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Background: Leprosy reactions represent immunologically mediated episodes of acute inflammation that, if not diagnosed and treated promptly, can cause irreversible impairment of nerve function and permanent disabilities. A frequent type of reaction experienced by patients with lepromatous leprosy (LL) and borderline lepromatous leprosy (BL) is erythema nodosum leprosum (ENL), an inflammatory complication that may become chronic or recur in multiple episodes. Although ENL is commonly described as a neutrophil-mediated immune disease, the role of neutrophils is not fully understood. In this study, we assess neutrophilic leukocytosis in a retrospective cohort of patients affected by BL or LL leprosy. Materials and methods: A retrospective observational study was performed using data from 146 patients with BL and LL leprosy diagnosed and treated at the Souza Araújo Outpatient Clinic, Fiocruz, Rio de Janeiro, Brazil. Clinical, demographic, and hematological data were extracted from medical records. Skin biopsy samples obtained from patients for ENL diagnosis were used for histopathological evaluations. Results: Most patients were male (75%) and had a reactional episode (85%), of which 65% were ENL. Multiple episodes were common, 55% of the 80 patients with ENL presented more than 2 episodes (average of 2.6 episodes). In treatment-naive BL/LL patients, the median blood neutrophil counts of patients who developed ENL at some points of their disease course were higher than those who did not experience any reaction (median= 4,567 cells/mm3 vs 3,731 cells/mm3 respectively, p=0.0286). A correlation between the increase in median neutrophil counts and ENL severity was confirmed (6,066 cells/mm3 for mild ENL vs 10,243 cells/mm3 for moderate/severe ENL, p=0.0009). A longitudinal assessment was also performed in 34 patients, confirming the neutrophilic leukocytosis (BL/LL: 4896 cells/mm3 vs ENL: 8408 cells/mm3, p<0.0001). Moreover, increased NLR was associated with a greater neutrophilic infiltration in ENL lesions. Conclusion: We demonstrate that ENL episodes in patients affected by leprosy are associated with elevated blood leukocyte and neutrophil counts and an increased NLR. These findings highlight the significant involvement of neutrophils in the ENL immunological/inflammatory process.
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Eritema Nodoso , Hanseníase Virchowiana , Leucocitose , Neutrófilos , Humanos , Eritema Nodoso/imunologia , Eritema Nodoso/diagnóstico , Eritema Nodoso/etiologia , Masculino , Estudos Retrospectivos , Feminino , Adulto , Neutrófilos/imunologia , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/diagnóstico , Pessoa de Meia-Idade , Adulto Jovem , Idoso , AdolescenteRESUMO
Copper can be opportunely complexed to modulate oncogenic pathways, being a promising strategy for cancer treatment. Herein, three new copper(II) complexes containing long-chain aliphatic hydrazides and 1,10-phenanthroline (1,10-phen), namely, [Cu(octh)(1,10-phen)(H2O)](NO3)21, [Cu(dech)(1,10-phen)(H2O)](NO3)22 and [Cu(dodh)(1,10-phen)(H2O)](NO3)2.H2O 3 (where octh = octanoic hydrazide, dech = decanoic hydrazide, dodh = dodecanoic hydrazide) were successfully prepared and characterized by several physical-chemical methods. Furthermore, X-ray structural analysis of complex 2 indicated that the geometry around the copper(II) ion is distorted square-pyramidal, in which hydrazide and 1,10-phenanthroline act as bidentate ligands. A water molecule in the apical position completes the coordination sphere of the metal ion. All new copper(II) complexes were cytotoxic to breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and MDA-MB-157) and selective when compared to the non tumor lineage MCF-10A. In particular, complex 2 showed half-maximal inhibitory concentration (IC50) values ranging between 2.7 and 13.4 µM in MDA-MB231 cells after 24 and 48 h of treatment, respectively. Furthermore, this complex proved to be more selective for tumor cell lines when compared to doxorubicin and docetaxel. Complex 2 inhibited the clonogenicity of MDA-MB231 cells, increasing adenosine diphosphate (ADP) hydrolysis and upregulating ecto-nucleoside triphosphate diphosphohydrolase 1 (ENTPD1) transcriptional levels. In this sense, we suggest that the inhibitory effect on cell proliferation may be related to the modulation of adenosine monophosphate (AMP) levels. Thus, a novel copper(II) complex with increased cytotoxic effects and selectivity against breast cancer cells was obtained, contributing to medicinal chemistry efforts toward the development of new chemotherapeutic agents.
