-Amazonas River system, with significant genetic differentiation between them. The red-bellied piranha populations presented limited gene flow between two groups of populations, which were explained by geographical distance between these lakes. However, high level of gene flow was observed between the lakes within of the biological populations. We have identified high divergence between the Catalão subpopulation and all other subpopulations. We suggest the creation of sustainable reserve for lakes near the city of Manaus to better manage and protect this species, whose populations suffer from both extractive and sport fishing.

Equine infectious anemia on Marajo Island at the mouth of the Amazon river / Anemia infecciosa equina na Ilha de Marajó na foz do Rio Amazonas

Equine infectious anemia (EIA) is a transmissible and incurable disease caused by a lentivirus, the equine infectious anemia virus (EIAV). There are no reports in the literature of this infection in Equidae on Marajo Island. The objective of this study was to diagnose the disease in the municipalities of Cachoeira do Arari, Salvaterra, Santa Cruz do Arari and Soure, on Marajó Island, state of Pará, Brazil. For serological survey samples were collected from 294 horses, over 5-month-old, males and females of puruca and marajoara breeds and from some half-breeds, which were tested by immunodiffusion in Agar gel (AGID). A prevalence of 46.26% (136/294) positive cases was found. EIA is considered endemic in the municipalities studied, due to the ecology of the region with a high numbered population of bloodsucking insect vectors and the absence of official measures for the control of the disease...

A anemia infecciosa equina (EIA) é uma importante enfermidade, transmissível e incurável causada por um lentivírus, equine infectious anemia vírus (EIAV), e não há relatos na literatura desta infecção em equinos da Ilha de Marajó. O objetivo deste estudo foi diagnosticar a anemia infecciosa equina nos municípios de Cachoeira do Arari, Salvaterra, Santa Cruz do Arari e Soure, Ilha de Marajó, no bioma amazônico do estado do Pará, Brasil. Para a pesquisa sorológica foram coletadas 294 amostras de animais da espécie equina, acima de cinco meses de idade, de ambos os sexos, das raças puruca, marajoara e de mestiços, testadas pela imunodifusão em gel de Agar (IDGA). Foi verificada uma prevalência de 46.26% (136/294) de casos positivos para EIA. A doença é considerada endêmica nos municípios estudados, tanto pelos aspectos ecológicos da região que propiciam a manutenção da população de insetos hematófagos vetores, quanto pela ausência de medidas oficiais de controle da doença...

Rickettsial infection in ticks from wild birds from Cerrado and the Pantanal region of Mato Grosso, midwestern Brazil.

The involvement of different species of ticks and wild animals, such as birds, play an important role in the epidemiology of tick-borne diseases. Birds may serve as reservoirs for some tick-borne diseases, and may carry and spread hematophagous ectoparasites mechanically. This study aimed to show the diversity of ticks on birds and molecular detection of rickettsial infection in ticks from Pantanal and Cerrado, two similar Brazilian biomes characterized by hydrological seasons. During two years, August 2012 to May 2014, ticks were collected from birds and from the environment in total of 14 visits for collecting samples, distributed in all hydrological seasons. A total of 674 birds were captured representing 113 species from 26 families. In total, 71 birds were parasitized (10.5%), and 155 ticks of the following 7 tick species (in decreasing order of prevalence) were identified: Amblyomma longirostre Koch, Amblyomma nodosum Neumann, Amblyomma cajennense Fabricius sensu lato (s.l.), Amblyomma calcaratum Neumann, Ornithodoros mimon Kohls, Clifford & Jones, Amblyomma ovale Koch, and Amblyomma triste Koch. Among free-living ticks collected in the environment, A. cajennense s.l. was the most common. This is the first occurrence of O. mimon on birds, and of A. triste on Passeriformes in Brazil. Molecular analyses revealed that 6 A. longirostre ticks were infected by 'Candidatus Rickettsia amblyommii', whereas 1 A. nodosum was infected by a Rickettsia parkeri-like agent, previously reported as Rickettsia sp. strain NOD. Spotted fever group (SFG) agents were, for the first time, reported in ticks from birds captured in Pantanal biome, and the potential involvement of these agents as human pathogens should be considered in further studies.

Are the barriers for physical activity practice equal for all peripheral artery disease patients?

OBJECTIVE: To investigate barriers to physical activity related to the sociodemographic comorbidities and clinical variables of patients with intermittent claudication. DESIGN: Cross-sectional study. SETTING: Ambulatory care. PARTICIPANTS: The medical histories of patients (N=145) aged ≥50 years with intermittent claudication were examined. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sociodemographic data (sex, race, level of education, socioeconomic status, marital status), comorbidities (overweight, hypertension, dyslipidemia, diabetes, currently smoking, heart disease), and clinical variables (initial claudication distance, total walking distance, ankle-brachial index). Information on personal and environmental barriers was obtained by questionnaire. RESULTS: Low economic status was most associated with "being afraid of falling" (odd ratios [OR]=2.22; 95% confidence interval [CI], 1.08-4.54). Low education level was most associated with "lack of street pedestrian crossing" (OR=3.34; 95% CI, 1.48-7.52). Diabetes was associated with lack of energy (OR=3.38; 95% CI, 1.68-6.79) and other medical conditions (eg, arthritis, angina) (OR=3.44; 95% CI, 1.65-7.16). Ankle brachial index was associated with "some difficulty in getting to a place where physical activity can be performed" (OR=2.75; 95% CI, 1.22-6.21). Walking capacity was strongly associated with barriers relating to leg pain (OR=7.39; 95% CI, 1.66-32.88). CONCLUSIONS: Older patients, those with a low education level, patients with diabetes, low ankle brachial index, and those with a lower walking capacity are more likely to experience barriers to physical activity.

