RESUMO

PURPOSE: This systematic review aimed to determine the effects of maternal exposure to bisphosphonates (BPs) during pregnancy on neonatal outcomes. It aimed to disclosfe the impact of BPs on neonates and identify aspects that require further investigation. METHODS: A comprehensive search of PubMed, Science Direct, LILACS, EMBASE, and Web of Science was conducted until August 2022, with no time restrictions. The selection criteria included studies published in English that evaluated pregnant women who were exposed to BPs. RESULTS: From an initial pool of 2169 studies, 13 met the inclusion criteria for this systematic review. These studies collectively included 106 women (108 pregnancies) who were exposed to BPs either before orduring pregnancy. A summary of the key characteristics of the selected studies and the risk of bias assessment are provided. Exposure to BPs occurs at various stages of pregnancy, with different indications for BP treatment. The most frequently reported neonatal outcomes were spontaneous abortion, congenital malformations, hypocalcemia, preterm birth, and low birth weight. CONCLUSION: Although previous reports have linked BPs before or during pregnancy with adverse neonatal outcomes, these associations should be interpreted with caution. Given the complexity of these findings, further research is necessary to provide more definitive insights to guide clinical decisions regarding the use of BPs in pregnant women.

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Queloides e cicatrizes hipertróficas são lesões formadas a partir da resposta fibroproliferativa anormal ao processo de cicatrização de feridas, gerando uma proliferação excessiva do colágeno nas lesões. Geralmente, predominam em pacientes do sexo feminino e em indivíduos com tons de pele mais escuros. A abordagem terapêutica dessas cicatrizes pode ser indicada de acordo com alguns critérios, como déficit funcional, tamanho e tempo de cicatrização da ferida. Nesse sentido, o presente estudo objetivou realizar uma revisão descritiva da literatura, buscando as evidências de tratamento dos últimos cinco anos neste tema. A revisão foi realizada com base no guideline PRISMA, utilizando as bases de dados PubMed, LILACS, Cochrane Library, SCOPUS, Web of Science e Grey Literature, entre os anos de 2018 e 2022. Foram encontrados 740 artigos, dos quais 16 ensaios clínicos randomizados foram selecionados. Foi evidenciado que manejo do queloide apresenta abordagem multimodal, não havendo um padrão-ouro de tratamento, com taxa de recorrência baixa. Além disso, a terapia combinada de diferentes agentes pareceu ser superior ao uso isolado de métodos terapêuticos no tratamento dessas lesões.

Keloids and hypertrophic scars are lesions formed from the abnormal fibroproliferative response to the wound healing process, generating excessive collagen proliferation in the lesions. They generally predominate in female patients and individuals with darker skin tones. The therapeutic approach to these scars can be indicated according to criteria such as functional deficit, size, and wound healing time. In this sense, the present study aimed to conduct a descriptive review of the literature, seeking evidence of treatment over the last five years. The review was carried out based on the PRISMA guideline, using the databases PubMed, LILACS, Cochrane Library, SCOPUS, Web of Science, and Grey Literature between 2018 and 2022. Seven hundred forty articles were found, of which 16 randomized clinical trials were selected. It was demonstrated that keloid management presents a multimodal approach, with no gold standard of treatment with a low recurrence rate. Furthermore, combined therapy with different agents appeared superior to the isolated therapeutic methods in treating these injuries.

RESUMO

Liposuction is among the most performed plastic surgery procedures in Brazil. According to data from the International Society of Aesthetic Plastic Surgery (ISAPS), 231,604 liposuctions were performed, 15.5% of all aesthetic procedures in the country in 2019. Adopting liposuction as a single procedure or adjunct to other cosmetic procedures stimulated its technical evolution from simple fat aspiration to more sophisticated body shaping. Thus, this review aimed to systematically evaluate the published data regarding the complications found in liposuction. A review was conducted using PubMed, SciELO, LILACS, Cochrane Library, SCOPUS, Web of Science, and gray literature databases, published between 2016 and 2021, using the descriptors "Liposuction" and "Complications." A total of 187 articles were found in the searched databases, of which 16 were selected according to the outcome "to assess safety through the prevalence of complications in liposuction as a single procedure and associated with other procedures such as abdominoplasty and fat grafting." We found a mortality rate ranging from 0 to 0.06 among all procedures and a predominance of venous thromboembolism, hematoma, seroma, and hyperpigmentation concerning all complications, being more common when liposuction is associated with other procedures. Therefore, through this review, it was possible to verify that liposuction as a single procedure has lower complication rates when compared to liposuction combined with other procedures.

