CD73 mitigates ZEB1 expression in papillary thyroid carcinoma.

BACKGROUND: ZEB1, a core transcription factor involved in epithelial-mesenchymal transition (EMT), is associated with aggressive cancer cell behavior, treatment resistance, and poor prognosis across various tumor types. Similarly, the expression and activity of CD73, an ectonucleotidase implicated in adenosine generation, is an important marker of tumor malignancy. Growing evidence suggests that EMT and the adenosinergic pathway are intricately linked and play a pivotal role in cancer development. Therefore, this study focuses on exploring the correlations between CD73 and ZEB1, considering their impact on tumor progression. METHODS: We employed CRISPR/Cas9 technology to silence CD73 expression in cell lines derived from papillary thyroid carcinoma. These same cells underwent lentiviral transduction of a reporter of ZEB1 non-coding RNA regulation. We conducted studies on cell migration using scratch assays and analyses of cellular speed and polarity. Additionally, we examined ZEB1 reporter expression through flow cytometry and immunocytochemistry, complemented by Western blot analysis for protein quantification. For further insights, we applied gene signatures representing different EMT states in an RNA-seq expression analysis of papillary thyroid carcinoma samples from The Cancer Genome Atlas. RESULTS: Silencing CD73 expression led to a reduction in ZEB1 non-coding RNA regulation reporter expression in a papillary thyroid carcinoma-derived cell line. Additionally, it also mitigated ZEB1 protein expression. Moreover, the expression of CD73 and ZEB1 was correlated with alterations in cell morphology characteristics crucial for cell migration, promoting an increase in cell polarity index and cell migration speed. RNA-seq analysis revealed higher expression of NT5E (CD73) in samples with BRAF mutations, accompanied by a prevalence of partial-EMT/hybrid state signature expression. CONCLUSIONS: Collectively, our findings suggest an association between CD73 expression and/or activity and the post-transcriptional regulation of ZEB1 by non-coding RNA, indicating a reduction in its absence. Further investigations are warranted to elucidate the relationship between CD73 and ZEB1, with the potential for targeting them as therapeutic alternatives for cancer treatment in the near future.

FGFR inhibition augments anti-PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression.

The combination of targeted therapy with immune checkpoint inhibition (ICI) is an area of intense interest. We studied the interaction of fibroblast growth factor receptor (FGFR) inhibition with ICI in urothelial carcinoma (UC) of the bladder, in which FGFR3 is altered in 50% of cases. Using an FGFR3-driven, Trp53-mutant genetically engineered murine model (UPFL), we demonstrate that UPFL tumors recapitulate the histology and molecular subtype of their FGFR3-altered human counterparts. Additionally, UPFL1 allografts exhibit hyperprogression to ICI associated with an expansion of T regulatory cells (Tregs). Erdafitinib blocked Treg proliferation in vitro, while in vivo ICI-induced Treg expansion was fully abrogated by FGFR inhibition. Combined erdafitinib and ICI resulted in high therapeutic efficacy. In aggregate, our work establishes that, in mice, co-alteration of FGFR3 and Trp53 results in high-grade, non-muscle-invasive UC and presents a previously underappreciated role for FGFR inhibition in blocking ICI-induced Treg expansion.

Naproxen administration affects murine late folliculogenesis, reduces granulosa cell proliferation and the number of ovulated oocytes.

Naproxen reduces the production of prostaglandins via inhibition of the cyclooxygenase. Studies have shown that its administration in women can be related to failed ovulation. Therefore, preclinical investigations must be performed in order to investigate its effects in experimental models. Thus, the aim of this study was to evaluate the effects of naproxen on murine folliculogenesis, ovulation, and female fertility. Female C57BL/6 mice (n = 128 - 6 weeks old) were divided into Control, low (10 mg/kg), and high naproxen (50 mg/kg) groups, who were treated for 8 days and directed to morphofunctional analyses. Follicular quantification showed a reduced percentage of antral follicles in naproxen-treated animals. These treated animals also showed smaller oocytes included in secondary and antral follicles, and the diameter of secondary and antral follicles was also reduced. A reduction in the percentage of Ki67-positive granulosa cells was observed in treated animals that also showed down-regulation of Igf1r compared to control. After an ovarian stimulation protocol, naproxen-treated animals showed a reduction in the percentage of secondary and antral follicles, a reduced number of ovulated oocytes and, corpora lutea, and an increased number of failed ovulations. Finally, naproxen-treated animals also showed a reduction in mating index and pregnancy rate. Our findings suggested that, in mice, naproxen administration (eight days treatment) negatively affects molecular and morphological aspects related to late folliculogenesis, ovulation, and fertility.

