hTERT gene methylation in circulating DNA, tumor, and surrounding tissue in breast cancer: a prospective study.

BACKGROUND: The human telomerase reverse transcriptase (hTERT) enzyme, encoded by the hTERT gene, synthesizes protective telomeric sequences on chromosomes and plays a fundamental role in cancer formation. Methylation of the hTERT gene has an upregulatory effect, increasing hTERT enzyme synthesis and allowing continuous tumor cell division. OBJECTIVE: In a group of patients with breast cancer, we aimed to analyze the methylation status of hTERT in the tumor, surrounding tissue, and circulating free deoxyribonucleic acid (cfDNA) of blood collected on the day of mastectomy and then approximately one year later. DESIGN AND SETTING: A prospective study was conducted at a university hospital in Rio de Janeiro, Brazil. METHODS: Samples were collected from 15 women with breast cancer on the day of mastectomy and approximately one year postoperatively. cfDNA was analyzed by sodium bisulfite conversion, followed by polymerase chain reaction, electrophoresis, and silver nitrate staining. RESULTS: Methylation of hTERT was detected in the tumors and surrounding tissues of all 15 patients. Five patients displayed hTERT methylation in the cfDNA from the blood of the first collection. Of the ten patients who returned for the second collection, three showed methylation. Two patients with methylation in the first collection did not display methylation in the second collection. One patient with no methylation in the first collection displayed methylation in the second collection, and one patient had a diminished level of methylation in the second collection. CONCLUSION: Only one-third of patients displayed methylation in their cfDNA, which may be related to the success of chemotherapy.

Molecular monitoring by CDKN2A/p16INK4A and RB1 gene methylation in breast cancer.

OBJECTIVE: This prospective study aimed to provide a comprehensive analysis of the methylation status of two pivotal genes, CDKN2A/p16INK4A (cyclin-dependent kinase inhibitor 2A) and RB1 (retinoblastoma transcriptional corepressor 1), in breast cancer patients. METHODS: Samples were obtained from 15 women diagnosed with breast cancer and who underwent a total mastectomy. DNA was extracted from the tumor, non-tumor tissue, and peripheral blood (circulating cell-free DNA). The methylation pattern of cell-free DNA extracted from blood collected on the day of mastectomy was compared with the methylation pattern of cell-free DNA from blood collected 1 year post-surgery. The methylation analysis was carried out by sodium bisulfite conversion and polymerase chain reaction, followed by electrophoresis. RESULTS: Methylation of CDKN2A/p16INK4A was identified in 13 tumor samples and 12 non-tumor tissue samples. Two patients exhibited CDKN2A/p16INK4A methylation in the cell-free DNA of the first blood collection, while another showed methylation only in the cell-free DNA of the subsequent blood collection. Regarding RB1, 11 tumors and 8 non-tumor tissue samples presented methylation of the gene. CONCLUSION: This study presents a novel approach for monitoring breast cancer patients through the analysis of cell-free DNA methylation. This analysis can detect changes in methylation patterns before any visible sign of cancer appears in breast tissue and could help predict the recurrence of malignant breast tumors.

Effects of low-dose rapamycin on lymphoid organs of mice prone and resistant to accelerated senescence.

Aging is a complex, natural, and irreversible phenomenon that subjects the body to numerous changes in the physiological process, characterized by a gradual decline in the organism's homeostatic mechanisms, closely related to immunosenescence. Here, we evaluated the regulation of immunosenescence in lymphoid organs of senescence-accelerated prone 8 (SAM-P8) and senescence-accelerated resistant 1 (SAM-R1) mice treated with a low dose of rapamycin (RAPA). Mice were treated with a dose of 7.1 µg/kg RAPA for 2 months and had body mass and hematological parameters analyzed prior and during treatment. Cellular and humoral parameters of serum, bone marrow, thymus, and spleen samples were evaluated by ELISA, histology, and flow cytometry. Changes in body mass, hematological parameters, cell number, and in the secretion of IL-1ß, IL-6, TNF-α, IL-7, and IL-15 cytokines were different between the 2 models used. In histological analyses, we observed that SAM-P8 mice showed faster thymic involution than SAM-R1 mice. Regarding the T lymphocyte subpopulations in the spleen, CD4+ and CD8+ T cell numbers were higher and lower, respectively, in SAM-P8 mice treated with RAPA, with the opposite observed in SAM-R1. Additionally, we found that the low dose of RAPA used did not trigger changes that could compromise the immune response of these mice and the administered dose may have contributed to changes in important lymphocyte populations in the adaptive immune response and the secretion of cytokines that directly collaborate with the maturation and proliferation of these cells.