A lipoaspiração está entre os procedimentos da cirurgia plástica mais realizados no Brasil. Segundo dados da International Society of Aesthetic Plastic Surgery (ISAPS), foram totalizadas 231.604 lipoaspirações, 15,5% dentre todos os procedimentos estéticos realizados no país em 2019. A adoção da lipoaspiração como procedimento único ou coadjuvante a outros procedimentos cosméticos estimulou sua evolução técnica da simples aspiração de gordura para uma modelagem corporal mais sofisticada. Desse modo, esta revisão objetivou avaliar sistematicamente os dados publicados em relação às complicações encontradas na lipoaspiração. Foi realizada uma revisão utilizando os bancos de dados PubMed, SciELO, LILACS, Cochrane Library, SCOPUS, Web of Science e grey literature, publicados entre os anos de 2016 e 2021, através dos descritores "Liposuction" and "Complications". Foram encontrados 187 artigos nas bases de dados pesquisadas, dos quais 16 foram selecionados de acordo com o desfecho "avaliar a segurança através da prevalência de complicações na lipoaspiração como procedimento único e a associada a outros procedimentos como abdominoplastia e lipoenxertia". Encontramos uma taxa de mortalidade que varia de 0 a 0,06 dentre todos os procedimentos e um predomínio de tromboembolismo venoso, hematoma, seroma e hiperpigmentação em relação a todas as complicações, sendo mais encontradas quando a lipoaspiração é associada a outros procedimentos. Logo, por meio desta revisão foi possível constatar que a lipoaspiração como procedimento único apresenta menores taxas de complicações quando comparada à lipoaspiração combinada com outros procedimentos.

RESUMO

Objective Intracranial aneurysms (AIs) are acquired vascular abnormalities that cause sacculations in the arterial wall and are present in ~2 to 5% of the population. Among the treatment options are endovascular interventions with the use of flow-redirecting stents. In the present study, we analyzed the flow re-direction endoluminal device (FRED). Methods The present study aims to describe the results obtained from treatment with FRED in a series of patients affected by aneurysms in intracranial segments of the internal carotid artery. This is a cross-sectional, epidemiological, and observational study, whose data were obtained from the medical records of 81 patients from July 2018 to July 2019. Results One hundred and three internal carotid artery aneurysms were observed in 81 patients, with a prevalence of women (91.35%), small (< 10 mm) (89.33%), and located at the C6 level (73.78%) of the internal carotid artery. Of the 81 patients, 16 had multiple aneurysms in the same artery. One hundred and three FRED stents were used in the treatment. These patients underwent angiography 6 months after the surgery, using the O'Kelly-Marotta classification (OKM) to assess the effectiveness of the device, and it was observed that: in 91 of the 103 procedures (88.34%), the FRED was fully open and well positioned, thus restoring the arterial flow and leading to a statistically significant result. In addition, a low complication rate (4.85%) was found, with ischemic stroke being the main complication (1.94%). Conclusion This device can be an effective option in the treatment of internal carotid aneurysms since the aneurysm occlusion rate is excellent with a low rate of complications.