Antiviral activity of terpenes isolated from marine brown seaweeds against herpes simplex virus type 2.

Herpes simplex virus type 2 (HSV-2) is the most common agent of sexually transmitted infections around the world. Currently, no vaccine is available, and acyclovir is the reference compound in treatment HSV-2 infections. However, the emergence of resistant strains has reduced the efficacy in treatment. Several studies have shown marine seaweed biological activities, but there are no studies yet about the activity anti-HSV-2 of two its secundary metabolites, atomaric acid (1) and marine dolastane (2), isolated from Stypopodium zonale and Canistrocarpus cervicornis respectively. Therefore, we evaluated the anti-HSV-2 activity of compounds 1 and 2. Both compounds showed anti-HSV-2 activity with low cytotoxicity and compound 1 inactivated 90% of the viral particles at 50 µM. Both compounds inhibited the penetration and results in silico indicated the compound 1 as possible therapy alternative anti -HSV-2.

Mitochondrial response of glioma cells to temozolomide.

Metabolic adaptations are central for carcinogenesis and response to therapy, but little is known about the contribution of mitochondrial dynamics to the response of glioma cells to the standard treatment with temozolomide (TMZ). Glioma cells responded to TMZ with mitochondrial mass increased and the production of round structures of dysfunctional mitochondria. At single-cell level, asymmetric mitosis contributed to the heterogeneity of mitochondrial levels. It affected the fitness of cells in control and treated condition, indicating that the mitochondrial levels are relevant for glioma cell fitness in the presence of TMZ.

Effect of rapamycin on Cryptococcus neoformans: cellular organization, biophysics and virulence factors.

Background: Cryptococcus neoformans is an opportunistic fungal pathogen that causes infections mainly in immunosuppressed individuals, such as transplant recipients. Aims: This study investigated the effects of rapamycin, an immunosuppressant drug, on the cellular organization, biophysical characteristics, and main virulence factors of C. neoformans. Methods: Morphological, structural, physicochemical and biophysical analyses of cells and secreted polysaccharides of the reference H99 C. neoformans strain were investigated under the effect of subinhibitory concentrations of rapamycin. Results: Rapamycin at a minimum inhibitory concentration of 2.5 µM reduced C. neoformans cell viability by 53%, decreased capsule, increased cell size, chitin and lipid body formation, and changed peptidase and urease activity. Conclusion: Further studies are needed to assess how rapamycin affects the virulence factors and pathogenicity of C. neoformans.

Cryptococcosis is a fungal infection caused by a type of fungus called Cryptococcus. Among the Cryptococcus group, Cryptococcus neoformans is often linked to fungal infections in people who have a weak immune system (known as being immunosuppressed). The main aim of this work was to look at the effect of an immunosuppressant called rapamycin, which is commonly used to prevent organ transplant rejection, on the ability of C. neoformans to cause infection. The results showed that this drug stopped the growth of the fungus, dampening its ability to cause disease.

Assessing the In Vitro Potential of Glatiramer Acetate (Copaxone®) as a Chemotherapeutic Candidate for the Treatment of Cryptococcus neoformans Infection.

Cryptococcosis is a systemic mycosis affecting immunosuppressed individuals, caused by various Cryptococcus species. The current treatment utilizes a combination of antifungal drugs, but issues such as nephrotoxicity, restricted or limited availability in certain countries, and resistance limit their effectiveness. Repurposing approved drugs presents a viable strategy for developing new antifungal options. This study investigates the potential of glatiramer acetate (Copaxone®) as a chemotherapy candidate for Cryptococcus neoformans infection. Various techniques are employed to evaluate the effects of glatiramer acetate on the fungus, including microdilution, XTT analysis, electron and light microscopy, and physicochemical measurements. The results demonstrate that glatiramer acetate exhibits antifungal properties, with an IC50 of 0.470 mg/mL and a minimum inhibitory concentration (MIC) of 2.5 mg/mL. Furthermore, it promotes enhanced cell aggregation, facilitates biofilm formation, and increases the secretion of fungal polysaccharides. These findings indicate that glatiramer acetate not only shows an antifungal effect but also modulates the key virulence factor-the polysaccharide capsule. In summary, repurposing glatiramer acetate as a potential chemotherapy option offers new prospects for combating C. neoformans infection. It addresses the limitations associated with current antifungal therapies by providing an alternative treatment approach.

