Life expectancy and death pattern associated with systemic lupus erythematosus diagnosis in Brazil between 2000 and 2019.

OBJECTIVES: to evaluate the main factors associated with mortality and determine the life expectancy of SLE patients between 2000 and 2019 years in Brazil. METHODS: death data related to SLE available in the Brazilian Unified Health System (SUS) (DATASUS) were evaluated in all Brazilian states. Three groups of death causes potentially associated from SLE were evaluated: cardiovascular and kidney diseases and infections. RESULTS: The main causes of death associated with SLE were infection and kidney disease. Most SLE patients died between 19 and 50 years of age. Deaths associated with kidney disease were proportionally higher than in the general population with progressive decrease during the period. Instead, there have been an increase in the proportion of deaths due to infections both in SLE and in the general population. CONCLUSIONS: SLE patients presented higher mortality compared to the general population matched for sex and age and the main causes associated with death were infection and kidney disease. Public health policies that promote early diagnosis, treatment and prevention of damage are necessary to reduce morbidity and mortality in SLE patients.

Identification of Eimeria spp. in domestic chickens raised in alternative poultry production systems in the State of São Paulo, Brazil.

The objective of this study was to identify Eimeria spp. in alternative poultry production systems (APPS) in the State of São Paulo, Brazil. Fecal samples (168) and DNA extracted from fecal samples obtained in APPS located in different Municipalities in the State of São Paulo (93) were examined by microscopy or genera-specific PCR (ITS-1 locus). Samples positive for Eimeria spp. were examined using Eimeria lata, Eimeria nagambie, and Eimeria zaria species-specific PCR protocols (ITS-2 locus) and another E. lata-specific PCR (candidate IMP1 genomic locus) followed by molecular cloning (E. lata and E. zaria ITS-2 amplicons) and genetic sequencing. All positive DNA samples were also submitted to genera-specific nested PCR (18S rRNA gene) followed by next-generation sequencing to identify Eimeria spp. Eimeria nagambie, E. zaria, and Eimeria sp. were identified by ITS2-targeted species-specific PCRs and genetic sequencing. Next-generation sequencing identified, in order of prevalence: E. nagambie; Eimeria acervulina; Eimeria mivati; Eimeria praecox; Eimeria brunetti; Eimeria mitis; Eimeria sp.; Eimeria maxima; E. zaria, and Eimeria necatrix/tenella. Our results confirmed, for the first time in Brazil, the identification of E. nagambie, E. zaria, and Eimeria spp. ITS-2 and 18S rRNA gene sequences not yet described in Brazil.

Co-expression analysis suggests lncRNA-mRNA interactions enhance antiviral immune response during acute Chikungunya fever in whole blood of pediatric patients.

Chikungunya virus is an arbovirus that causes the neglected tropical disease chikungunya fever, common in tropical areas worldwide. There is evidence that arboviruses alter host transcriptome and modulate immune response; this modulation may involve transcriptional and post-transcriptional control mechanisms mediated by long non-coding RNAs (lncRNAs). Herein, we employed bioinformatic analysis to evaluate co-expression of lncRNAs and their putative target mRNAs in whole blood during natural Chikungunya infection in adolescent boys. Sequencing data from GSE99992 was uploaded to the Galaxy web server, where data was aligned with HISAT2, gene counts were estimated with HTSeq-count, and differential expression was run with DESeq2. After gene classification with Biomart, Pearson's correlation was applied to identify potential interactions between lncRNAs and mRNAs, which were later classified into cis and trans according to genomic location (FEELnc) and binding potential (LncTar), respectively. We identified 1,975 mRNAs and 793 lncRNAs that were differentially expressed between the acute and convalescent stages of infection in the blood. Of the co-expressed lncRNAs and mRNAs, 357 potentially interact in trans and 9 in cis; their target mRNAs enriched pathways related to immune response and viral infections. Out of 52 enriched KEGG pathways, the RIG-I like receptor signaling is enriched by the highest number of target mRNAs. This pathway starts with the recognition of viral pathogens, leading to innate immune response mediated by the production of IFN-I and inflammatory cytokines. Our findings indicate that alterations in lncRNA expression in adolescent boys, induced by acute Chikungunya infection, potentially modulate mRNAs that contribute to antiviral immune responses.