Molecular monitoring by CDKN2A/p16INK4A and RB1 gene methylation in breast cancer

SUMMARY OBJECTIVE: This prospective study aimed to provide a comprehensive analysis of the methylation status of two pivotal genes, CDKN2A/p16INK4A (cyclin-dependent kinase inhibitor 2A) and RB1 (retinoblastoma transcriptional corepressor 1), in breast cancer patients. METHODS: Samples were obtained from 15 women diagnosed with breast cancer and who underwent a total mastectomy. DNA was extracted from the tumor, non-tumor tissue, and peripheral blood (circulating cell-free DNA). The methylation pattern of cell-free DNA extracted from blood collected on the day of mastectomy was compared with the methylation pattern of cell-free DNA from blood collected 1 year post-surgery. The methylation analysis was carried out by sodium bisulfite conversion and polymerase chain reaction, followed by electrophoresis. RESULTS: Methylation of CDKN2A/p16INK4A was identified in 13 tumor samples and 12 non-tumor tissue samples. Two patients exhibited CDKN2A/p16INK4A methylation in the cell-free DNA of the first blood collection, while another showed methylation only in the cell-free DNA of the subsequent blood collection. Regarding RB1, 11 tumors and 8 non-tumor tissue samples presented methylation of the gene. CONCLUSION: This study presents a novel approach for monitoring breast cancer patients through the analysis of cell-free DNA methylation. This analysis can detect changes in methylation patterns before any visible sign of cancer appears in breast tissue and could help predict the recurrence of malignant breast tumors.

hTERT gene methylation in circulating DNA, tumor, and surrounding tissue in breast cancer: a prospective study

ABSTRACT BACKGROUND: The human telomerase reverse transcriptase (hTERT) enzyme, encoded by the hTERT gene, synthesizes protective telomeric sequences on chromosomes and plays a fundamental role in cancer formation. Methylation of the hTERT gene has an upregulatory effect, increasing hTERT enzyme synthesis and allowing continuous tumor cell division. OBJECTIVE: In a group of patients with breast cancer, we aimed to analyze the methylation status of hTERT in the tumor, surrounding tissue, and circulating free deoxyribonucleic acid (cfDNA) of blood collected on the day of mastectomy and then approximately one year later. DESIGN AND SETTING: A prospective study was conducted at a university hospital in Rio de Janeiro, Brazil. METHODS: Samples were collected from 15 women with breast cancer on the day of mastectomy and approximately one year postoperatively. cfDNA was analyzed by sodium bisulfite conversion, followed by polymerase chain reaction, electrophoresis, and silver nitrate staining. RESULTS: Methylation of hTERT was detected in the tumors and surrounding tissues of all 15 patients. Five patients displayed hTERT methylation in the cfDNA from the blood of the first collection. Of the ten patients who returned for the second collection, three showed methylation. Two patients with methylation in the first collection did not display methylation in the second collection. One patient with no methylation in the first collection displayed methylation in the second collection, and one patient had a diminished level of methylation in the second collection. CONCLUSION: Only one-third of patients displayed methylation in their cfDNA, which may be related to the success of chemotherapy.

The role of captopril in leukotriene deficient type 1 diabetic mice.

T1D can be associated with metabolic disorders and several impaired pathways, including insulin signaling, and development of insulin resistance through the renin-angiotensin system (RAS). The main precursor of RAS is angiotensinogen (Agt) and this system is often linked to autophagy dysregulation. Dysregulated autophagy has been described in T1D and linked to impairments in both glucose metabolism, and leukotrienes (LTs) production. Here, we have investigated the role of RAS and LTs in both muscle and liver from T1D mice, and its effects on insulin and autophagy pathways. We have chemically induced T1D in 129sve and 129sve 5LO-/- mice (lacking LTs) with streptozotocin (STZ). To further inhibit ACE activity, mice were treated with captopril (Cap). In muscle of T1D mice, treatment with Cap increased the expression of RAS (angiotensinogen and angiotensin II receptor), insulin signaling, and autophagy markers, regardless of the genotype. In the liver of T1D mice, the treatment with Cap increased the expression of RAS and insulin signaling markers, mostly when LTs were absent. 5LO-/- T1D mice showed increased insulin sensitivity, and decreased NEFA, after the Cap treatment. Cap treatment impacted both insulin signaling and autophagy pathways at the mRNA levels in muscle and liver, indicating the potential role of ACE inhibition on insulin sensitivity and autophagy in T1D.

Brazilian headache registry: methods and preliminary data of the pilot study.