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Antineoplásicos , Complexos de Coordenação , Neoplasias de Mama Triplo Negativas , Humanos , Cobre/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Hidrazinas , Hidrólise , Antineoplásicos/farmacologia , Antineoplásicos/química , Fenantrolinas/farmacologia , Fenantrolinas/química , Difosfato de Adenosina , Cristalografia por Raios XRESUMO
Breast cancer (BC) is the most diagnosed cancer worldwide, mainly affecting the epithelial cells from the mammary glands. When it expresses the estrogen receptor (ER), the tumor is called luminal BC, which is eligible for endocrine therapy with hormone signaling blockade. Hormone therapy is essential for the survival of patients, but therapeutic resistance has been shown to be worrying, significantly compromising the prognosis. In this context, the need to explore new compounds emerges, especially compounds of plant origin, since they are biologically active and particularly promising. Natural products are being continuously screened for treating cancer due to their chemical diversity, reduced toxicity, lower side effects, and low price. This review summarizes natural compounds for the treatment of luminal BC, emphasizing the activities of these compounds in ER-positive cells. Moreover, their potential as an alternative to endocrine resistance is explored, opening new opportunities for the design of optimized therapies.
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INTRODUCTION: Unplanned peritoneal dialysis (PD) is an important option for chronic kidney disease (CKD) patients requiring kidney replacement therapy urgently as it offers the convenience of home-based therapy. The objective of this study was to assess the Brazilian urgent-start PD program in three different dialysis centers where there is shortage of hemodialysis (HD) beds. METHODS: This prospective, multicentric cohort study included incident patients with stage 5 CKD and no permanent vascular access established who started urgent PD between July 2014 and July 2020 in three different hospitals. Urgent-start PD was defined as initiation of treatment up to 72 h after catheter placement. Patients were followed up from catheter insertion and assessed according to mechanical and infectious complications related to PD, patients, and technique survival. RESULTS: Over 6 years, 370 patients were included in all three study centers. Mean patient age was 57.8 ± 16.32 years. Diabetic kidney disease was the main underlying condition (35.1%) and uremia was the main cause for dialysis indication (81.1%). Concerning complications related to PD, 24.3% had mechanical complications, 27.3% had peritonitis, 28.01% had technique failure, and 17.8% died. On logistic regression, hospitalization (p = 0.003) and exit site infection (p = 0.002) were identified as predictors of peritonitis, while mechanical complications (p = 0.004) and peritonitis (p < 0.001) were identified as predictors of technique failure and switching to HD. Age (p < 0.001), hospitalization (p = 0.012), and bacteremia (p = 0.021) were observed to predict death. The number of patients on PD increased at least 140% in all three participating centers. CONCLUSION: PD is a feasible option for patients starting dialysis in an unplanned manner and may be a useful tool for reducing shortage of HD beds.
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Falência Renal Crônica , Diálise Peritoneal , Peritonite , Insuficiência Renal Crônica , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Diálise Renal , Estudos de Coortes , Estudos Prospectivos , Brasil/epidemiologia , Diálise Peritoneal/efeitos adversos , Diálise Peritoneal/métodos , Falência Renal Crônica/terapia , Insuficiência Renal Crônica/etiologia , Peritonite/epidemiologia , Peritonite/etiologiaRESUMO
Glyphosate (GLY) was developed in the early 1970s and has become the most used broad-spectrum herbicide in the world so far. Its main metabolite is aminomethylphosphonic acid (AMPA), and the accumulation of GLY and its derivative compounds raises some concerns regarding possible health outcomes. In this study, we aimed to evaluate the effects of GLY and AMPA on prostate cell lines by evaluating cell viability, proliferation, gene and protein expression, and cellular pathways involved in the response to oxidative stress. Our results indicated that GLY and AMPA reduced the cell viability of tumorigenic and non-tumorigenic prostate cell lines only at higher concentrations (10 mM GLY and 20 mM AMPA). In contrast, both compounds increased the clonogenicity of non-tumorigenic PNT2 cells, mainly at concentrations below the IC50 (5 mM GLY and 10 mM AMPA). Moreover, treatment of non-tumorigenic cells with low concentrations of GLY or AMPA for 48 h increased GSTM3 expression at both mRNA and protein levels. In contrast, the treatments decrease the GST activity and induced an increase in oxidative stress, mainly at lower concentrations. Therefore, both compounds can cause cellular damage even at lower concentrations in non-tumorigenic PNT2 cells, mainly affecting cell proliferation and oxidative stress.