A Multivalent Peptoid Conjugate Modulates Androgen Receptor Transcriptional Activity to Inhibit Therapy-resistant Prostate Cancer.

Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPC) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. Here, we investigated the antitumor effects of compound MPC309, a trivalent display of ethisterone conjugated to a peptoid oligomer backbone that binds to the AR with nanomolar affinity. MPC309 exhibited potent antiproliferative effects on various enzalutamide-resistant prostate cancer models, including those with AR splice variants, ligand-binding mutations, and noncanonical AR gene expression programs, as well as mouse prostate organoids harboring defined genetic alterations that mimic lethal human prostate cancer subtypes. MPC309 is taken up by cells through macropinocytosis, an endocytic process more prevalent in cancer cells than in normal ones, thus providing an opportunity to target tumors selectively. MPC309 triggers a distinct AR transcriptome compared with DHT and enzalutamide, a clinically used antiandrogen. Specifically, MPC309 enhances the expression of differentiation genes while reducing the expression of genes needed for cell division and metabolism. Mechanistically, MPC309 increases AR chromatin occupancy and alters AR interactions with coregulatory proteins in a pattern distinct from DHT. In xenograft studies, MPC309 produced significantly greater tumor suppression than enzalutamide. Altogether, MPC309 represents a promising new AR modulator that can combat resistant disease by promoting an AR antiproliferative gene expression program.

Prática esportiva em paciente com valva aórtica bivalvular: quando limitar? / Sports practice in a patient with bivalvular aortic valve: when to limit?

INTRODUÇÃO: A Válvula Aórtica Bicúspide (VAB) é a anomalia congênita cardíaca mais comum, podendo cursar com alterações valvares do tipo estenose ou insuficiência, assim como dilatação da aorta. Apesar de sua considerável prevalência, não há estudos que demonstrem o impacto da prática de atividade física competitiva na progressão de tais alterações. RELATO DE CASO: Paciente masculino, 27 anos, ciclista, percorrendo em média 20 quilômetros ao dia, 5 vezes por semana. Assintomático do ponto de vista cardiovascular em consultas de acompanhamento. Avaliado com teste cardiopulmonar considerado máximo, VO2 alcançando 47,6 e capacidade funcional normal; porém em ecocardiografia foi evidenciada válvula aórtica de abertura bivalvular com insuficiência aórtica moderada e ectasia de aorta ascendente de 38mm. Cavidades cardíacas de dimensões normais, com função ventricular preservada. Teste ergométrico sem alterações isquêmicas. Paciente foi liberado para prática de exercícios competitivos, com orientação de acompanhamento regular para avaliação valvar e do diâmetro da aorta. DISCUSSÃO: Presença de dilatação aórtica em atletas não é comum, não devendo ser considerada resposta fisiológica ao exercício. Segundo os guidelines da 36ª Conferência de Bethesda, pacientes sem dilatação aórtica e sem insuficiência ou estenose aórtica significativas, estão aptos a participar de esportes competitivos. Já aqueles com dilatação aórtica entre 40-45mm, podem participar de esportes competitivos leves e moderados. Pacientes portadores de VAB com dilatação aórtica > 45mm podem participar de esportes competitivos de baixa intensidade. Quanto ao grau de obstrução valvar, a prática de esportes deve ser liberada em pacientes assintomáticos com estenose leve; já naqueles com obstrução moderada, poderá participar de atividades leves a moderadas desde que não apresente grau importante de hipertrofia ventricular esquerda. Pacientes sintomáticos ou com obstrução moderada/grave devem ser afastados de práticas esportivas devido ao risco potencial de morte súbita e dissecção de aorta. CONCLUSÃO Pacientes atletas com VAB devem ter acompanhamento médico regular, com avaliação ecocardiográfica anual, a fim de avaliar competência valvar, além de diâmetros de segmentos aórticos. A presença de VAB não deve ser limitante quanto à elegibilidade de atividade esportiva em jovens com função valvar normal, sem dilatação significativa de aorta. Nos demais casos, os pacientes deverão ser individualizados quanto à presença de sintomas e grau de alteração valvar ou aórtica.