Políticas de saúde e organização do processo de trabalho em Saúde da Família

Este módulo tem foco no contexto no qual acontece o trabalho cotidiano e a organização das Equipes de Saúde da Família. É composto por três lições que abordam os seguintes temas: diagnóstico inicial das competências dos participantes e o instrumento de acompanhamento; direito à saúde e características específicas do SUS, a Estratégia de Saúde da Família (ESF) e os desafios da relação da ESF com o conjunto da rede de serviço do SUS; mecanismo de gestão participativa no SUS; processo de trabalho da ESF na prática multiprofissional com abordagem interdisciplinar e intersetorial. Procura-se convidar os participantes a refletir sobre suas atividades do dia a dia, procurando a expressão de dinâmicas sociais mais amplas e possibilidade de melhora da sua organização.

Use of psychotropic medications during pregnancy: perception of teratogenic risk among physicians in two Latin American countries

Objective: Pregnant women and their health care professionals commonly believe that use of medications during pregnancy may be harmful to the unborn fetus. The objective of this study was to evaluate the risk perception of psychotropic drug use in pregnancy among physicians in different medical specialties. Method: This was a convenience survey conducted at outpatient clinics in the cities of Recife, Brazil, and La Plata, Bahía Blanca, and Buenos Aires, Argentina. Physicians who agreed to participate were asked to rate their perception of teratogenic risk among different classes of drugs, which included antidepressants, antipsychotics, anticonvulsants, and benzodiazepines. Results: Two hundred and thirty-eight physicians completed the survey (response rate, 98%). These included psychiatrists, obstetricians, neurologists, cardiologists, gastroenterologists, and general practitioners. Among different specialties, a minority of psychiatrists perceived psychotropic drugs to be highly teratogenic (antidepressants, 12.5%; antipsychotics, 15%; benzodiazepines, 25%) as compared with other specialties (p < 0.003 for each drug class). There was no difference in perceived risk of antiepileptic drugs among specialties, including psychiatrists. Conclusion: The risk associated with use of psychotropic drugs in pregnancy was overestimated by physicians of all medical specialties, except psychiatry. All physicians should be aware of the safety/risk of psychotropic agents in pregnancy, as they may be required to give advice and/or prescribe these drugs to pregnant women. .

Use of psychotropic medications during pregnancy: perception of teratogenic risk among physicians in two Latin American countries.

OBJECTIVE: Pregnant women and their health care professionals commonly believe that use of medications during pregnancy may be harmful to the unborn fetus. The objective of this study was to evaluate the risk perception of psychotropic drug use in pregnancy among physicians in different medical specialties. METHOD: This was a convenience survey conducted at outpatient clinics in the cities of Recife, Brazil, and La Plata, Bahía Blanca, and Buenos Aires, Argentina. Physicians who agreed to participate were asked to rate their perception of teratogenic risk among different classes of drugs, which included antidepressants, antipsychotics, anticonvulsants, and benzodiazepines. RESULTS: Two hundred and thirty-eight physicians completed the survey (response rate, 98%). These included psychiatrists, obstetricians, neurologists, cardiologists, gastroenterologists, and general practitioners. Among different specialties, a minority of psychiatrists perceived psychotropic drugs to be highly teratogenic (antidepressants, 12.5%; antipsychotics, 15%; benzodiazepines, 25%) as compared with other specialties (p < 0.003 for each drug class). There was no difference in perceived risk of antiepileptic drugs among specialties, including psychiatrists. CONCLUSION: The risk associated with use of psychotropic drugs in pregnancy was overestimated by physicians of all medical specialties, except psychiatry. All physicians should be aware of the safety/risk of psychotropic agents in pregnancy, as they may be required to give advice and/or prescribe these drugs to pregnant women.

Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity.

We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.

SYNTHESIS AND BIOLOGICAL ACTIVITY OF SULFUR COMPOUNDS SHOWING STRUCTURAL ANALOGY WITH COMBRETASTATIN A-4.

We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15).

Synthesis method for thiosulfonate and report of its insecticidal activity in Anagasta kuehniella (Lepidoptera: Pyralidae).

Insect pests have caused economic losses valued at billions of dollars in agricultural production. Anagasta kuehniella (Zeller), the Mediterranean flour moth, is of major economic importance as a flour and grain feeder and is often a severe pest in flourmills. This study provides a suitable route for the direct preparation of thiosulfonates 2 and 3 from thiols, under mild conditions, with good yields; these thiosulfonates were tested for their regulatory effect on insect growth. The chronic ingestion of thiosulfonates resulted in a significant reduction in larval survival and weight. In addition, the tryptic activity of larvae was sensitive to these thiosulfonates. Results suggest that thiosulfonates 2 and 3 have a potential antimetabolic effect when ingested by A. kuehniella. The use of AgNO(3)/BF(3)·OEt(2) and Al(H(2)PO(4))(3)/HNO(3) provides a suitable route for the direct preparation of thiosulfonates from thiols under mild conditions with good yields. These thiosulfonates were toxic for A. kuehniella larvae, suggesting their potential as biotechnological tools.