BACKGROUND: Evaluation and treatment of primary and secondary headaches is a global public health challenge. Recognizing the epidemiological impact of headaches, a group of researchers linked to the Brazilian Headache Society proposed the Brazilian Headache Registry and drew up its initial protocol. OBJECTIVE: Here we describe the methods and preliminary data obtained from the pilot study. METHODS: This was a multicenter longitudinal observational study conducted between September 2020 and August 2021. Prospective data were collected in three specialist centers for headache care in states in southern and southeastern Brazil. Patients aged 18 years or older who sought care for headache in tertiary centers and who agreed to participate in the study, were considered eligible. RESULTS: Sixty-six patients were included in the pilot study: 43 (65%) from Rio Grande do Sul state and 23 (35%) from Minas Gerais state. Overall, 90% were female, and the subjects' mean age was 38.2 ± 11.2 years. Primary headaches accounted for 85.3% of the diagnoses made. Among secondary headaches, medication overuse headache was the most frequent type (7.1%). CONCLUSIONS: The pilot study showed the feasibility of the research protocol developed for tertiary centers. The Brazilian Headache Registry will form a source of longitudinal data with the aim of contributing to better characterization of the various phenotypes of patients with primary and secondary headaches, and to detailing the use of health resources and identifying predictors of better clinical outcomes.

ANTECEDENTES: A avaliação e o tratamento das cefaleias primárias e secundárias são um desafio global de saúde pública. Reconhecendo o impacto epidemiológico das cefaleias, um grupo de pesquisadores vinculados à Sociedade Brasileira de Cefaleia propôs a criação de um Registro Brasileiro de Cefaleia e elaborou seu protocolo inicial. OBJETIVO: Nesta publicação descrevemos os métodos e dados preliminares obtidos a partir do estudo piloto. MéTODOS: Trata-se de um estudo prospectivo observacional longitudinal multicêntrico, realizado entre setembro de 2020 e agosto de 2021. Foram coletados dados em três centros especializados no atendimento de cefaleia, em estados da região sul e sudeste do Brasil. Pacientes com idade igual ou superior a 18 anos que procuraram os centros terciários por queixa de cefaleia e concordaram em participar do estudo foram considerados elegíveis. RESULTADOS: Sessenta e seis pacientes foram incluídos no estudo piloto, 43 (65%) do Rio Grande do Sul e 23 (35%) de Minas Gerais. Da amostra total, 90% eram do sexo feminino e a idade média dos sujeitos foi de 38,2 ± 11,2 anos. As cefaleias primárias representaram 85,3% dos diagnósticos realizados. Entre as cefaleias secundárias, a cefaleia por uso excessivo de medicamentos foi a mais frequente (7,1%). CONCLUSõES: O estudo piloto evidenciou a viabilidade do protocolo de pesquisa desenvolvido para centros terciários. O Registro Brasileiro de Cefaleia constituirá uma fonte de dados longitudinais com o objetivo de contribuir para melhor caracterização dos diversos fenótipos de pacientes com cefaleias primárias e secundárias, detalhar o uso de recursos de saúde e identificar preditores de melhores desfechos clínicos.

Brazilian headache registry: methods and preliminary data of the pilot study / Registro brasileiro de cefaleia: métodos e dados preliminares do estudo piloto

Abstract Background Evaluation and treatment of primary and secondary headaches is a global public health challenge. Recognizing the epidemiological impact of headaches, a group of researchers linked to the Brazilian Headache Society proposed the Brazilian Headache Registry and drew up its initial protocol. Objective Here we describe the methods and preliminary data obtained from the pilot study. Methods This was a multicenter longitudinal observational study conducted between September 2020 and August 2021. Prospective data were collected in three specialist centers for headache care in states in southern and southeastern Brazil. Patients aged 18 years or older who sought care for headache in tertiary centers and who agreed to participate in the study, were considered eligible. Results Sixty-six patients were included in the pilot study: 43 (65%) from Rio Grande do Sul state and 23 (35%) from Minas Gerais state. Overall, 90% were female, and the subjects' mean age was 38.2 ± 11.2 years. Primary headaches accounted for 85.3% of the diagnoses made. Among secondary headaches, medication overuse headache was the most frequent type (7.1%). Conclusions The pilot study showed the feasibility of the research protocol developed for tertiary centers. The Brazilian Headache Registry will form a source of longitudinal data with the aim of contributing to better characterization of the various phenotypes of patients with primary and secondary headaches, and to detailing the use of health resources and identifying predictors of better clinical outcomes.