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Glutationa Transferase , Herbicidas , Masculino , Humanos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , Próstata/metabolismo , Herbicidas/farmacologia , Herbicidas/metabolismo , Tetrazóis/farmacologia , GlifosatoRESUMO
Introduction and objectives: To minimize our peritoneal dialysis (PD) population exposure to coronavirus disease (COVID-19), in April 2020 we developed and implemented a telemedicine program. In this investigation, we aimed to compare the hospitalization rates and metabolic disorders in patients undergoing PD 6 months before and after the COVID-19 pandemic and telemedicine implementation. Materials and methods: This single-center retrospective analysis included all active prevalent patients undergoing PD from April 2020. Dialysis records were reviewed to obtain clinical, demographic, laboratory, appointment, and hospitalization data. We compared hospitalization rates (total, non-PD-related, and PD-related), hospitalization-associated factors, and metabolic disorders (hemoglobin, serum potassium, and serum phosphate) 6 months before and after the pandemic. Results: Our sample comprised 103 participants. During the pre-pandemic and post-pandemic periods, there were 13 and 27 hospital admissions, respectively. The total hospitalization incident rate ratio (IRR) was 2.48 (95% confidence interval [CI], 1.29-4.75). PD-related hospitalizations increased from 3 to 15 episodes (IRR = 7.25 [95% CI, 2.11-24.78]). In the pre-pandemic period, the educational level was lower in participants hospitalised due to PD-related issues than in participants not hospitalised. In the post-pandemic period, only sex distribution differed between patients not hospitalised and those hospitalised due to non-PD-related issues. Only serum potassium levels changed significantly in the post-pandemic period (4.79 ± 0.48 vs. 4.93 ± 0.54 mg/dL; P < 0.01). Conclusion: This study showed a significant increase in hospitalization rates after the COVID-19 pandemic period and telemedicine implementation, mainly due to PD-related infectious causes. Strategies to improve distance monitoring assistance are needed for the PD population.
Introducción y objetivos: Para minimizar la exposición de nuestra población de diálisis peritoneal (DP) a la enfermedad por coronavirus (COVID-19), en abril del 2020 desarrollamos e implementamos un programa de telemedicina. En esta investigación, nuestro objetivo fue comparar las tasas de hospitalización y los trastornos metabólicos en pacientes sometidos a DP 6 meses antes y después de la pandemia de COVID-19 y la implementación de la telemedicina. Materiales y métodos: Este análisis retrospectivo de un solo centro incluyó a todos los pacientes prevalentes activos sometidos a DP desde abril del 2020. Se revisaron los registros de diálisis para obtener datos clínicos, demográficos, de laboratorio, de citas y de hospitalización. Comparamos las tasas de hospitalización (total, no relacionada con la DP y relacionada con la DP), los factores asociados a la hospitalización y los trastornos metabólicos (hemoglobina, potasio sérico y fosfato sérico) 6 meses antes y después de la pandemia. Resultados: Nuestra muestra fue compuesta por 103 participantes. Durante los períodos prepandémico y pospandémico, hubo 13 y 27 ingresos hospitalarios, respectivamente. La razón de la tasa de incidentes de hospitalización (TIR) total fue de 2,48 (intervalo de confianza [IC] del 95%, 1,29-4,75). Las hospitalizaciones relacionadas con la DP aumentaron de 3 a 15 episodios (TIR = 7,25 [IC del 95%, 2,11-24,78]). En el período prepandémico, el nivel educativo fue más bajo en los participantes hospitalizados debido a problemas relacionados con la DP que en los participantes no hospitalizados. En el período posterior a la pandemia, solo la distribución por sexo difirió entre los pacientes no hospitalizados y los hospitalizados debido a problemas no relacionados con la DP. Solo los niveles de potasio sérico cambiaron significativamente en el período pospandémico (4.79 ± 0.48 frente a 4.93 ± 0.54 mg/dL; P < 0.01). Conclusión: Este estudio mostró un aumento significativo en las tasas de hospitalización después del período pandémico de COVID-19 y la implementación de la telemedicina, principalmente debido a causas infecciosas relacionadas con la DP. Se necesitan estrategias para mejorar la asistencia de monitoreo a distancia para la población con DP.