Deep infiltrating endometriosis: cine magnetic resonance imaging in the evaluation of uterine contractility.

Objective: To evaluate uterine function by using cine magnetic resonance imaging to visualize the contractile movements of the uterus in patients with and without deep infiltrating endometriosis (with or without associated adenomyosis). Materials and Methods: This was a prospective case-control study. The study sample comprised 43 women: 18 in the case group and 25 in the control group. We performed cine magnetic resonance imaging in a 3.0 T scanner, focusing on the presence, direction, and frequency of uterine peristalsis. Results: The frequency of uterine peristalsis was higher in the case group than in the control group, in the periovulatory phase (3.83 vs. 2.44 peristaltic waves in two minutes) and luteal phase (1.20 vs. 0.91 peristaltic waves in two minutes). However, those differences were not statistically significant. There was a significant difference between the patients with adenomyosis and those without in terms of the frequency of peristalsis during the late follicular/periovulatory phase (0.8 vs. 3.18 peristaltic waves in two minutes; p < 0.05). Conclusion: The frequency of uterine peristalsis appears to be higher during the periovulatory and luteal phases in patients with deep infiltrating endometriosis, whereas it appears to be significantly lower during the late follicular/periovulatory phase in patients with adenomyosis. Both of those effects could have a negative impact on sperm transport and on the early stages of fertilization.

Objetivo: Avaliar a função uterina mediante visualização dos movimentos contráteis do útero por meio de cine-ressonância magnética em pacientes com e sem endometriose infiltrativa profunda (com ou sem adenomiose associada). Materiais e Métodos: Estudo caso-controle prospectivo. A amostra foi composta por 43 mulheres, sendo 18 mulheres no grupo caso e 25 mulheres no grupo controle. A cine-ressonância magnética foi realizada com magneto 3.0 T, com foco na presença, direção e frequência do peristaltismo uterino. Resultados: O peristaltismo uterino foi mais frequente nas pacientes do grupo endometriose do que no grupo controle na fase periovulatória (3,83 × 2,44 peristalses em dois minutos) e lútea (1,20 × 0,91 peristalse em dois minutos). No entanto, esses resultados não foram estatisticamente significantes. Nas pacientes com adenomiose, observou-se redução significativa na frequência de peristaltismo durante a primeira fase do ciclo menstrual (3,18 × 0,8 peristalses; p < 0,05). Conclusão: A frequência de peristaltismo uterino parece estar aumentada durante a fase periovulatória e lútea em pacientes com endometriose infiltrativa profunda e significativamente reduzida em pacientes com adenomiose durante a primeira fase do ciclo menstrual. Ambos os efeitos têm potencial de interferir negativamente no transporte de espermatozoides e nos primeiros estágios de fecundação.

Behavior of total alkaline phosphatase after radium-233 therapy in metastatic castration-resistant prostate cancer: a single-center, real-world retrospective study.

Objective: To describe the behavior of total alkaline phosphatase (tALP) in patients with metastatic castration-resistant prostate cancer receiving radium-223 therapy, in a real-world scenario, and to describe overall survival (OS) among such patients. Materials and Methods: This was a retrospective study involving 97 patients treated between February 2017 and September 2020. Patients were stratified by the baseline tALP (normal/elevated). A tALP response was defined as a ≥ 30% reduction from baseline at week 12. For patients with elevated baseline tALP, we also evaluated treatment response as a ≥ 10% reduction in tALP after the first cycle of treatment. We defined OS as the time from the first treatment cycle to the date of death. Results: There was a significant reduction in the median tALP after each cycle of treatment (p < 0.05 for all). Data for tALP at week 12 were available for 71 of the 97 patients. Of those 71 patients, 26 (36.6%) responded. Elevated baseline tALP was observed in 47 patients, of whom 19 (40.4%) showed a response. Longer OS was observed in the patients with normal baseline tALP, in those with elevated baseline tALP that showed a response to treatment (≥ 10% reduction), and in those who received 5-6 cycles of therapy. Conclusion: The tALP may be used to predict which patients will benefit from treatment with a greater number of cycles of radium-223 therapy and will have longer OS.