Fechamento espontâneo de comunicação interventricular em atleta de 51 anos / Spontaneous closure of a ventricular septal defect in a 51-year-old athlete

INTRODUÇÃO: As comunicações interventriculares (CIV) são um grupo comum de cardiopatia congênita, correspondendo cerca de 20 a 30% dos defeitos cardíacos congênitos. Dentre as CIV, as mais prevalentes são as que acometem o septo membranoso, chamadas de perimembranosas. Dentre elas, as CIV funcionalmente pequenas podem se fechar espontaneamente e são, geralmente, consideradas benignas, não necessitando de tratamento cirúrgico. O fechamento espontâneo ocorre, em aproximadamente 48% dos casos, nos primeiros 19 meses de vida4. A partir dessa idade, a taxa de fechamento reduz, chegando próximo de zero aos 7 anos de idade. As CIV funcionalmente pequenas evoluem em sua maioria sem complicações, mas podem apresentar complicações na vida adulta, como endocardite infecciosa, regurgitação aórtica, sobrecarga de câmaras e necessidade de correção cirúrgica. O fechamento cirúrgico das CIV é seguro, entretanto as principais complicações são bloqueio atrioventricular, síndrome pós-pericardiotomia, infecções e manutenção de CIV residual. RELATO: Paciente masculino, 51 anos, atleta amador de alta intensidade, portador de CIV perimembranosa funcionalmente pequena e sem outras comorbidades, assintomático do ponto de vista cardiovascular, em acompanhamento em ambulatório de Cardiologia do Esporte. Apresentava em ecocardiogramas prévios de seguimento anual, CIV perimembranosa com pequeno shunt esquerdo direito e dilatação biatrial moderada, evoluindo estudo ecocardiográfico de rotina com fechamento espontâneo de CIV sem shunt residual. Apesar de cardiopatia congênita, não apresentava limitação funcional e apresentou em teste ergométrico excelente aptidão cardiorrespiratória de 23 METs. DISCUSSÃO: No presenta caso, o paciente era atleta e assintomático, com poucas complicações estruturais secundárias à CIV perimembranosa, excelente capacidade funcional e evoluiu com fechamento espontâneo de CIV numa idade incomum para tal. Estudos prévios indicam que a maioria dos fechamentos espontâneos ocorrem na infância, chegando próximo de zero após os 7 anos de idade. CONCLUSÃO: O presente caso demonstra a importância do seguimento ambulatorial de atletas, muitas vezes com diagnóstico tardio e acidental de cardiopatias congênitas. Apesar da evolução benigna da CIV perimembranosa funcionalmente pequena, o fechamento espontâneo aos 51 anos de idade é incomum e sem relato descrito na pesquisa bibliográfica.

The role of mitosis in generating fitness heterogeneity.

Cancer cells have heterogeneous fitness, and this heterogeneity stems from genetic and epigenetic sources. Here, we sought to assess the contribution of asymmetric mitosis (AM) and time on the variability of fitness in sister cells. Around one quarter of sisters had differences in fitness, assessed as the intermitotic time (IMT), from 330 to 510 min. Phenotypes related to fitness, such as ERK activity (herein referring to ERK1 and ERK2, also known as MAPK3 and MAPK1, respectively), DNA damage and nuclear morphological phenotypes were also asymmetric at mitosis or turned asymmetric over the course of the cell cycle. The ERK activity of mother cell was found to influence the ERK activity and the IMT of the daughter cells, and cells with ERK asymmetry at mitosis produced more offspring with AMs, suggesting heritability of the AM phenotype for ERK activity. Our findings demonstrate how variabilities in sister cells can be generated, contributing to the phenotype heterogeneities in tumor cells.

Ecologically driven differences in individual diet specialization across three populations of Guiana dolphin.