Objetivo Aneurismas intracranianos (AIs) são anormalidades vasculares adquiridas, presentes em aproximadamente 2 a 5% da população, que causam saculações na parede arterial. Entre as opções de tratamento, estão as intervenções endovasculares com uso de stents de redirecionamento de fluxo. Neste estudo, analisamos o dispositivo de redirecionamento de fluxo endoluminal (FRED, na sigla em inglês). Métodos Este estudo tem como objetivo descrever os resultados obtidos no tratamento com FRED em uma série de pacientes acometidos por aneurismas em segmentos intracranianos da artéria carótida interna. Trata-se de um estudo transversal, epidemiológico e observacional, cujos dados foram obtidos dos prontuários de 81 pacientes no período de julho de 2018 a julho de 2019. Resultados Foram observados 103 aneurismas da artéria carótida interna em 81 pacientes, com a prevalência de mulheres (91,35%), aneurismas de pequeno porte (< 10 mm) (89,33%) e localizados no nível C6 (73,78%) da artéria carótida interna. Dos 81 pacientes, 16 apresentaram múltiplos aneurismas na mesma artéria. Cento e três stents FRED foram utilizados no tratamento. Esses pacientes foram submetidos à angiografia 6 meses após a cirurgia, e utilizando a classificação de O'Kelly-Marotta (OKM) para avaliar a eficácia do dispositivo, observou-se que em 91 dos 103 procedimentos (88,34%), o FRED estava totalmente aberto e bem-posicionado, levando assim à restauração do fluxo arterial e a um resultado estatisticamente significante. Além disso, foi encontrado baixo índice de complicações (4,85%), sendo o acidente vascular cerebral isquêmico a principal complicação (1,94%). Conclusão Este dispositivo pode ser uma opção eficaz no tratamento dos aneurismas carotídeos internos, visto que a taxa de oclusão do aneurisma é excelente com baixa taxa de complicações.

RESUMO

Objective Intracranial aneurysms (IAs) are present in 2 to 5% of the population. Several treatments have been used, including endovascular options such as flow diverter devices (FDDs). The present study retrospectively analyzed the effectiveness of three FDDs in the treatment of 291 aneurysms in the internal carotid artery. The devices analyzed were the flow-redirection endoluminal device (FRED), the SILK Embolization Device and the PIPELINE Embolization Device (PED). Method This is a cross-sectional study which evaluates the outcome of control arteriography. The O'Kelly-Marotta (OKM) Scale was used to assess the degree of filling and flow stasis in the aneurysm 12 months after surgery. Results Conjoining the result of the three devices, most aneurysms (87.9%) were from the classification C-D, that is, they presented complete or almost complete aneurysmal occlusion. However, 6.6% did not obtain aneurysm occlusion, so they were classified as belonging to group A. In group B, a subocclusion was presented in 5.5%. In addition, by analyzing individually the result of each device, there was a bigger proportion of those classified in the group A among those who used SILK and in the group C-D among those who used FRED. Regarding complications, 10 cases were found, corresponding to 4.23% of all 236 patients. Therefore, four of these patients had complications when treated with PED; this proportion is higher than expected concerning the other groups. Conclusion The three devices are safe choices. Particularly, the FRED was found to be the most effective in treating internal carotid artery aneurysms.

Objetivo Aneurismas intracranianos (AIs) estão presentes em 2 a 5% da população. Vários tratamentos têm sido utilizados, incluindo opções endovasculares, como redirecionadores de fluxo (RFs). O presente estudo analisou retrospectivamente a eficácia de três dispositivos: dispositivo endoluminal de redirecionamento de fluxo (FRED, na sigla em inglês), dispositivo de embolização SILK e dispositivo de embolização pipeline (PED, na sigla em inglês), no tratamento de 291 aneurismas da artéria carótida interna. Método Trata-se de um estudo transversal, avaliando o desfecho quanto ao grau de enchimento e a estase de fluxo no aneurisma com arteriografia de controle após 12 meses da cirurgia usando a Escala O'Kelly-Marotta (OKM). Resultados Combinando o resultado dos três dispositivos, mais aneurismas (87,9%) eram do grupo D ou C, ou seja, apresentaram oclusão aneurismática completa ou quase completa; 5,5% apresentaram suboclusão, classificação B, e 6,6% não obtiveram oclusão do aneurisma, sendo da classificação A. Além disso, ao analisar individualmente o resultado de cada aparelho, houve maior proporção daqueles classificados no grupo A entre os que usaram SILK, e C-D entre os que usaram o FRED. Quanto às complicações, foram encontrados 10 casos, ou seja, 4,23% de todos os 236 pacientes, 4 destes pacientes tiveram complicações quando tratados com PED, sendo essa proporção maior do que o esperado em relação aos demais grupos. Conclusão Os três dispositivos são escolhas seguras, sendo o FRED o mais eficaz no tratamento de aneurismas de artéria carótida interna.