Objetivo: Descrever o comportamento da fosfatase alcalina total (tALP) em pacientes com carcinoma de próstata metastático resistente a castração, submetidos a terapia com rádio-223 em um cenário do mundo real, e a sobrevida global (SG) desses pacientes. Materiais e Métodos: Estudo retrospectivo envolvento 97 pacientes, no período de fevereiro/2017 a setembro/2020. Os pacientes foram estratificados de acordo com a tALP basal (normal/elevada). A resposta à tALP foi definida como uma redução em relação à linha de base de ≥ 30% na semana-12. Para pacientes com tALP basal elevada, também foi avaliada a resposta ao tratamento como uma redução de ≥ 10% de tALP após o primeiro ciclo. A SG foi definida como o tempo entre o primeiro ciclo e a data do óbito. Resultados: A redução da tALP média após cada ciclo foi significativa (p < 0,05). A tALP na semana 12 estava disponível para 71 dos 97 pacientes. Desses 71 pacientes, 26 (36,6%) responderam. Dezenove (40,4%) dos 47 pacientes com tALP elevada apresentaram resposta. Foi observada uma SG mais longa nos pacientes com tALP basal normal, nos pacientes com tALP basal elevada que apresentaram resposta ao tratamento (redução de ≥ 10%) e nos pacientes que receberam 5-6 ciclos. Conclusão: A tALP pode ser usada para prever parte dos pacientes que se beneficiarão do tratamento com um maior número de ciclos e uma SG mais longa.

Co-expression analysis of lncRNA and mRNA suggests a role for ncRNA-mediated regulation of host-parasite interactions in primary skin lesions of patients with American tegumentary leishmaniasis.

Leishmaniasis, caused by different Leishmania species, manifests as cutaneous or visceral forms. In the American continent, the cutaneous form is called American tegumentary leishmaniasis (ATL) and is primarily caused by Leishmania (Viannia) braziliensis. Mucosal leishmaniasis (ML), the most severe form of ATL, arises in approximately 20% of patients from a primary cutaneous lesion. Evidence indicates changes in overall expression patterns of mRNAs and lncRNAs of the host in response to Leishmania infection, with the parasite capable of modulating host immune response, which may contribute to disease progression. We evaluated whether the co-expression of lncRNAs and their putative target mRNAs in primary cutaneous lesions of patients with ATL could be associated with the development of ML. Previously available public RNA-Seq data from primary skin lesions of patients infected with L. braziliensis was employed. We identified 579 mRNAs and 46 lncRNAs differentially expressed in the primary lesion that subsequently progressed to mucosal disease. Co-expression analysis revealed 1324 significantly correlated lncRNA-mRNA pairs. Among these, we highlight the positive correlation and trans-action between lncRNA SNHG29 and mRNA S100A8, both upregulated in the ML group. S100A8 and its heterodimeric partner S100A9 form a pro-inflammatory complex expressed by immune cells and seems to participate in host innate immune response processes of infection. These findings expand the knowledge of the Leishmania-host interaction and indicate that the expression of lncRNAs in the primary cutaneous lesion could regulate mRNAs and play roles in disease progression.

Deep infiltrating endometriosis: cine magnetic resonance imaging in the evaluation of uterine contractility / Endometriose infiltrativa profunda: cine ressonância magnética na avaliação da contratilidade uterina

Abstract Objective: To evaluate uterine function by using cine magnetic resonance imaging to visualize the contractile movements of the uterus in patients with and without deep infiltrating endometriosis (with or without associated adenomyosis). Materials and Methods: This was a prospective case-control study. The study sample comprised 43 women: 18 in the case group and 25 in the control group. We performed cine magnetic resonance imaging in a 3.0 T scanner, focusing on the presence, direction, and frequency of uterine peristalsis. Results: The frequency of uterine peristalsis was higher in the case group than in the control group, in the periovulatory phase (3.83 vs. 2.44 peristaltic waves in two minutes) and luteal phase (1.20 vs. 0.91 peristaltic waves in two minutes). However, those differences were not statistically significant. There was a significant difference between the patients with adenomyosis and those without in terms of the frequency of peristalsis during the late follicular/periovulatory phase (0.8 vs. 3.18 peristaltic waves in two minutes; p < 0.05). Conclusion: The frequency of uterine peristalsis appears to be higher during the periovulatory and luteal phases in patients with deep infiltrating endometriosis, whereas it appears to be significantly lower during the late follicular/periovulatory phase in patients with adenomyosis. Both of those effects could have a negative impact on sperm transport and on the early stages of fertilization.