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Abstract Introduction: Urgent-start peritoneal dialysis (US-PD) has been proposed as a safe modality of renal replacement therapy (RRT) for end-stage renal disease (ESRD) patients with an indication for emergency dialysis initiation. We aimed to compare the characteristics, 30-day complications, and clinical outcomes of US-PD and planned peritoneal dialysis (Plan-PD) patients over the first year of therapy. Methods: This was a single-center retrospective study that included incident adult patients followed for up to one year. US-PD was considered when incident patients started therapy within 7 days after Tenckhoff catheter implantation. Plan-PD group consisted of patients who started therapy after the breaking period (15 days). Mechanical and infectious complications were compared 30 days from PD initiation. Hospitalization and technique failure during the first 12 months on PD were assessed by Kaplan-Meier curves and the determinants were calculated by Cox regression models. Results: All patients starting PD between October/2016 and November/2019 who fulfilled the inclusion criteria were analyzed. We evaluated 137 patients (70 in the US-PD x 67 Plan-PD). The main complications in the first 30 days were catheter tip migration (7.5% Plan-PD x 4.3% US-PD - p= 0.49) and leakage (4.5% Plan-PD x 5.7% US-PD - p=0.74). Most catheters were placed using the Seldinger technique. The main cause of dropout was death in US-PD patients (15.7%) and transfer to HD in Plan-PD patients (13.4%). The occurrence of complications in the first 30 days was the only risk factor for dropout (OR = 2.9; 95% CI 1.1-7.5, p = 0.03). Hospitalization rates and technique survival were similar in both groups. Conclusion: The lack of significant differences in patients' outcomes between groups reinforces that PD is a safe and applicable dialysis method in patients who need immediate dialysis.
Resumo Introdução: A diálise peritoneal de início urgente (US-PD) foi proposta como modalidade segura de terapia renal substitutiva (TRS) para pacientes com doença renal em estágio 5 (DRC-5) com indicação de início de diálise de emergência. Buscamos comparar características, complicações em 30 dias e desfechos clínicos de pacientes em US-PD e diálise peritoneal planejada (DP-plan) no primeiro ano de terapia. Métodos: Estudo retrospectivo de centro único, que incluiu pacientes adultos incidentes em DP acompanhados por até um ano. Considerou-se US-PD quando os pacientes iniciaram terapia até 7 dias após implante do cateter Tenckhoff. O grupo DP-plan consistiu de pacientes iniciando terapia após período break-in (15 dias). Compararam-se complicações mecânicas e infecciosas 30 dias após o início da DP. Hospitalização e falha da técnica durante os primeiros 12 meses em terapia foram avaliados por curvas Kaplan-Meier e os seus determinantes foram analisados por modelos de regressão de Cox. Resultados: Analisaram-se todos os pacientes iniciando DP entre Outubro/2016-Novembro/2019 que preencheram os critérios de inclusão. Avaliamos 137 pacientes (70 US-PD x 67 DP-plan). As principais complicações nos primeiros 30 dias foram migração da ponta do cateter (7,5% DP-plan x 4,3% US-PD - p= 0,49) e extravasamento (4,5% DP-plan x 5,7% US-PD - p=0,74). A maioria dos cateteres foi implantada pela técnica de Seldinger. A principal causa de saída da terapia foi óbito em pacientes em US-PD (15,7%) e transferência para HD em pacientes em DP-plan (13,4%). A ocorrência de complicações nos primeiros 30 dias foi o único fator de risco para saída da terapia (OR = 2,9; IC 95% 1,1-7,5, p = 0,03). Taxas de hospitalização e sobrevida da técnica foram similares em ambos os grupos. Conclusão: A ausência de diferenças significativas nos desfechos dos pacientes entre os grupos reforça que DP é um método de diálise seguro e aplicável em pacientes que necessitam diálise imediata.
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Multidrug therapy (MDT) has been successfully used in the treatment of leprosy. However, although patients are cured after the completion of MDT, leprosy reactions, permanent disability, and occasional relapse/reinfection are frequently observed in patients. The immune system of multibacillary patients (MB) is not able to mount an effective cellular immune response against M. leprae. Consequently, clearance of bacilli from the body is a slow process and after 12 doses of MDT not all MB patients reduce bacillary index (BI). In this context, we recruited MB patients at the uptake and after 12-month of MDT. Patients were stratified according to the level of reduction of the BI after 12 doses MDT. A reduction of at least one log in BI was necessary to be considered a responder patient. We evaluated the pattern of host gene expression in skin samples with RNA sequencing before and after MDT and between samples from patients with or without one log reduction in BI. Our results demonstrated that after 12 doses of MDT there was a reduction in genes associated with lipid metabolism, inflammatory response, and cellular immune response among responders (APOBEC3A, LGALS17A, CXCL13, CXCL9, CALHM6, and IFNG). Also, by comparing MB patients with lower BI reduction versus responder patients, we identified high expression of CDH19, TMPRSS4, PAX3, FA2H, HLA-V, FABP7, and SERPINA11 before MDT. From the most differentially expressed genes, we observed that MDT modulates pathways related to immune response and lipid metabolism in skin cells from MB patients after MDT, with higher expression of genes like CYP11A1, that are associated with cholesterol metabolism in the group with the worst response to treatment. Altogether, the data presented contribute to elucidate gene signatures and identify differentially expressed genes associated with MDT outcomes in MB patients.