Populations usually considered foraging generalists may include specialized individuals that feed on a restricted subset of the prey spectrum consumed by the population. By analyzing the time series of δ13C and δ15N values in sequential growth layer groups within tooth dentin, we measured population- and individual-level variation in resource use of three populations of Guiana dolphins (Sotalia guianensis)-Caravelas River, Babitonga Bay, and Norte Bay-along a latitudinal gradient in the southwestern Atlantic Ocean. We show that the Guiana dolphin at Caravelas River is a generalist population consisting of individual dietary specialists, likely due to the absence of other resident dolphin populations thus allowing individuals to target prey across a wide range of habitats. The Babitonga Bay population is also composed of individual specialists potentially due to the selective foraging behavior of some individuals on high-quality prey sources within and near the bay. In contrast, the Norte Bay population comprises individual generalists, which likely reflects its distinctive cohesive social organization, coexistence with two other dolphin species, and an opportunistic foraging strategy in response to resource fluctuations inherent to the southern limit of the species distribution. Although the Guiana dolphin is generally considered to be a dietary generalist at the population level, our findings reveal that the total niche width of populations and the degree of individual diet specialization are highly context dependent, suggesting dietary plasticity that may be related to a latitudinal gradient in resource availability and environmental conditions.

Raising the suspicion of a non-autochthonous infection: identification of Leishmania guyanensis from Costa Rica exhibits a Leishmaniavirus related to Brazilian north-east and French Guiana viral genotypes.

BACKGROUND: Costa Rica has a history of neglecting prevention, control and research of leishmaniasis, including limited understanding on Leishmania species causing human disease across the country and a complete lack of knowledge on the Leishmania RNA virus, described as a factor linked to the worsening and metastasis of leishmanial lesions. OBJECTIVES: The aim of this work was to describe a case of cutaneous leishmaniasis by Leishmania (Viannia) guyanensis, bearing infection with Leishmaniavirus 1 (LRV1) in Costa Rica, raising the suspicion of imported parasites in the region. METHODS: The Leishmania strain was previously identified by routine hsp70 polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in Costa Rica and subsequently characterised by isoenzyme electrophoresis and Sanger sequencing in Brazil. Screening for LRV1 was conducted with a dual RT-PCR approach and sequencing of the fragment obtained. FINDINGS: Since 2016 Costa Rica performs Leishmania isolation and typing as part of its epidemiological surveillance activities. Amongst 113 strains typed until 2019, only one was characterised as a L. (V.) guyanensis, corresponding to the first confirmed report of this species in the country. Interestingly, the same strain tested positive for LRV1. Sequencing of the viral orf1 and 2, clustered this sample with other LRV1 genotypes of South American origin, from the Northeast of Brazil and French Guiana. MAIN CONCLUSION: The unique characteristics of this finding raised the suspicion that it was not an autochthonous strain. Notwithstanding its presumed origin, this report points to the occurrence of said endosymbiont in Central American Leishmania strains. The possibility of its local dispersion represents one more challenge faced by regional health authorities in preventing and controlling leishmaniasis.

Impacto da obesidade infantil sobre a pressão arterial no período noturno / Impact of childhood obesity on blood pressure at night

INTRODUÇÃO E/OU FUNDAMENTOS: A Pressão Arterial (PA) é regulada por mecanismos complexos e varia de acordo com o ritmo circadiano. Disfunção endotelial, inflamação crônica subclínica e aumento da atividade simpática, associadas ao acúmulo de gordura visceral e obesidade, culminam com Hipertensão Arterial (HA) e redução do descenso noturno (DN), eventos que podem ser observados precocemente através da Monitorização Ambulatorial da Pressão Arterial (MAPA). MÉTODOS: Coorte retrospectiva, incluindo pacientes pediátricos obesos encaminhados para centro de referência em São Paulo, com suspeita de HA. As médias de PA em três consultas, com intervalo de 2-4 semanas com técnica auscultatória e manguito adequado foram comparadas com os resultados da MAPA, para avaliar a prevalência de HA mascarada, HA no período do sono e alterações do DN. Para MAPA utilizou-se dispositivo validado em pediatria e laudo fornecido obedeceu às diretrizes vigentes. O DN foi considerado normal entre 10-20%. Para os pacientes com HA confirmada, procedeu-se investigação de lesão de órgãos alvo. O tratamento medicamentoso foi prescrito quando indicado. RESULTADOS: Foram acompanhados 14 pacientes sendo 71% meninos, idade média 13.4 anos (±3.4), cujo peso variou entre 54 e 141 kg com média de 94 kg (± 25.6), índice de massa corporal (IMC) médio de 35 kg/m2 (± 7,8), com 71% de história familiar de HA. Em consultório 14% (2) tinham PA normal, 29% (4) PA elevada, 43% (6) HA estágio I e 14% (2) HA estágio II. Pela MAPA 1 paciente confirmou-se normotenso, 14% (2) HA jaleco branco, 29% (4) HA mascarada e 50% (7) HA. Dos 3 normotensos ou com HA jaleco branco, 2 (66%) apresentam redução do DN. Entre os 11 pacientes hipertensos, 5 (45%) apresentam redução do DN e 100% HA noturna. Exames complementares para investigar apnéia obstrutiva do sono não foram realizados, porém assume-se que este seja um dos fatores associados. Nenhum paciente apresentou lesão de órgãos alvo e todos necessitaram de drogas anti-hipertensivas, além das modificações no estilo de vida.CONCLUSÃO: Apesar da limitada amostra, HA noturna e redução do descenso do sono foram alterações frequentes observadas em pacientes pediátricos obesos, inclusive normotensos. Sendo a redução do DN um alto preditor de HA, reitera-se a importância da MAPA no acompanhamento desta população.