RESUMO

Leprosy is a chronic granulomatous disease that remains a serious public health problem in developing countries. According to the Madrid classification, leprosy presents in four clinical forms: two immunologically unstable forms (indeterminate and borderline) and two stable polar forms (tuberculoid and lepromatous). In leprosy, the relationship of cell death to clinical disease outcome remains unclear. Therefore, we investigated the extent of autophagy and different cell death mechanisms-such as apoptosis, necroptosis, and pyroptosis-in cutaneous lesions of patients with leprosy, as well as the role of these mechanisms in clinical disease progression. This cross-sectional analytical study included 30 patients with a confirmed diagnosis of leprosy, with 10 patients in each of the following groups: lepromatous (LL), tuberculoid (TT), and indeterminate (II) leprosy groups. For histopathological analysis, skin samples were subjected to haematoxylin-eosin staining and immunostaining for apoptotic and necroptotic markers. The results indicated that FasL expression was much higher in the LL form than in the TT and II forms. Similar results (higher expression in the LL form than in the TT and II forms) were observed for caspase 8, RIP1, and RIP3 expressions. MLKL, BAX, and caspase 3 expression levels were highest in the LL form, especially in globular foamy macrophages. Beclin-1 expression was highest in the TT form but was low in LL and II forms. Caspase 1 expression was highest in the LL form, followed by that in the TT and II forms. In conclusion, our study elucidates the role of different cell death mechanisms in the pathophysiology of various forms of leprosy and suggests measures that may be used to control the host response to infection and disease progression.

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The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012-2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance.

RESUMO

A doença celíaca representa uma enteropatia inflamatória crônica do intestino delgado, imunomediada, que ocorre como resposta a uma intolerância permanente ao glúten em pessoas geneticamente predispostas. Essa doença tem várias manifestações clínicas, pode ser assintomática, e em gestantes celíacas não diagnosticadas tem sido associada a risco aumentado de recém­nascidos com baixo peso ao nascer. Esta revisão tem como objetivo fornecer uma melhor compreensão dos mecanismos fisiopatológicos envolvidos na associação entre doença celíaca materna e baixo peso ao nascer por meio de uma revisão bibliográfica das publicações mais relevantes no tema nos últimos 20 anos.(AU)

Celiac disease is a chronic, immune­mediated, inflammatory disorder of the small intestine, that occurs in response to a permanent intolerance to gluten in genetically predisposed individuals. Its clinical manifestations may vary significantly, including an asymptomatic presentation. In undiagnosed celiac pregnant women, it has been associated with increased risk of low birth weight newborns. This review aims to provide a better understanding of the pathophysiological mechanisms involved in the association between maternal celiac disease and low birth weight through a literature review of the most relevant publications on the subject in the last 20 years.(AU)

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Toxoplasmosis is a zoonotic disease caused by the protozoan Toxoplasma gondii. The aim of the present study was to determine the occurrence and identify the risk factors associated with transmission of T. gondii to chickens raised in different systems (free-ranged and confined) to produce eggs or meat. The 810 animals were allocated in two experimental groups according to the production system purpose: 460 broiler chickens (Group 1) and 350 layer chickens (Group 2). In order to analyze the possible factors involved in T. gondii infection in the chickens, an epidemiological questionnaire was developed for all properties.The serological detection of anti-Toxoplasma gondii antibodies was performed by Indirect Immunofluorescence (IFAT) and by Enzime Linked Imunossorbent Assay (ELISA). Since the agreement index (kappa) between these two serological techniques was considered high, 21.2% of the 810 animals were considered reactive. In Group 1, 12.2% (56/460) were positive, while in the Group 2 the positivity rate was 33.1% (116/350). The production system may be influencing the seropositivity of the animals in both groups. However, only in Group 2 it was possible to notice a statistically significant relationship between the breeding system and the frequency of positive sera. This result indicates that, at least for laying hens, the production system is directly involved in T. gondii infection. The contact with cats in Group 1 did not influence the distribution of seroreactive animals, but in Group 2 a significant relationship was observed. The occurrence of anti-T. gondii antibodies was high in both groups (broiler and posture chickens). Free-ranged chickens raised for egg production proved to be the most exposed group to the T. gondii infection. This can be related to the fact that these animals stay for longer periods in the farms, in direct contact with possibly contaminated soil by the presence of domestic cats.(AU)