Resumo Antecedentes A avaliação e o tratamento das cefaleias primárias e secundárias são um desafio global de saúde pública. Reconhecendo o impacto epidemiológico das cefaleias, um grupo de pesquisadores vinculados à Sociedade Brasileira de Cefaleia propôs a criação de um Registro Brasileiro de Cefaleia e elaborou seu protocolo inicial. Objetivo Nesta publicação descrevemos os métodos e dados preliminares obtidos a partir do estudo piloto. Métodos Trata-se de um estudo prospectivo observacional longitudinal multicêntrico, realizado entre setembro de 2020 e agosto de 2021. Foram coletados dados em três centros especializados no atendimento de cefaleia, em estados da região sul e sudeste do Brasil. Pacientes com idade igual ou superior a 18 anos que procuraram os centros terciários por queixa de cefaleia e concordaram em participar do estudo foram considerados elegíveis. Resultados Sessenta e seis pacientes foram incluídos no estudo piloto, 43 (65%) do Rio Grande do Sul e 23 (35%) de Minas Gerais. Da amostra total, 90% eram do sexo feminino e a idade média dos sujeitos foi de 38,2 ± 11,2 anos. As cefaleias primárias representaram 85,3% dos diagnósticos realizados. Entre as cefaleias secundárias, a cefaleia por uso excessivo de medicamentos foi a mais frequente (7,1%). Conclusões O estudo piloto evidenciou a viabilidade do protocolo de pesquisa desenvolvido para centros terciários. O Registro Brasileiro de Cefaleia constituirá uma fonte de dados longitudinais com o objetivo de contribuir para melhor caracterização dos diversos fenótipos de pacientes com cefaleias primárias e secundárias, detalhar o uso de recursos de saúde e identificar preditores de melhores desfechos clínicos.

The influence of high glucose conditions on macrophages and its effect on the autophagy pathway.

Introduction: Macrophages are central cells in mediating the inflammatory response. Objective and Methods: We evaluated the effect of high glucose conditions on the inflammatory profile and the autophagy pathway in Bone-Marrow Derived Macrophages (BMDM) from diabetic (D-BMDM) (alloxan: 60mg/kg, i.v.) and non-diabetic (ND-BMDM) C57BL/6 mice. BMDM were cultured in medium with normal glucose (5.5 mM), or high glucose (25 mM) concentration and were primed with Nigericin (20µM) stimulated with LPS (100 ng/mL) at times of 30 minutes; 2; 4; 6 and 24 hours, with the measurement of IL-6, IL-1ß and TNF-α cytokines. Results: We have further identified changes in the secretion of pro-inflammatory cytokines IL-6, IL-1ß and TNF-α, where BMDM showed increased secretion of these cytokines after LPS + Nigericin stimulation. In addition, changes were observed in the autophagy pathway, where the increase in the autophagic protein LC3b and Beclin-1 occurred by macrophages of non-diabetic animals in hyperglycemic medium, without LPS stimulation. D-BMDM showed a reduction on the expression of LC3b and Beclin-1, suggesting an impaired autophagic process in these cells. Conclusion: The results suggest that hyperglycemia alters the inflammatory pathways in macrophages stimulated by LPS, playing an important role in the inflammatory response of diabetic individuals.

Experimental Yellow Fever in the Squirrel Monkey (Saimiri spp.): Hematological, Biochemical, and Immunological Findings.

Between 2016 and 2018, Brazil experienced the largest sylvatic epidemic of yellow fever virus (YFV). Despite to the magnitude and rapid spread of the epidemic, little is known about YFV dispersion. The study evaluated whether the squirrel monkey is a good model for yellow fever (YF) studies. Methods: Ten animals were infected with 1 × 106 PFU/mL of YFV, with one negative control. Blood samples were collected daily during the first 7 days and at 10, 20 and 30 days post infection (dpi) for detection of viral load and cytokines by RT-qPCR; measurements of AST, ALT, urea and creatinine were taken; IgM/IgG antibodies were detected by ELISA, and hemagglutination inhibition and neutralization tests were performed. The animals exhibited fever, flushed appearance, vomiting and petechiae, and one animal died. Viremia was detected between 1 and 10 dpi, and IgM/IgG antibodies appeared between 4 and 30 dpi. The levels of AST, ALT and urea increased. The immune responses were characterized by expression of S100 and CD11b cells; endothelial markers (VCAM-1, ICAM-1 and VLA-4), cell death and stress (Lysozyme and iNOS); and pro-inflammatory cytokines (IL-8, TNF-α, and IFN-γ) and anti-inflammatory cytokines (IL-10 and TGF-ß). The squirrel monkeys showed changes similar to those described in humans with YF, and are a good experimental model for the study of YF.

Consensus of the Brazilian Headache Society (SBCe) for prophylactic treatment of episodic migraine: part II.

