Cranial bone regeneration with collagen type I and polyvinylpyrrolidone (Fibroquel®) combined with hyaluronic acid in Wistar rats: morphological study / Regeneración ósea craneal con colágeno tipo I y polivinilpirrolidona (Fibroquel®) combinado con ácido hialurónico en ratas Wistar: estudio morfológico

SUMMARY: The purpose of this study was to evaluate by morphological methods, if a mixture of Fibroquel® and hyaluronic acid implanted in an animal model of cranial bone injury could promote bone regeneration. 12 Wistar rats were divided in three groups, control group, bone injury without treatment and bone injury with treatment. After experimental period, bone samples were taken and stained with H & E, Masson trichrome, PAS-D, immunohistochemistry with anti-PCNA monoclonal antibody and applied a semiquantitative morphometric method. Treatment group showed extensive areas of collagen fibers in contact with normal bone tissue, areas of normal histology, PAS positive material and less cellular proliferation. We demonstrated for the first time that a mixture of Fibroquel® and hyaluronic acid implanted in an animal model of cranial bone injury promotes bone regeneration.

RESUMEN: El propósito de este estudio fue evaluar por métodos morfológicos, si una mezcla de Fibroquel® y ácido hialurónico implantado en un modelo animal de lesión del hueso craneal podría promover la regeneración ósea. Se dividieron 12 ratas Wistar en tres grupos, grupo control, lesión ósea sin tratamiento y lesión ósea con tratamiento. Después del período experimental, se tomaron muestras de hueso y se tiñeron con H & E, tricrómico de Masson, PAS-D, inmunohistoquímica con anticuerpo monoclonal anti-PCNA y se aplicó un método morfométrico semicuantitativo. El grupo de tratamiento mostró áreas extensas de fibras de colágeno en contacto con tejido óseo normal, áreas de histología normal, material PAS positivo y menor proliferación celular. Demostramos por primera vez que una mezcla de Fibroquel® y ácido hialurónico implantado en un modelo animal de lesión del hueso craneal promueve la regeneración ósea.

Cyclosporine A impairs bone repair in critical defects filled with different osteoconductive bone substitutes

Abstract The aim of this study was to assess the influence of cyclosporine administration on the repair of critical-sized calvaria defects (CSDs) in rat calvaria filled with diverse biomaterials. Sixty animals were divided into two groups: the control (CTR) group (saline solution) and the cyclosporine (CCP) group (cyclosporine, 10 mg/kg/day). These medications were administered daily by gavage, beginning 15 days before the surgical procedure and lasting until the day the animals were euthanized. A CSD (5 mm Ø) was made in the calvaria of each animal, which was allocated to one of 3 subgroups, according to the biomaterial used to fill the defect: coagulum (COA), deproteinized bovine bone (DBB), or biphasic calcium phosphate ceramics of hydroxyapatite and β-phosphate tricalcium (HA/TCP). Euthanasia of the animals was performed 15 and 60 days after the surgical procedure (n = 5 animals/period/subgroup). Bone repair (formation) assessment was performed through microtomography and histometry, while the analyses of the expression of the BMP2, Osteocalcin, and TGFβ1 proteins were performed using immunohistochemistry. The CSDs not filled with biomaterials demonstrated lower bone formation in the CCP group. At 15 days, less bone formation was observed in the CSDs filled with DBB, a smaller volume of mineralized tissue was observed in the CSDs filled with HA/TCP, and the expression levels of BMP2 and osteocalcin were lower in the CCP group compared to the CTR group. The use of cyclosporine impaired bone repair in CSD, and this effect can be partially explained by the suppression of BMP2 and osteocalcin expression.

Cyclosporine A impairs bone repair in critical defects filled with different osteoconductive bone substitutes

Abstract The aim of this study was to assess the influence of cyclosporine administration on the repair of critical-sized calvaria defects (CSDs) in rat calvaria filled with diverse biomaterials. Sixty animals were divided into two groups: the control (CTR) group (saline solution) and the cyclosporine (CCP) group (cyclosporine, 10 mg/kg/day). These medications were administered daily by gavage, beginning 15 days before the surgical procedure and lasting until the day the animals were euthanized. A CSD (5 mm Ø) was made in the calvaria of each animal, which was allocated to one of 3 subgroups, according to the biomaterial used to fill the defect: coagulum (COA), deproteinized bovine bone (DBB), or biphasic calcium phosphate ceramics of hydroxyapatite and β-phosphate tricalcium (HA/TCP). Euthanasia of the animals was performed 15 and 60 days after the surgical procedure (n = 5 animals/period/subgroup). Bone repair (formation) assessment was performed through microtomography and histometry, while the analyses of the expression of the BMP2, Osteocalcin, and TGFβ1 proteins were performed using immunohistochemistry. The CSDs not filled with biomaterials demonstrated lower bone formation in the CCP group. At 15 days, less bone formation was observed in the CSDs filled with DBB, a smaller volume of mineralized tissue was observed in the CSDs filled with HA/TCP, and the expression levels of BMP2 and osteocalcin were lower in the CCP group compared to the CTR group. The use of cyclosporine impaired bone repair in CSD, and this effect can be partially explained by the suppression of BMP2 and osteocalcin expression.