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Hanseníase Multibacilar , Hanseníase , Citidina Desaminase , Quimioterapia Combinada , Expressão Gênica , Humanos , Hansenostáticos/farmacologia , Hansenostáticos/uso terapêutico , Hanseníase Multibacilar/tratamento farmacológico , Hanseníase Multibacilar/genética , Mycobacterium leprae/genética , ProteínasRESUMO
In leprosy patients, acute inflammatory episodes, known as erythema nodosum leprosum (ENL), are responsible for high morbidity and tissue damage that occur during the course of Mycobacterium leprae infection. In a previous study, we showed evidence implicating DNA-sensing via TLR9 as an important inflammatory pathway in ENL. A likely important consequence of TLR9 pathway activation is the production of type I interferons (IFN-I) by plasmacytoid dendritic cells (pDCs), also implicated in the pathogenesis of several chronic inflammatory diseases. In this study, we investigated whether the IFN-I pathway is activated during ENL. Blood samples and skin lesions from multibacillary patients diagnosed with ENL were collected and the expression of genes of the IFN-I pathway and interferon-stimulated genes were compared with samples collected from non-reactional multibacillary (NR) patients. Whole blood RNAseq analysis suggested higher activation of the IFN-I pathway in ENL patients, confirmed by RT-qPCR. Likewise, significantly higher mRNA levels of IFN-I-related genes were detected in ENL skin biopsies when compared to NR patient lesions. During thalidomide administration, the drug of choice for ENL treatment, a decrease in the mRNA and protein levels of some of these genes both in the skin and blood was observed. Indeed, in vitro assays showed that thalidomide was able to block the secretion of IFN-I by peripheral blood mononuclear cells in response to M. leprae sonicate or CpG-A, a TLR9 ligand. Finally, the decreased frequencies of peripheral pDCs in ENL patients, along with the higher TLR9 expression in ENL pDCs and the enrichment of CD123+ cells in ENL skin lesions, suggest the involvement of these cells as IFN-I producers in this type of reaction. Taken together, our data point to the involvement of the pDC/type I IFN pathway in the pathogenesis of ENL, opening new avenues in identifying biomarkers for early diagnosis and new therapeutic targets for the better management of this reactional episode.
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INTRODUCTION: Urgent-start peritoneal dialysis (US-PD) has been proposed as a safe modality of renal replacement therapy (RRT) for end-stage renal disease (ESRD) patients with an indication for emergency dialysis initiation. We aimed to compare the characteristics, 30-day complications, and clinical outcomes of US-PD and planned peritoneal dialysis (Plan-PD) patients over the first year of therapy. METHODS: This was a single-center retrospective study that included incident adult patients followed for up to one year. US-PD was considered when incident patients started therapy within 7 days after Tenckhoff catheter implantation. Plan-PD group consisted of patients who started therapy after the breaking period (15 days). Mechanical and infectious complications were compared 30 days from PD initiation. Hospitalization and technique failure during the first 12 months on PD were assessed by Kaplan-Meier curves and the determinants were calculated by Cox regression models. RESULTS: All patients starting PD between October/2016 and November/2019 who fulfilled the inclusion criteria were analyzed. We evaluated 137 patients (70 in the US-PD x 67 Plan-PD). The main complications in the first 30 days were catheter tip migration (7.5% Plan-PD x 4.3% US-PD - p= 0.49) and leakage (4.5% Plan-PD x 5.7% US-PD - p=0.74). Most catheters were placed using the Seldinger technique. The main cause of dropout was death in US-PD patients (15.7%) and transfer to HD in Plan-PD patients (13.4%). The occurrence of complications in the first 30 days was the only risk factor for dropout (OR = 2.9; 95% CI 1.1-7.5, p = 0.03). Hospitalization rates and technique survival were similar in both groups. CONCLUSION: The lack of significant differences in patients' outcomes between groups reinforces that PD is a safe and applicable dialysis method in patients who need immediate dialysis.