BACKGROUND: Migraine affects 1 billion people worldwide and > 30 million Brazilians; besides, it is an underdiagnosed and undertreated disorder. OBJECTIVE: The need to disseminate knowledge about the prophylactic treatment of migraine is known, so the Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee of authors with the objective of establishing a consensus with recommendations on the prophylactic treatment of episodic migraine based on articles from the world literature as well as from personal experience. METHODS: Meetings were held entirely online, with the participation of 12 groups that reviewed and wrote about the pharmacological categories of drugs and, at the end, met to read and finish the document. The drug classes studied in part II of this Consensus were: antihypertensives, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, calcium channel blockers, other drugs, and rational polytherapy. RESULTS: From this list of drugs, only candesartan has been established as effective in controlling episodic migraine. Flunarizine, venlafaxine, duloxetine, and pizotifen were defined as likely to be effective, while lisinopril, enalapril, escitalopram, fluvoxamine, quetiapine, atorvastatin, simvastatin, cyproheptadine, and melatonin were possibly effective in prophylaxis of the disease. CONCLUSIONS: Despite an effort by the scientific community to find really effective drugs in the treatment of migraine, given the large number of drugs tested for this purpose, we still have few therapeutic options.

ANTECEDENTES: Migrânea afeta um bilhão de pessoas em todo o mundo e mais de 30 milhões de brasileiros; além disso, é um distúrbio subdiagnosticado e subtratado. OBJETIVO: Sabe-se sobre a necessidade de difundir o conhecimento sobre o tratamento profilático da migrânea; por isso, a Sociedade Brasileira de Cefaleias (SBCe) nomeou um comitê de autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da migrânea episódica com base em artigos da literatura mundial, assim como da experiência pessoal. MéTODOS: As reuniões foram realizadas inteiramente online, com a participação de 12 grupos que revisaram e escreveram sobre as categorias farmacológicas dos medicamentos e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de medicamentos estudadas na parte II deste Consenso foram: anti-hipertensivos, inibidores seletivos de recaptação de serotonina, inibidores de recaptação de serotonina e noradrenalina, bloqueadores dos canais de cálcio, outros medicamentos e politerapia racional. RESULTADOS: Desta lista de medicamentos, apenas o candesartan foi estabelecido como eficaz no controle da migrânea episódica. Flunarizina, venlafaxina, duloxetina e pizotifeno foram definidos como provavelmente eficazes, enquanto lisinopril, enalapril, escitalopram, fluvoxamina, quetiapina, atorvastatina, sinvastatina, ciproheptadina e melatonina foram possivelmente eficazes na profilaxia da doença. CONCLUSõES: Apesar do esforço da comunidade científica em encontrar medicamentos realmente eficazes no tratamento da migrânea, dado o grande número de medicamentos testados para este fim, ainda dispomos de poucas opções terapêuticas.

Consensus of the Brazilian Headache Society (SBCe) for the Prophylactic Treatment of Episodic Migraine: part I.

The Brazilian Headache Society (Sociedade Brasileira de Cefaleia, SBCe, in Portuguese) nominated a Committee of Authors with the aim of establishing a consensus with recommendations regarding prophylactic treatment for episodic migraine based on articles published in the worldwide literature, as well as personal experience. Migraine affects 1 billion people around the world and more than 30 million Brazilians. In addition, it is an underdiagnosed and undertreated disorder. It is well known within the medical community of neurologists, and especially among headache specialists, that there is a need to disseminate knowledge about prophylactic treatment for migraine. For this purpose, together with the need for drug updates and to expand knowledge of the disease itself (frequency, intensity, duration, impact and perhaps the progression of migraine), this Consensus was developed, following a full online methodology, by 12 groups who reviewed and wrote about the pharmacological categories of the drugs used and, at the end of the process, met to read and establish conclusions for this document. The drug classes studied were: anticonvulsants, tricyclic antidepressants, monoclonal anti-calcitonin gene-related peptide (anti-CGRP) antibodies, beta-blockers, antihypertensives, calcium channel inhibitors, other antidepressants (selective serotonin reuptake inhibitors, SSRIs, and dual-action antidepressants), other drugs, and polytherapy. Hormonal treatment and anti-inflammatories and triptans in minimum prophylaxis schemes (miniprophylaxis) will be covered in a specific chapter. The drug classes studied for part I of the Consensus were: anticonvulsants, tricyclic antidepressants, monoclonal anti-CGRP antibodies, and beta-blockers.