Resumo Objetivo: Avaliar a função uterina mediante visualização dos movimentos contráteis do útero por meio de cine-ressonância magnética em pacientes com e sem endometriose infiltrativa profunda (com ou sem adenomiose associada). Materiais e Métodos: Estudo caso-controle prospectivo. A amostra foi composta por 43 mulheres, sendo 18 mulheres no grupo caso e 25 mulheres no grupo controle. A cine-ressonância magnética foi realizada com magneto 3.0 T, com foco na presença, direção e frequência do peristaltismo uterino. Resultados: O peristaltismo uterino foi mais frequente nas pacientes do grupo endometriose do que no grupo controle na fase periovulatória (3,83 × 2,44 peristalses em dois minutos) e lútea (1,20 × 0,91 peristalse em dois minutos). No entanto, esses resultados não foram estatisticamente significantes. Nas pacientes com adenomiose, observou-se redução significativa na frequência de peristaltismo durante a primeira fase do ciclo menstrual (3,18 × 0,8 peristalses; p < 0,05). Conclusão: A frequência de peristaltismo uterino parece estar aumentada durante a fase periovulatória e lútea em pacientes com endometriose infiltrativa profunda e significativamente reduzida em pacientes com adenomiose durante a primeira fase do ciclo menstrual. Ambos os efeitos têm potencial de interferir negativamente no transporte de espermatozoides e nos primeiros estágios de fecundação.

Behavior of total alkaline phosphatase after radium-233 therapy in metastatic castration-resistant prostate cancer: a single-center, real-world retrospective study / Estudo retrospectivo de vida-real, em centro único, para avaliação do comportamento da fosfatase alcalina total após terapia com rádio-223 no câncer de próstata resistente a castração

Abstract Objective: To describe the behavior of total alkaline phosphatase (tALP) in patients with metastatic castration-resistant prostate cancer receiving radium-223 therapy, in a real-world scenario, and to describe overall survival (OS) among such patients. Materials and Methods: This was a retrospective study involving 97 patients treated between February 2017 and September 2020. Patients were stratified by the baseline tALP (normal/elevated). A tALP response was defined as a ≥ 30% reduction from baseline at week 12. For patients with elevated baseline tALP, we also evaluated treatment response as a ≥ 10% reduction in tALP after the first cycle of treatment. We defined OS as the time from the first treatment cycle to the date of death. Results: There was a significant reduction in the median tALP after each cycle of treatment (p < 0.05 for all). Data for tALP at week 12 were available for 71 of the 97 patients. Of those 71 patients, 26 (36.6%) responded. Elevated baseline tALP was observed in 47 patients, of whom 19 (40.4%) showed a response. Longer OS was observed in the patients with normal baseline tALP, in those with elevated baseline tALP that showed a response to treatment (≥ 10% reduction), and in those who received 5-6 cycles of therapy. Conclusion: The tALP may be used to predict which patients will benefit from treatment with a greater number of cycles of radium-223 therapy and will have longer OS.

Resumo Objetivo: Descrever o comportamento da fosfatase alcalina total (tALP) em pacientes com carcinoma de próstata metastático resistente a castração, submetidos a terapia com rádio-223 em um cenário do mundo real, e a sobrevida global (SG) desses pacientes. Materiais e Métodos: Estudo retrospectivo envolvento 97 pacientes, no período de fevereiro/2017 a setembro/2020. Os pacientes foram estratificados de acordo com a tALP basal (normal/elevada). A resposta à tALP foi definida como uma redução em relação à linha de base de ≥ 30% na semana-12. Para pacientes com tALP basal elevada, também foi avaliada a resposta ao tratamento como uma redução de ≥ 10% de tALP após o primeiro ciclo. A SG foi definida como o tempo entre o primeiro ciclo e a data do óbito. Resultados: A redução da tALP média após cada ciclo foi significativa (p < 0,05). A tALP na semana 12 estava disponível para 71 dos 97 pacientes. Desses 71 pacientes, 26 (36,6%) responderam. Dezenove (40,4%) dos 47 pacientes com tALP elevada apresentaram resposta. Foi observada uma SG mais longa nos pacientes com tALP basal normal, nos pacientes com tALP basal elevada que apresentaram resposta ao tratamento (redução de ≥ 10%) e nos pacientes que receberam 5-6 ciclos. Conclusão: A tALP pode ser usada para prever parte dos pacientes que se beneficiarão do tratamento com um maior número de ciclos e uma SG mais longa.

