Impact on the expression of IGF1R and RANKL and serum levels of IGF-1 and IGFBP-3 from the treatment of zoledronic acid compared to pamidronate in children with Osteogenesis Imperfecta

A osteogênese imperfeita (OI) é uma doença genética caracterizada por alterações no colágeno do tipo I, que determinam um espectro amplo de alterações clínicas. Embora não haja tratamento específico, os medicamentos da classe bisfosfonatos são utilizados com o objetivo da melhora na qualidade óssea com redução dos eventos de fraturas e ganho na qualidade de vida. No Brasil, os protocolos atuais utilizam o pamidronato, bisfosfonato de segunda geração. O uso do ácido zoledrônico, bisfosfonato de terceira geração, apresenta segurança e efeitos similares, com a vantagem de reduzir o tempo de permanência hospitalar. O ligante do RANK (RANKL) é o principal atuante na diferenciação dos osteoclastos da qual também participa o IGF-1 mediante interação com seu receptor específico tipo 1 (IGF1R). Entretanto, não existem estudos comparando o tratamento com bisfosfonatos no que diz respeito a seu impacto sobre o sistema IGF, o ligante do RANK e fatores determinantes do crescimento. Esse trabalho objetivou avaliar as expressões de RNAm de IGF1R e RANKL, e as concentrações séricas de IGF-1 e IGFBP-3 e marcadores ósseos, em pacientes com OI em uso de bisfosfonatos e comparar esses parâmetros em grupos de pacientes em uso de pamidronato com aqueles em uso de ácido zoledrônico. Foram estudados 21 pacientes com diagnóstico de OI em modelos transversal e longitudinal. As variáveis foram comparadas entre as formas leves e moderadas-graves da OI. Os participantes foram randomizados em dois grupos: grupo A em uso de pamidronato e o grupo B que houve a troca do pamidronato por ácido zoledrônico. Esses foram acompanhados de forma longitudinal para avaliar influência do pamidronato e do ácido zoledrônico em um e dois ciclos das medicações. No estudo transversal, em que todos os participantes estavam em uso de pamidronato, foi encontrado, sem diferença estatística, menor expressão de IGF1R e menores níveis de IGF-1, IGFBP-3 e osteocalcina e maior expressão de RANKL, na OI tipo III. Quando os indivíduos foram agrupados de acordo com a gravidade, a altura, as concentrações de fosfatase alcalina sérica e a densidade mineral óssea foram maiores no grupo com a forma leve. Embora não tenha encontrado diferença estatística, a expressão de RNAm de RANKL foi menor e a de IGF1R foi maior no grupo com forma leve da doença. Quando avaliados a influência de um ciclo de medicações diferentes, não houve diferenças significantes das variações das médias das variáveis entre os grupos de tratamento, embora ocorreu aumento da expressão de RNAm de IGF1R e RANKL mais evidente no grupo B. Na avaliação de dois ciclos das medicações houve diferença significativa das variações das médias das variáveis na análise de IGF1R, com aumento da expressão no grupo B e queda no grupo A. Em conclusão, os dados sugerem que ocorre aumento da expressão do IGF1R após dois ciclos do tratamento com ácido zoledrônico em crianças previamente tratadas com pamidronato. Ao passo que as expressões de RANKL, concentrações séricas de IGF-1 ou IGFBP-3 são normais e semelhantes tanto nos indivíduos em uso de pamidronato quanto nos em uso de ácido zoledrônico.Osteogenesis imperfecta (OI) is a genetic disease characterized by changes in type I collagen, which determine a broad spectrum of clinical changes. Although there is no specific treatment, bisphosphonate drugs are used to improve bone quality by reducing fracture events and improving quality of life. In Brazil, current protocols use pamidronate, second generation bisphosphonate. The use of zoledronic acid, third generation bisphosphonate, has safety and similar effects, with the advantage of reducing the hospitalization time. The RANK ligand (RANKL) is the main agent in the differentiation of osteoclasts in which IGF-1 also participates through interaction with its specific type 1 receptor (IGF1R). However, there are no studies comparing bisphosphonate treatment concerning their impact on the IGF system, the RANK ligand and growth-determining factors. This work aimed to evaluate the IGF1R and RANKL mRNA expressions, the serum concentrations of IGF-1 and IGFBP-3 and bone markers, in patients with OI using bisphosphonates and to compare these parameters in groups of patients using pamidronate with those in use of zoledronic acid. Twenty-one patients diagnosed with OI were studied in cross-sectional and longitudinal models. The variables were compared between mild and moderate-severe forms of OI. The participants were randomized into two groups: group A using pamidronate and group B that pamidronate was replaced by zoledronic acid. These were followed up longitudinally to assess the influence of pamidronate and zoledronic acid in one and two cycles of medications. In the cross-sectional study, in which all participants were using pamidronate, without statistical difference, less expression of IGF1R and lower levels of IGF-1, IGFBP-3 and osteocalcin were found and greater expression of RANKL, in OI type III. When individuals were grouped according to severity, height, serum alkaline phosphatase concentrations and bone mineral density were higher values in the group with the mild form. Although there was no statistical difference, the expression of RANKL mRNA was lower and that of IGF1R was higher in the group with mild form of the disease. When assessing the influence of different medication cycle, there were no significant differences in the variations of the means of the variables between the treatment groups, although there was an increase in the expression of IGF1R and RANKL mRNA in group B. In the assessment of two medications cycles, there was a significant difference in the variations of the means of the variables in the IGF1R analysis, with an increase in expression in group B and a decrease in group A. In conclusion, the data suggest that there is an increase in the expression of IGF1R after two cycles of treatment with zoledronic acid in children previously treated with pamidronate. Whereas the expressions of RANKL, serum concentrations of IGF-1 or IGFBP-3 are normal and similar both in individuals using pamidronate and in those using zoledronic acid

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved

Delayed colorectal cancer care during covid-19 pandemic (decor-19). Global perspective from an international survey

Background The widespread nature of coronavirus disease 2019 (COVID-19) has been unprecedented. We sought to analyze its global impact with a survey on colorectal cancer (CRC) care during the pandemic. Methods The impact of COVID-19 on preoperative assessment, elective surgery, and postoperative management of CRC patients was explored by a 35-item survey, which was distributed worldwide to members of surgical societies with an interest in CRC care. Respondents were divided into two comparator groups: 1) ‘delay’ group: CRC care affected by the pandemic; 2) ‘no delay’ group: unaltered CRC practice. Results A total of 1,051 respondents from 84 countries completed the survey. No substantial differences in demographics were found between the ‘delay’ (745, 70.9%) and ‘no delay’ (306, 29.1%) groups. Suspension of multidisciplinary team meetings, staff members quarantined or relocated to COVID-19 units, units fully dedicated to COVID-19 care, personal protective equipment not readily available were factors significantly associated to delays in endoscopy, radiology, surgery, histopathology and prolonged chemoradiation therapy-to-surgery intervals. In the ‘delay’ group, 48.9% of respondents reported a change in the initial surgical plan and 26.3% reported a shift from elective to urgent operations. Recovery of CRC care was associated with the status of the outbreak. Practicing in COVID-free units, no change in operative slots and staff members not relocated to COVID-19 units were statistically associated with unaltered CRC care in the ‘no delay’ group, while the geographical distribution was not. Conclusions Global changes in diagnostic and therapeutic CRC practices were evident. Changes were associated with differences in health-care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical factors. Strategic planning is required to optimize CRC care