A Sociedade Brasileira de Cefaleia (SBCe) nomeou um Comitê de Autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da enxaqueca episódica com base em artigos da literatura mundial e da experiência pessoal. A enxaqueca é um distúrbio subdiagnosticado e subtratado que acomete um bilhão de pessoas no mundo e mais de 30 milhões de brasileiros. É conhecido na comunidade médica de neurologistas e, sobretudo, dos especialistas em cefaleia, a necessidade de se divulgar o conhecimento sobre o tratamento profilático da enxaqueca. Com esta finalidade, aliada às necessidades de atualizações de drogas e de se aumentar o conhecimento sobre a doença em si (frequência, intensidade, duração, impacto e talvez a progressão da enxaqueca), foi elaborado este Consenso, com metodologia totalmente on-line, por 12 grupos que revisaram e escreveram sobre as categorias farmacológicas das drogas e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de drogas estudadas para este Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais do antipeptídeo relacionado ao gene da calcitonina (peptídeo relacionado ao gene da calcitonina ­ anti-CGRP), betabloqueadores, anti-hipertensivos, inibidores dos canais de cálcio, outros antidepressivos (inibidores seletivos de recaptação de serotonina, ISRSs, e antidepressivos de ação dual), outras drogas, e politerapia. O tratamento hormonal, bem como anti-inflamatórios e triptanas em esquema de profilaxia mínima (miniprofilaxia), será abordado em um capítulo próprio. As classes de drogas estudadas na parte I do Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais anti-CGRP, e betabloqueadores.

Consensus of the Brazilian Headache Society (SBCe) for prophylactic treatment of episodic migraine: part II / Consenso da Sociedade Brasileira de Cefaleia (SBCe) para o tratamento profilático da migrânea episódica: parte II

Abstract Background Migraine affects 1 billion people worldwide and > 30 million Brazilians; besides, it is an underdiagnosed and undertreated disorder. Objective The need to disseminate knowledge about the prophylactic treatment of migraine is known, so the Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee of authors with the objective of establishing a consensus with recommendations on the prophylactic treatment of episodic migraine based on articles from the world literature as well as from personal experience. Methods Meetings were held entirely online, with the participation of 12 groups that reviewed and wrote about the pharmacological categories of drugs and, at the end, met to read and finish the document. The drug classes studied in part II of this Consensus were: antihypertensives, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, calcium channel blockers, other drugs, and rational polytherapy. Results From this list of drugs, only candesartan has been established as effective in controlling episodic migraine. Flunarizine, venlafaxine, duloxetine, and pizotifen were defined as likely to be effective, while lisinopril, enalapril, escitalopram, fluvoxamine, quetiapine, atorvastatin, simvastatin, cyproheptadine, and melatonin were possibly effective in prophylaxis of the disease. Conclusions Despite an effort by the scientific community to find really effective drugs in the treatment of migraine, given the large number of drugs tested for this purpose, we still have few therapeutic options.

Resumo Antecedentes Migrânea afeta um bilhão de pessoas em todo o mundo e mais de 30 milhões de brasileiros; além disso, é um distúrbio subdiagnosticado e subtratado. Objetivo Sabe-se sobre a necessidade de difundir o conhecimento sobre o tratamento profilático da migrânea; por isso, a Sociedade Brasileira de Cefaleias (SBCe) nomeou um comitê de autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da migrânea episódica com base em artigos da literatura mundial, assim como da experiência pessoal. Métodos As reuniões foram realizadas inteiramente online, com a participação de 12 grupos que revisaram e escreveram sobre as categorias farmacológicas dos medicamentos e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de medicamentos estudadas na parte II deste Consenso foram: anti-hipertensivos, inibidores seletivos de recaptação de serotonina, inibidores de recaptação de serotonina e noradrenalina, bloqueadores dos canais de cálcio, outros medicamentos e politerapia racional. Resultados Desta lista de medicamentos, apenas o candesartan foi estabelecido como eficaz no controle da migrânea episódica. Flunarizina, venlafaxina, duloxetina e pizotifeno foram definidos como provavelmente eficazes, enquanto lisinopril, enalapril, escitalopram, fluvoxamina, quetiapina, atorvastatina, sinvastatina, ciproheptadina e melatonina foram possivelmente eficazes na profilaxia da doença. Conclusões Apesar do esforço da comunidade científica em encontrarmedicamentos realmente eficazes no tratamento da migrânea, dado o grande número de medicamentos testados para este fim, ainda dispomos de poucas opções terapêuticas.

Consensus of the Brazilian Headache Society (SBCe) for the Prophylactic Treatment of Episodic Migraine: part I / Consenso da Sociedadade Brasileira de Cefaleia (SBCe) para o tratamento profilático da migrânea episódica: parte I