Cytotoxic effect of crotoxin on cancer cells and its antitumoral effects correlated to tumor microenvironment: A review.

Cancer is the second leading cause of death worldwide, and despite the effort of standard treatments, the search for new tools against this disease is necessary. Importantly, it is known that the tumor microenvironment plays a crucial role in tumor initiation, progression, and response to therapies. Therefore, studies of potential drugs that act on these components are as critical as studies regarding antiproliferative substances. Through the years, studies of several natural products, including animal toxins, have been conducted to guide the development of medical compounds. In this review, we present the remarkable antitumor activities of crotoxin, a toxin from the rattlesnake Crotalus durissus terrificus, highlighting its effects on cancer cells and in the modulation of relevant elements in the tumor microenvironment as well as the clinical trials conducted with this compound. In summary, crotoxin acts through several mechanisms of action, such as activation of apoptosis, induction of cell cycle arrest, inhibition of metastasis, and decrease of tumor growth, in different tumor types. Crotoxin also modulates tumor-associated fibroblasts, endothelial cells, and immune cells, which contribute to its antitumoral effects. In addition, preliminary clinical studies confirm the promising results of crotoxin and support its potential future use as an anticancer drug.

Does a three-degree hypoechogenicity grading improve ultrasound thyroid nodule risk stratification and affect the TI-RADS 4 category? A retrospective observational study.

Objective: The aim of this study was to determine whether classifying hypoechogenicity in three degrees (mild, moderate, and marked) could improve the distinction between benign and malignant nodules and whether such an approach could influence Category 4 of the Thyroid Imaging Reporting and Data System (TI-RADS). Materials and methods: In total, 2,574 nodules submitted to fine needle aspiration, classified by the Bethesda System, were retrospectively assessed. Further, a subanalysis considering solid nodules without any additional suspicious findings (n = 565) was performed with the purpose of evaluating mainly TI-RADS 4 nodules. Results: Mild hypoechogenicity was significantly less related to malignancy (odds ratio [OR]: 1.409; CI: 1.086-1.829; p = 0.01), compared to moderate (OR: 4.775; CI: 3.700-6.163; p < 0.001) and marked hypoechogenicity (OR: 8.540; CI: 6.355-11.445; p < 0.001). In addition, mild hypoechogenicity (20.7%) and iso-hyperechogenicity (20.5%) presented a similar rate in the malignant sample. Regarding the subanalysis, no significant association was found between mildly hypoechoic solid nodules and cancer. Conclusion: Stratifying hypoechogenicity into three degrees influences the confidence in the assessment of the rate of malignancy, indicating that mild hypoechogenicity has a unique low-risk biological behavior that resembles iso-hyperechogenicity, but with minor malignant potential when compared to moderate and marked hypoechogenicity, with special influence on the TI-RADS 4 category.

Co-expression analysis of lncRNA and mRNA identifies potential adipogenesis regulatory non-coding RNAs involved in the transgenerational effects of tributyltin.

The obesity epidemic is considered a global public health crisis, with an increase in caloric intake, sedentary lifestyles and/or genetic predispositions as contributing factors. Although the positive energy balance is one of the most significant causes of obesity, recent research has linked early exposure to Endocrine-Disrupting Chemicals (EDCs) such as the obesogen tributyltin (TBT) to the disease epidemic. In addition to their actions on the hormonal profile, EDCs can induce long-term changes in gene expression, possibly due to changes in epigenetic patterns. Long non-coding RNAs (lncRNAs) are epigenetic mediators that play important regulatory roles in several biological processes, through regulation of gene transcription and/or translation. In this study, we explored the differential expression of lncRNAs in gonadal white adipose tissue samples from adult male C57BL/6J F4 generation, female C57BL/6J offspring exposed (F0 generation) to 50 nM TBT or 0.1% DMSO (control of vehicle) via drinking water provided during pregnancy and lactation, analyzing RNA-seq data from a publicly available dataset (GSE105051). A total of 74 lncRNAs were differentially expressed (DE), 22 were up-regulated and 52 were down-regulated in the group whose F4 ancestor was exposed in utero to 50nM TBT when compared to those exposed to 0.1% DMSO (control). Regulation of DE lncRNAs and their potential partner genes in gonadal white adipose tissue of mice ancestrally exposed to EDC TBT may be related to the control of adipogenesis, as pathway enrichment analyses showed that these gene partners are mainly involved in the metabolism of lipids and glucose and in insulin-related pathways, which are essential for obesity onset and control.

Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H3 and dopamine D3 receptors.

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H3 and dopamine D3 receptors (H3R and D3R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H3R and D3R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the Ki and IC50 values. Results showed that several compounds were ligands at H3R (n = 10), D3R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (Ki H3R 2.8 µM; D3R 0.7 µM; IC50 BChE 26.3 µM) and LINS05015 (Ki H3R 1.1 µM; D3R 3.1 µM; IC50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.

Does a three-degree hypoechogenicity grading improve ultrasound thyroid nodule risk stratification and affect the TI-RADS 4 category? A retrospective observational study

ABSTRACT Objective: The aim of this study was to determine whether classifying hypoechogenicity in three degrees (mild, moderate, and marked) could improve the distinction between benign and malignant nodules and whether such an approach could influence Category 4 of the Thyroid Imaging Reporting and Data System (TI-RADS). Materials and methods: In total, 2,574 nodules submitted to fine needle aspiration, classified by the Bethesda System, were retrospectively assessed. Further, a subanalysis considering solid nodules without any additional suspicious findings (n = 565) was performed with the purpose of evaluating mainly TI-RADS 4 nodules. Results: Mild hypoechogenicity was significantly less related to malignancy (odds ratio [OR]: 1.409; CI: 1.086-1.829; p = 0.01), compared to moderate (OR: 4.775; CI: 3.700-6.163; p < 0.001) and marked hypoechogenicity (OR: 8.540; CI: 6.355-11.445; p < 0.001). In addition, mild hypoechogenicity (20.7%) and iso-hyperechogenicity (20.5%) presented a similar rate in the malignant sample. Regarding the subanalysis, no significant association was found between mildly hypoechoic solid nodules and cancer. Conclusion: Stratifying hypoechogenicity into three degrees influences the confidence in the assessment of the rate of malignancy, indicating that mild hypoechogenicity has a unique low-risk biological behavior that resembles iso-hyperechogenicity, but with minor malignant potential when compared to moderate and marked hypoechogenicity, with special influence on the TI-RADS 4 category.

Cytotoxic effect of crotoxin on cancer cells and its antitumoral effects correlated to tumor microenvironment: A review

Cancer is the second leading cause of death worldwide, and despite the effort of standard treatments, the search for new tools against this disease is necessary. Importantly, it is known that the tumor microenvironment plays a crucial role in tumor initiation, progression, and response to therapies. Therefore, studies of potential drugs that act on these components are as critical as studies regarding antiproliferative substances. Through the years, studies of several natural products, including animal toxins, have been conducted to guide the development of medical compounds. In this review, we present the remarkable antitumor activities of crotoxin, a toxin from the rattlesnake Crotalus durissus terrificus, highlighting its effects on cancer cells and in the modulation of relevant elements in the tumor microenvironment as well as the clinical trials conducted with this compound. In summary, crotoxin acts through several mechanisms of action, such as activation of apoptosis, induction of cell cycle arrest, inhibition of metastasis, and decrease of tumor growth, in different tumor types. Crotoxin also modulates tumor-associated fibroblasts, endothelial cells, and immune cells, which contribute to its antitumoral effects. In addition, preliminary clinical studies confirm the promising results of crotoxin and support its potential future use as an anticancer drug.

Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems.

Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or induce undesirable effects. Crotalphine is a 14 amino acids synthetic peptide that induces a potent and long-lasting analgesic effect on acute and chronic pain models, peripherally mediated by the endogenous release of dynorphin A and the desensitization of the transient receptor potential ankyrin 1 (TRPA1) receptor. However, the effects of crotalphine on the central nervous system (CNS) and the signaling pathway have not been investigated. Thus, the central effect of crotalphine was evaluated on the partial sciatic nerve ligation (PSNL)-induced chronic neuropathic pain model. Crotalphine (100 µg/kg, p.o.)-induced analgesia on the 14th day after surgery lasting up to 24 h after administration. This effect was prevented by intrathecal administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists. Besides that, crotalphine-induced analgesia was reversed by CTOP, nor-BNI, and naltrindole, antagonists of mu, kappa, and delta-opioid receptors, respectively, and also by the specific antibodies for ß-endorphin, dynorphin-A, and met-enkephalin. Likewise, the analgesic effect of crotalphine was blocked by the intrathecal administration of minocycline, an inhibitor of microglial activation and proliferation. Additionally, crotalphine decreased the PSNL-induced IL-6 release in the spinal cord. Importantly, in vitro, crotalphine inhibited LPS-induced CD86 expression and upregulated CD206 expression in BV-2 cells, demonstrating a polarization of microglial cells towards the M2 phenotype. These results demonstrated that crotalphine, besides activating opioid and cannabinoid analgesic systems, impairs central neuroinflammation, confirming the neuromodulatory mechanism involved in the crotalphine analgesic effect.

Evaluation of the histamine H3 receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies.

Histamine is involved in several central nervous system processes including cognition. In the last years, H3 receptor (H3 R) antagonists have been widely explored for their potential on dementias and other cognitive dysfunctions, and the cooperative role between histamine and acetylcholine neurotransmissions on cognitive processes is widely known in literature. This motivated us to assess the potential of 1-[(2,3-dihydrobenzofuran-1-yl)methyl]piperazines (LINS01 compounds) as inhibitors of cholinesterases, and thus this work presents the inhibitory effect of such compounds against acetyl (AChE) and butyrylcholinesterase. A set of 16 selected compounds were evaluated, being compounds 2d and 2e the most potent inhibitors of both cholinesterases (IC50 13.2-33.9 µM) by competitive mechanism, as indicated by the kinetic assays. Molecular docking simulations suggested that the allylpiperazine and dihydrobenzofuran motifs present in these compounds are important to perform π-interactions with key tryptophan residues from the enzymes, increasing their affinity for both H3 R and cholinesterases. Metric analysis support that compound 2d (LINS01022) should be highlighted due to its balanced lipophilicity (ClogP 2.35) and efficiency (LE 0.32) as AChE inhibitor. The results add important information to future design of dual H3 R-cholinesterases ligands.

Predisposing factors for increased cortisol levels in oral cancer patients.

Cancer patients may have a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and abnormal secretion of cortisol. Increased cortisol levels have been associated with worse prognosis in patients with different types of tumors. Although anxiety and depression can trigger an abnormal cortisol secretion, little is known regarding the influence of these emotional disorders on HPA axis dysregulation in cancer patients when evaluating together with demographic, clinicopathological and biobehavioral variables. This cross-sectional study analyzed the pre-treatment plasma cortisol levels of 133 patients with oral squamous cell carcinoma (OSCC) and its association with demographic, clinicopathological, biobehavioral and psychological variables. Plasma cortisol levels were measured by electrochemiluminescence, and anxiety and depression symptoms were assessed using Beck Anxiety Inventory (BAI) and Depression (BDI), respectively. Demographic, clinicopathological and biobehavioral data were collected from patients' medical records. Results from multivariate analysis showed that the occurrence of cancer-induced pain was predictive for higher cortisol levels (OR = 5.388, p = 0.003). Men with OSCC were 4.5 times more likely to have higher plasma cortisol levels than women (OR = 4.472, p = 0.018). The effect of sex on cortisol concentrations was lost in the adjusted model for clinical staging (OR = 2.945, p = 0.116). The absence of chronic alcohol consumption history was a protective factor for highest hormone concentrations in oral cancer patients (OR = 0.104, p = 0.004). Anxiety symptoms measured by BAI as "hands trembling" (OR = 0.192, p = 0.016) and being "nervous" (OR = 0.207, p = 0.0004) were associated with lower cortisol levels. In contrast, the feeling of "fear of losing control" was a risk factor for highest hormone concentrations (OR = 6.508, p = 0.0004). The global score and specific symptoms of depression measured by the BDI were not predictive for plasma hormone levels (p > 0.05). Together, our results show that pain, alcohol consumption and feeling fear are independent factors for increased systemic cortisol levels in patients with oral cancer. Therefore, psychological intervention, as well as control of pain and alcohol consumption, should be considered to prevent the negative effects of cortisol secretion dysregulation in cancer patients.