A toxoplasmose é uma zoonose causada pelo protozoário Toxoplasma gondii. O objetivo deste estudo foi determinar a ocorrência e identificar os fatores de risco associados à transmissão de T. gondii para frangos criados em diferentes sistemas (caipira e confinado) para produzir ovos ou carne. Os 810 animais foram divididos em dois grupos experimentais de acordo com o propósito do sistema de produção: 460 frangos de corte (Grupo 1) e 350 galinhas poedeiras (Grupo 2). A fim de analisar os possíveis fatores envolvidos na infecção pelo T. gondii nas galinhas, um questionário epidemiológico foi respondido por todos os proprietários. A detecção sorológica de anticorpos anti-Toxoplasma gondii foi realizada pela técnica de imunofluorescência indireta (RIFI) e Enzime Linked Assay Imunossorbent (ELISA). Uma vez que o índice de concordância (kappa) entre estas duas técnicas sorológicas foi considerada alta, 21,2% dos 810 animais foram considerados reativos. No Grupo 1, 12,2% (56/460) foram positivos, enquanto no Grupo 2 a taxa de positividade foi de 33,1% (116/350). O sistema de produção pode estar influenciando a soropositividade dos animais em ambos os grupos. No entanto, apenas no Grupo 2, foi possível notar uma relação estatisticamente significativa entre o sistema de produção e da freqüência de soros positivos. Este resultado indica que, pelo menos para as galinhas poedeiras, o sistema de produção está diretamente envolvido na infecção pelo T. gondii. O contato com os gatos no Grupo 1 não influenciou a distribuição dos animais sororreagentes, mas no Grupo 2 uma relação estatisticamente significativa foi observada. A ocorrência de anticorpos anti-T. gondii foi alta nos dois grupos (frangos de corte e postura). Galinhas cairpiras criadas para produção de ovos provou ser o grupo mais exposto à infecção T. gondii. Isto pode estar relacionado ao fato de que estes animais ficam por períodos mais longos nas fazendas, em contato direto com o solo possivelmente contaminado pela presença de gatos domésticos.(AU)

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RESUMO

Toxoplasmosis is a zoonotic disease caused by the protozoan Toxoplasma gondii. The aim of the present study was to determine the occurrence and identify the risk factors associated with transmission of T. gondii to chickens raised in different systems (free-ranged and confined) to produce eggs or meat. The 810 animals were allocated in two experimental groups according to the production system purpose: 460 broiler chickens (Group 1) and 350 layer chickens (Group 2). In order to analyze the possible factors involved in T. gondii infection in the chickens, an epidemiological questionnaire was developed for all properties.The serological detection of anti-Toxoplasma gondii antibodies was performed by Indirect Immunofluorescence (IFAT) and by Enzime Linked Imunossorbent Assay (ELISA). Since the agreement index (kappa) between these two serological techniques was considered high, 21.2% of the 810 animals were considered reactive. In Group 1, 12.2% (56/460) were positive, while in the Group 2 the positivity rate was 33.1% (116/350). The production system may be influencing the seropositivity of the animals in both groups. However, only in Group 2 it was possible to notice a statistically significant relationship between the breeding system and the frequency of positive sera. This result indicates that, at least for laying hens, the production system is directly involved in T. gondii infection. The contact with cats in Group 1 did not influence the distribution of seroreactive animals, but in Group 2 a significant relationship was observed. The occurrence of anti-T. gondii antibodies was high in both groups (broiler and posture chickens). Free-ranged chickens raised for egg production proved to be the most exposed group to the T. gondii infection. This can be related to the fact that these animals stay for longer periods in the farms, in direct contact with possibly contaminated soil by the presence of domestic cats.