Abstract The Brazilian Headache Society (Sociedade Brasileira de Cefaleia, SBCe, in Portuguese) nominated a Committee of Authors with the aim of establishing a consensus with recommendations regarding prophylactic treatment for episodic migraine based on articles published in the worldwide literature, as well as personal experience. Migraine affects 1 billion people around the world and more than 30 million Brazilians. In addition, it is an underdiagnosed and undertreated disorder. It is well known within the medical community of neurologists, and especially among headache specialists, that there is a need to disseminate knowledge about prophylactic treatment for migraine. For this purpose, together with the need for drug updates and to expand knowledge of the disease itself (frequency, intensity, duration, impact and perhaps the progression of migraine), this Consensus was developed, following a full online methodology, by 12 groups who reviewed and wrote about the pharmacological categories of the drugs used and, at the end of the process, met to read and establish conclusions for this document. The drug classes studied were: anticonvulsants, tricyclic antidepressants, monoclonal anti-calcitonin gene-related peptide (anti-CGRP) antibodies, beta-blockers, antihypertensives, calcium channel inhibitors, other antidepressants (selective serotonin reuptake inhibitors, SSRIs, and dual-action antidepressants), other drugs, and polytherapy. Hormonal treatment and anti-inflammatories and triptans in minimum prophylaxis schemes (miniprophylaxis) will be covered in a specific chapter. The drug classes studied for part I of the Consensus were: anticonvulsants, tricyclic antidepressants, monoclonal anti-CGRP antibodies, and beta-blockers.

Resumo A Sociedade Brasileira de Cefaleia (SBCe) nomeou um Comitê de Autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da enxaqueca episódica com base em artigos da literatura mundial e da experiência pessoal. A enxaqueca é um distúrbio subdiagnosticado e subtratado que acomete um bilhão de pessoas no mundo e mais de 30 milhões de brasileiros. É conhecido na comunidade médica de neurologistas e, sobretudo, dos especialistas em cefaleia, a necessidade de se divulgar o conhecimento sobre o tratamento profilático da enxaqueca. Com esta finalidade, aliada às necessidades de atualizações de drogas e de se aumentar o conhecimento sobre a doença em si (frequência, intensidade, duração, impacto e talvez a progressão da enxaqueca), foi elaborado este Consenso, com metodologia totalmente on-line, por 12 grupos que revisaram e escreveram sobre as categorias farmacológicas das drogas e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de drogas estudadas para este Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais do antipeptídeo relacionado ao gene da calcitonina (peptídeo relacionado ao gene da calcitonina — anti-CGRP), betabloqueadores, anti-hipertensivos, inibidores dos canais de cálcio, outros antidepressivos (inibidores seletivos de recaptação de serotonina, ISRSs, e antidepressivos de ação dual), outras drogas, e politerapia. O tratamento hormonal, bem como anti-inflamatórios e triptanas em esquema de profilaxia mínima (miniprofilaxia), será abordado em um capítulo próprio. As classes de drogas estudadas na parte I do Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais anti-CGRP, e betabloqueadores.

Endangered Lymphocytes: The Effects of Alloxan and Streptozotocin on Immune Cells in Type 1 Induced Diabetes.

Alloxan (ALX) and streptozotocin (STZ) are extensively used to induce type 1 diabetes (T1D) in animal models. This study is aimed at evaluating the differences in immune parameters caused by ALX and STZ. T1D was induced either with ALX or with STZ, and the animals were followed for up to 180 days. Both ALX and STZ induced a decrease in the total number of circulating leukocytes and lymphocytes, with an increase in granulocytes when compared to control mice (CT). STZ-treated mice also exhibited an increase in neutrophils and a reduction in the lymphocyte percentage in the bone marrow. In addition, while the STZ-treated group showed a decrease in total CD3+, CD4-CD8+, and CD4+CD8+ T lymphocytes in the thymus and CD19+ B lymphocytes in the pancreas and spleen, the ALX group showed an increase in CD4-CD8+ and CD19+ only in the thymus. Basal levels of splenic interleukin- (IL-) 1ß and pancreatic IL-6 in the STZ group were decreased. Both diabetic groups showed atrophy of the thymic medulla and degeneration of pancreatic islets of Langerhans composed of inflammatory infiltration and hyperemia with vasodilation. ALX-treated mice showed a decrease in reticuloendothelial cells, enhanced lymphocyte/thymocyte cell death, and increased number of Hassall's corpuscles. Reduced in vitro activation of splenic lymphocytes was found in the STZ-treated group. Furthermore, mice immunized with ovalbumin (OVA) showed a more intense antigen-specific paw edema response in the STZ-treated group, while production of anti-OVA IgG1 antibodies was similar in both groups. Thereby, important changes in immune cell parameters in vivo and in vitro were found at an early stage of T1D in the STZ-treated group, whereas alterations in the ALX-treated group were mostly found in the chronic phase of T1D, including increased mortality rates. These findings suggest that the effects of ALX and STZ influenced, at different times, lymphoid organs and their cell populations.

Multilocus phylogeny and historical biogeography of Hypostomus shed light on the processes of fish diversification in La Plata Basin.