Hearing impairment among workers and satisfaction with the use of hearing aids.

BACKGROUND: Hearing problems can have adverse effects on an individual's job performance, as well as on unemployment or underemployment and increased risk of stress-related sick leave. OBJECTIVE: To investigate hearing impairment among workers and satisfaction with the use of hearing aids. METHODS: Cross-sectional study with workers who are hearing aid users. Subjects underwent pure tone audiometry and answered the Hearing Handicap Inventory for Adults and the Satisfaction with Amplification in Daily Life questionnaires. RESULTS: Participants were 36 workers between 36 and 75 years old, with an average age of 53.47 years, 52.7% male and 47.3% female. There was a mild to moderate hearing handicap perception, with worse results for women in the emotional domain. As hearing loss increased, workers' frustration increased when talking to coworkers. Everyone was satisfied with the use of their hearing aids. Satisfaction increased with increasing age and decreased with increasing hearing loss. The greater the frustration when talking to co-workers, the lower the overall satisfaction with hearing aid use; the lower the satisfaction with the competence of the professional who assisted in adapting the hearing aid; the lower the satisfaction in environments with background noise and overall worse personal image. The worse the attitudes and emotional responses of workers regarding their hearing impairment, the lower the overall satisfaction with the hearing aid. CONCLUSIONS: Despite the use of hearing aids, workers perceive having a hearing impairment, especially women. As hearing loss and frustration in talking with co-workers increased, satisfaction decreased.

Three-dimensional printing models increase inter-rater agreement for classification and treatment of proximal humerus fractures.

BACKGROUND: Proximal humerus fractures (PHF) are frequent, however, several studies show low inter-rater agreement in the diagnosis and treatment of these injuries. Differences are usually related to the experience of the evaluators and/or the diagnostic methods used. This study was designed to investigate the hypothesis that shoulder surgeons and diagnostic imaging specialists using 3D printing models and shoulder CT scans in assessing proximal humerus fractures. METHODS: We obtained 75 tomographic exams of PHF to print three-dimensional models. After, two shoulder surgeons and two specialists in musculoskeletal imaging diagnostics analyzed CT scans and 3D models according to the Neer and AO/OTA group classification and suggested a treatment recommendation for each fracture based on the two diagnostic methods. RESULTS: The classification agreement for PHF using 3D printing models among the 4 specialists was moderate (global k = 0.470 and 0.544, respectively for AO/OTA and Neer classification) and higher than the CT classification agreement (global k = 0.436 and 0.464, respectively for AO/OTA and Neer). The inter-rater agreement between the two shoulder surgeons were substantial. For the AO/OTA classification, the inter-rater agreement using 3D printing models was higher (k = 0.700) than observed for CT (k = 0.631). For Neer classification,  inter-rater agreement with 3D models was similarly higher (k = 0.784) than CT images (k = 0.620). On the other hand, the inter-rater agreement between the two specialists in diagnostic imaging was moderate. In the AO/OTA classification, the agreement using CT was higher (k = 0.532) than using 3D printing models (k = 0.443), while for Neer classification, the agreement was similar for both 3D models (k = 0.478) and CT images (k = 0.421). Finally, the inter-rater agreement in the treatment of PHF by the 2 surgeons was higher for both classifications using 3D printing models (AO/OTA-k = 0.818 for 3D models and k = 0.537 for CT images). For Neer classification, we saw k = 0.727 for 3D printing models and k = 0.651 for CT images. CONCLUSION: The insights from this diagnostic pilot study imply that for shoulder surgeons, 3D printing models improved the diagnostic agreement, especially the treatment indication for PHF compared to CT for both AO/OTA and Neer classifications On the other hand, for specialists in diagnostic imaging, the use of 3D printing models was similar to CT scans for diagnostic agreement using both classifications. TRIAL REGISTRATION: Brazil Platform under no. CAAE 12273519.7.0000.5505.