A toxoplasmose é uma zoonose causada pelo protozoário Toxoplasma gondii. O objetivo deste estudo foi determinar a ocorrência e identificar os fatores de risco associados à transmissão de T. gondii para frangos criados em diferentes sistemas (caipira e confinado) para produzir ovos ou carne. Os 810 animais foram divididos em dois grupos experimentais de acordo com o propósito do sistema de produção: 460 frangos de corte (Grupo 1) e 350 galinhas poedeiras (Grupo 2). A fim de analisar os possíveis fatores envolvidos na infecção pelo T. gondii nas galinhas, um questionário epidemiológico foi respondido por todos os proprietários. A detecção sorológica de anticorpos anti-Toxoplasma gondii foi realizada pela técnica de imunofluorescência indireta (RIFI) e Enzime Linked Assay Imunossorbent (ELISA). Uma vez que o índice de concordância (kappa) entre estas duas técnicas sorológicas foi considerada alta, 21,2% dos 810 animais foram considerados reativos. No Grupo 1, 12,2% (56/460) foram positivos, enquanto no Grupo 2 a taxa de positividade foi de 33,1% (116/350). O sistema de produção pode estar influenciando a soropositividade dos animais em ambos os grupos. No entanto, apenas no Grupo 2, foi possível notar uma relação estatisticamente significativa entre o sistema de produção e da freqüência de soros positivos. Este resultado indica que, pelo menos para as galinhas poedeiras, o sistema de produção está diretamente envolvido na infecção pelo T. gondii. O contato com os gatos no Grupo 1 não influenciou a distribuição dos animais sororreagentes, mas no Grupo 2 uma relação estatisticamente significativa foi observada. A ocorrência de anticorpos anti-T. gondii foi alta nos dois grupos (frangos de corte e postura). Galinhas cairpiras criadas para produção de ovos provou ser o grupo mais exposto à infecção T. gondii. Isto pode estar relacionado ao fato de que estes animais ficam por períodos mais longos nas fazendas, em contato direto com o solo possivelmente contaminado pela presença de gatos domésticos.

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The alternative synthesis of 12 1,2,4-oxadiazoles using ultrasound irradiation from trichloroacetoamidoxime and acyl chlorides is reported. Seven of them are novel compounds. The 3-trichloromethyl-5alkyl(aryl)-1,2,4-oxadiazoles have been synthesised in better yields and shorter reaction times compared to the conventional method. This protocol can be applicable for preparation of 1,2,4-oxadiazoles containing aryl or alkyl groups attached at their C-5 side-chain.

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RESUMO

This study aimed to verify the population size and to show possible allometric variations between individuals. A total of 167 individuals were observed, from witch 69 were males, 78 were females and 20 were immature. Parental care was observed during all the study. The females were always near their clutches that were laid on the walls of the cave. Six aggregations were observed. There was an average of 8,67 individuals per aggregation, and females were more common, representing 64,4% of the aggregated individuals. The operational sex ratio was 1:1,18. The species is trogloxen, leaving the cave regularly to feed in the nearest trees and rocky walls, and returning in the morning. A Principal Components Analysis (PCA) evidenced a sexual dimorphism in the sizes of the second leg and its femur, the males with average leg length of 123,47 mm and femur length of 38,39 mm and the females with average leg length of79,13 mm and femur length of 25,14 mm.

RESUMO

This study aimed to verify the population size and to show possible allometric variations between individuals. A total of 167 individuals were observed, from witch 69 were males, 78 were females and 20 were immature. Parental care was observed during all the study. The females were always near their clutches that were laid on the walls of the cave. Six aggregations were observed. There was an average of 8,67 individuals per aggregation, and females were more common, representing 64,4% of the aggregated individuals. The operational sex ratio was 1:1,18. The species is trogloxen, leaving the cave regularly to feed in the nearest trees and rocky walls, and returning in the morning. A Principal Components Analysis (PCA) evidenced a sexual dimorphism in the sizes of the second leg and its femur, the males with average leg length of 123,47 mm and femur length of 38,39 mm and the females with average leg length of79,13 mm and femur length of 25,14 mm.