Importância da mapa para diagnóstico de hipertensão arterial na infância e adolescência e possíveis impactos das novas recomendações / Importance of the map for the diagnosis of arterial hypertension in childhood and adolescence and possible impacts of the new recommendations

INTRODUÇÃO E/OU FUNDAMENTOS: O diagnóstico e o seguimento da hipertensão arterial (HA) dependem da acurácia e representatividade das medidas de pressão arterial (PA) obtidas por diferentes métodos. A Monitorização Ambulatorial da Pressão Arterial (MAPA) é mais precisa para o diagnóstico e prediz a gravidade da HA de forma mais precoce e assertiva. A recente atualização da American Heart Association (AHA) acerca da MAPA em pediatria recomenda sua interpretação baseada somente nos valores médios de PA, trazendo novos valores de referência para pacientes acima de 13 anos, e desconsidera a carga pressórica no diagnóstico e classificação de gravidade. MÉTODOS: Para avaliar o grau de assertividade das medidas de PA em consultório em comparação com a MAPA, desenhou-se uma coorte retrospectiva incluindo pacientes de 8 a 18 anos encaminhados com suspeita de HA primária para ambulatório de referência em São Paulo. A PA em consultório foi verificada por método auscultatório com técnica e manguito adequados, em 3 momentos diferentes com 2 semanas de intervalo e, classificada de acordo com sexo, idade e altura. A MAPA foi realizada com aparelhos validados para faixa pediátrica. Os parâmetros utilizados para os laudos estão na tabela 1. O diagnóstico obtido em consultório foi comparado com o resultado da MAPA nos cenários pré e pós 2022. RESULTADOS E CONCLUSÕES: Foram incluídos 16 pacientes, com idade média de 13 anos (±3,3), 62% meninos, média de 89 Kg (±28,9), sendo 87% sobrepesos ou obesos. A figura 1 apresenta os diagnósticos fenotípicos de HA conforme PA em consultório e MAPA, laudado com base nas recomendações pré e pós 2022. Observamos prevalência de HA mascarada de 31,25% (5/16) e efeito jaleco branco em 18,7% (3/16). A principal diferença observada entre as diretrizes da MAPA diz respeito à classificação da severidade da HA. Pela recomendação anterior, que possibilitava classificar o estágio da HA de acordo com a carga, 7 pacientes (43,75%) (HA estágio I pela recomendação atual) seriam recategorizados como estágio II e isto implica em modificações na estratégia terapêutica inicial. CONCLUSÃO: Para esta amostra de pacientes obesos e hipertensos, a MAPA mostrou-se fundamental para diagnóstico de HA. A recomendação atual exclui a classificação de acordo com a severidade, impactando no momento de início da terapia medicamentosa.

Interspecies and Intrastrain Interplay among Leishmania spp. Parasites.

Leishmania parasites present astonishing adaptative abilities that represent a matter of life or death within disparate environments during the heteroxenous parasite life cycle. From an evolutionary perspective, organisms develop methods of overcoming such challenges. Strategies that extend beyond the genetic diversity have been discussed and include variability between parasite cells during the infections of their hosts. The occurrence of Leishmania subpopulation fluctuations with variable structural genomic contents demonstrates that a single strain might shelter the variability required to overcome inconsistent environments. Such intrastrain variability provides parasites with an extraordinary ability to adapt and thus survive and propagate. However, different perspectives on this evolution have been proposed. Strains or species living in the same environment can cooperate but also compete. These interactions might increase the replication rate of some parasites but cause the loss of more aggressive competitors for others. Adaptive responses to intra- and interspecific competition can evolve as a fixed strategy (replication is adapted to the average genetic complexity of infections) or an optional strategy (replication varies according to the genetic complexity of the current infection). This review highlights the complexity of interspecies and intrastrain interactions among Leishmania parasites as well as the different factors that influence this interplay.