Distribution history of the widespread Neotropical genus Hypostomus was studied to shed light on the processes that shaped species diversity. We inferred a calibrated phylogeny, ancestral habitat preference, ancestral areas distribution, and the history of dispersal and vicariance events of this genus. The phylogenetic and distribution analyses indicate that Hypostomus species inhabiting La Plata Basin do not form a monophyletic clade, suggesting that several unrelated ancestral species colonized this basin in the Miocene. Dispersal to other rivers of La Plata Basin started about 8 Mya, followed by habitat shifts and an increased rate of cladogenesis. Amazonian Hypostomus species colonized La Plata Basin several times in the Middle Miocene, probably via the Upper Paraná and the Paraguay rivers that acted as dispersal corridors. During the Miocene, La Plata Basin experienced marine incursions, and geomorphological and climatic changes that reconfigured its drainage pattern, driving dispersal and diversification of Hypostomus. The Miocene marine incursion was a strong barrier and its retraction triggered Hypostomus dispersal, increased speciation rate and ecological diversification. The timing of hydrogeological changes in La Plata Basin coincides well with Hypostomus cladogenetic events, indicating that the history of this basin has acted on the diversification of its biota.

A database of freshwater fish species of the Amazon Basin.

The Amazon Basin is an unquestionable biodiversity hotspot, containing the highest freshwater biodiversity on earth and facing off a recent increase in anthropogenic threats. The current knowledge on the spatial distribution of the freshwater fish species is greatly deficient in this basin, preventing a comprehensive understanding of this hyper-diverse ecosystem as a whole. Filling this gap was the priority of a transnational collaborative project, i.e. the AmazonFish project - https://www.amazon-fish.com/. Relying on the outputs of this project, we provide the most complete fish species distribution records covering the whole Amazon drainage. The database, including 2,406 validated freshwater native fish species, 232,936 georeferenced records, results from an extensive survey of species distribution including 590 different sources (e.g. published articles, grey literature, online biodiversity databases and scientific collections from museums and universities worldwide) and field expeditions conducted during the project. This database, delivered at both georeferenced localities (21,500 localities) and sub-drainages grains (144 units), represents a highly valuable source of information for further studies on freshwater fish biodiversity, biogeography and conservation.

Annual indirect costs secondary to headache disability in Brazil.

BACKGROUND: Disability imposed by headache disorders constitutes an expressive economic burden, mostly from indirect costs due to absenteeism and presenteeism. OBJECTIVE: To estimate indirect costs from absenteeism and presenteeism due to headache disorders in Brazil. METHODS: In a secondary, descriptive analysis of two nationwide databases, we estimated indirect costs based on headache-related disability and socioeconomic data. RESULTS: In the first database analyzed (n = 3838), 12.8% of the employed population with headache disorders missed at least 1 day of work in the last 3 months (mean, 95% CI = 4.2 days [3.7-4.6]). Based on the prevalence of headache disorders, days lost due to headaches and income data, R$ 40.4 billion (Int$ 20 billion) are lost due to headache-related absenteeism annually. For presenteeism, 26.2% of the employed population with headache disorders worked at least 1 day in the last 3 months with 50% reduced productivity (mean, 95% CI = 5.7 days [5.3-6.2]), amounting to R$ 27.3 billion (Int$ 13.5 billion) of financial loss annually. In the other database analysed (n = 205,546), 14,052 (6.8%) respondents missed work/school or household duties in the past 2 weeks due to some disease. Of these, 4.7% attributed their days lost to headaches disorders in the economically active population, which ranked 4th as main cause of days lost due to disease, among 23 common diseases. CONCLUSIONS: The economic burden of headache disorders in Brazil, mostly due to migraine (55.4%), may cost up to R$ 67.6 billion (Int$ 33.5 billion) annually, and headache disorders represent a leading cause of absenteeism due to disease.

Migraine: a major debilitating chronic non-communicable disease in Brazil, evidence from two national surveys.

BACKGROUND: Even though migraine and other primary headache disorders are common and debilitating, major health surveys in Brazil have not included them. We repair this omission by combining data on non-communicable diseases (NCDs) in the Brazilian National Health Survey (PNS) 2013 with epidemiological data on migraine prevalence and severity in Brazil. The purpose is to rank migraine and its impact on public healthh among NCDs in order to support public-health policy toward better care for migraine in Brazil. METHODS: Data from PNS, a cross-sectional population-based study, were merged with estimates made by the Brazilian Headache Epidemiology Study (BHES) of migraine prevalence (numbers of people affected and of candidates for migraine preventative therapy) and migraine-attributed disability. RESULTS: Migraine ranked second in prevalence among the NCDs, and as the highest cause of disability among adults in Brazil. Probable migraine accounted for substantial additional disability. An estimated total of 5.5 million people in Brazil (or 9.5 million with probable migraine included) were in need of preventative therapy. CONCLUSION: On this evidence, migraine should be included in the next health surveys in Brazil. Public-health policy should recognize the burden of migraine expressed in public ill health, and promote health services offering better diagnosis and treatment.