Is office blood pressure underestimating reality in pediatric obese population?

INTRODUCTION: Hypertension (HTN) diagnosis depends on the accuracy and representativeness of blood pressure (BP) obtained by different methods. In pediatric obese patients, office BP can present great variability and does not detect nighttime changes. Ambulatory Blood Pressure Monitoring (ABPM) allows recognition of HTN phenotypes and predicts HTN severity in an earlier and assertive way. OBJECTIVE: To compare HTN stages defined by office BP with ABPM, and describe prevalence of masked HTM in pediatric sample from a reference service. METHODS: Retrospective cohort of pediatric patients with primary HTN. Patients underwent a detailed clinical history and examination. BP was measured by auscultatory method with technique adequacy. BP was checked at 2 other visits (2 week interval) and the mean BP of these 3 visits was used to classify BP according recommendations. ABPM was performed with pediatric validated device, with a revised report for this analysis, according to guidelines. Mean 24-hours awake and sleep BP and load were considered to identify HTN phenotypes according to 95th percentile for sex, age and height. Diagnosis and stages of HTN based on office BP were compared with ABPM. Patients with sustained HTN had secondary causes discharged after investigation and target organ damage (TOD) was also evaluated. RESULTS: Were included 16 patients with primary HTN, mean age 13 ± 3.3 years, 62% male, 87% obese or overweight (mean weight 89 ± 28.9kg) and 75% with first degree family history of HTN. Of these, as in Figure 1, masked hypertension was detected in 37.5% (6/16), white coat HTN in 12.5% (2/16), and in 68% of the sample (11/16) ABPM classified HTN at higher stage compared to office BP. Nocturnal HTN was present in 81% (13/16). None patient had TOD and at follow-up, 12 required antihypertensive drugs, with 68% of BP control. CONCLUSION: For this obese primary hypertensive pediatric sample, ABPM seems to be essential for HTN diagnosis and stratification, evidencing frequent nocturnal changes in BP. Complementary tests to investigate obstructive sleep apnea weren't done but this could be an associated factor.

Benznidazole and amiodarone combined treatment attenuates cytoskeletal damage in Trypanosoma cruzi-infected cardiac cells.

Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, is an important public health problem mainly in Latin America, leading to approximately 12,000 annual deaths. Current etiological treatment for CD is limited to two nitro compounds, benznidazole (Bz) and nifurtimox (Nif), both presenting relevant limitations. Different approaches have been employed to establish more effective and safer schemes to treat T. cruzi infection, mostly based on drug repurposing and combination therapies. Amiodarone (AMD), an antiarrhythmic medicament of choice for patients with the chronic cardiac form of CD, is also recognized as a trypanocidal agent. Therefore, our aim is to investigate the combined treatment Bz + AMD on trypomastigote viability, control of T. cruzi intracellular form proliferation, and recovery of the infection-induced cytoskeleton alterations in cardiac cells. The combination of Bz + AMD did not improve the direct trypanocidal effect of AMD on the infective blood trypomastigote and replicative intracellular forms of the parasite. Otherwise, the treatment of T. cruzi-infected cardiac cells with Bz plus AMD attenuated the infection-triggered cytoskeleton damage of host cells and the cytotoxic effects of AMD. Thus, the combined treatment Bz + AMD may favor parasite control and hamper tissue damage.

Fístula coronária como causa de angina, um relato de caso / Coronary fistula as a cause of angina, a case report

RELATO DE CASO: EJA, feminino, 57 anos, previamente hipertensa e com história familiar positiva para Doença Arterial Coronariana, referia queixa de angina CCS III há dois anos, progressiva, associada a tontura e síncope. Realizada investigação ambulatorial com cateterismo cardíaco que evidenciou imagem sugestiva de fístula proveniente da Artéria Coronária Esquerda (ACE) para estrutura extra pericárdica, sugestivo de shunt para Artéria Pulmonar (AP), sem lesões coronarianas importantes. Realizada complementação da investigação com Cintilografia de Perfusão Miocárdica que mostrou hipocaptação transitória de pequena extensão em segmento apical da parede anterior do Ventrículo Esquerdo e carga isquêmica de 1,5%, além de Angiotomografia Coronariana com imagem de pequena fístula entre a ACE e AP, com diâmetro de 1,3mm. Paciente evoluiu com melhora do quadro de angina após ajuste de terapia medicamentosa. As fístulas coronárias são responsáveis por 0,2% a 0,4% das anomalias cardíacas, sendo a sua principal origem congênita (provável persistência de porções dos sinusoides coronários embrionários que conectam as artérias coronárias primitivas às câmaras cardíacas), existindo também as causas adquiridas (secundárias à infecção, trauma e iatrogenia). A fístula é definida como uma comunicação entre a terminação de uma artéria coronária e uma câmara cardíaca, um grande vaso ou outra estrutura vascular, sendo mais comum o envolvimento da artéria coronária direita (60% dos casos) e mais raramente da artéria circunflexa. A área mais comum de drenagem é o ventrículo direito, seguida pelo átrio direito, artéria pulmonar e seio coronário. A maioria dos pacientes apresentam-se assintomáticos, tendo o diagnóstico incidental ao realizarem algum exame invasivo. A evolução dos sintomas está relacionada ao envelhecimento e o aumento do shunt, sendo mais prevalente dispneia aos esforços, angina, fadiga, podendo apresentar alguma complicação como insuficiência cardíaca congestiva, infarto agudo do miocárdio, derrame pericárdico e arritmias. Dentre os exames complementares disponíveis para seu diagnóstico, destaca-se a Angiotomografia Coronariana, que representa o exame não invasivo de referência para visualização da árvore coronariana. Seu tratamento deve ser individualizado, sendo baseado na presença ou ausência de sintomas, isquemia miocárdica e disfunção ventricular, além do grau de sobrecarga de volume cardíaco, com evidências mais recentes recomendado o fechamento de grandes fístulas independente dos sintomas.

Multifactorial aspects of systemic arterial hypertension in childhood / Hipertensão arterial na infância - seus aspectos multifatoriais

ABSTRACT Clinical case of a female patient referred to our Institution at the age of seven years old with Systemic Arterial Hypertension. The patient had been severely obese since she was 4 years old and high blood pressure levels were detected in several medical consultations a few months ago. She has a history of prematurity, a sedentary lifestyle, and an inadequate diet, in addition to a family history of obesity and high blood pressure. We discussed the investigation of the etiology, the presence of target organ lesions, and the treatment of arterial blood pressure in youth. In the follow-up, there was adequate control of blood pressure after initiation of angiotensin-converting enzyme inhibitor, with great difficulty in weight reduction. Even under nutritional guidelines and reinforcement regarding lifestyle changes, the patient had a weight gain of 25 kilos. We report this case in view of the significant increase in the prevalence of Systemic Arterial Hypertension in children and adolescents. There are multifactorial aspects to the development of this scenario, largely associated with an inadequate lifestyle. The difficulties related to its management and the presence of comorbidities, especially obesity, highlight the need for a multidisciplinary approach so that the evolution of the patient's condition becomes as desired.

RESUMO Caso clínico de uma paciente do sexo feminino, encaminhada a nossa Instituição aos sete anos de idade por provável Hipertensão Arterial Sistêmica. A paciente apresentava obesidade grave desde os quatro anos e há alguns meses foram detectadas medidas de pressão arterial elevadas em várias consultas médicas. Tem antecedentes de prematuridade, sedentarismo e dieta inadequada, além de história familiar também de obesidade e hipertensão arterial. Discutimos as condutas quanto a investigação da etiologia, da presença de lesões de órgãos alvo e do tratamento. Na evolução, houve controle adequado da pressão arterial após início de inibidores da enzima de conversão da angiotensina, mas grande dificuldade na redução do peso. Ao longo do seguimento, mesmo sob orientações nutricionais e reforço quanto a modificações do estilo de vida, a paciente apresentou ganho ponderal de 25 quilos. Relatamos este caso atendendo a necessidade de discussão do tema frente ao aumento significativo da prevalência de HAS em crianças e adolescente. Existem aspectos multifatoriais para o desenvolvimento da hipertensão arterial na infância, em grande parte associada a um estilo de vida inadequado. As dificuldades relacionadas ao seu manejo a presença de comorbidades, em especial da obesidade, ressaltam a necessidade de uma abordagem multiprofissional para que a evolução do quadro da paciente venha a ser o desejado.