Local effect of simvastatin combined with different osteoconductive biomaterials and collagen sponge on new bone formation in critical defects in rat calvaria

Abstract Purpose To evaluate the local effect of simvastatin (SVT) combined with deproteinized bovine bone (DBB) with hydroxyapatite/β-tricalcium phosphate biphasic ceramics (HA/TCP) and with collagen sponge (CS) on bone repair in critical size defects (CSDs) in rat calvaria. Methods Forty-two 5-mm diameter CSDs were made bilaterally in the calvaria of 18 rats. The animals were allocated according to the type of biomaterial and associations used to fill the CSD. After 8 weeks, the animals were euthanized, and their calvaria were evaluated for repaired tissue composition using histologic and histometric analyses. Results In the histometric analysis, the use of SVT showed to increase bone formation in the CSDs when combined with all the bone substitutes tested in this study (p<0.05). Greater bone formation was observed in the groups with SVT compared to the groups without SVT. Conclusions The use of SVT without the need for a vehicle and combined with a commercially available biomaterial may be a cheaper way to potentiate the formation of bone tissue without the need to produce new biomaterials. Therefore, SVT combined with DBB induced significantly greater new bone formation than did the other treatments.

Short-term use of resveratrol in alloplastic graft material applied with calvarial bone defects in rats

Abstract Purpose: The effects of resveratrol administration on calvarial bone defects with alloplastic graft material was investigated for osteoinductive reaction and bone development in rats. Methods: Healthy male rats were randomly divided into 3 groups consisting of 10 rats. Groups were as follows: control (defect) group, defect + graft group, and defect + graft + resveratrol group. A calvarial bone defect was created in all groups, alloplastic bone grafts were applied to the defect in the 2nd and 3rd group, resveratrol (5 mg/kg/day) was added to the drinking water of the animals following graft application for 28 days in the 3rd group. Results: Increase in osteoclasts and necrotic changes were observed histopathologically in the control group. In the 2nd group, reduction of inflammation, congestion of blood vessels, increased osteblastic activity, osteoinductive effect, progression of osteocyte development and increased collagen fibers in connective tissue were observed. In the 3rd group, osteoblasts seemed to secrete bone matrix and accelerate osteoinductive effect with increased osteopregenitor activity and positive osteopontin and osteonectin expressions. Conclusion: Resveratrol treatment was thought to be an alternative and supportive drug for implant application by inducing new bone formation in the calvaral defect region as a result of short-term treatment.

Ganoderma lucidum, a promising agent possessing antioxidant and anti-inflammatory effects for treating calvarial defects with graft application in rats

Abstract Purpose: Ganoderma lucidum, a kind of mushroom used for its antioxidant, anti-inflammatory, and immunomodulatory activities, was investigated in the present study for its possible healing effect on calvarial defects with bone grafts. Methods: Wistar male rats (n = 30) were divided into 3 groups: 1) the control (defect) group (n = 10), 2) defect and graft group (n = 10), and 3) defect, graft, and G. lucidum treated group (n = 10). The G. lucidum was administered to the rats at 20 mL/kg per day via gastric lavage. Results: In the defect and graft group, osteonectin positive expression was observed in osteoblast and osteocyte cells at the periphery of the small bone trabeculae within the graft area. In the defect, graft, and G. lucidum treated group, osteonectin expression was positive in the osteoblast and osteocyte cells and positive osteonectin expression in new bone trabeculae. The expression of matrix metalloproteinase-9 (MMP-9) was positive in the inflammatory cells, fibroblast cells, and degenerated collagen fibril areas within the defect area. Conclusion: This study shows that, with its antioxidant and anti-inflammatory properties, G. Lucidum is an important factor in the treatment of calvarial bone defects.

The effect of graft application and allopurinol treatment on calvarial bone defect in rats

Abstract Purpose: To investigate the effects of allopurinol administration on osteoinductive reaction and bone development with graft material. Methods: Thirty-six Wistar albino rats were divided into 3 groups. In the control group, calvarial bone defect was only created without any treatment. In the Defect + Graft group, allograft treatment was performed by forming 8 mm calvarial bone defect. In the Defect + Graft + Allopurinol group, alloplastic bone graft was placed in the calvarial bone defect and then, allopurinol (50 mg/kg/day) treatment was intraperitoneally applied for 28 days. Results: Histopathological examination revealed inflammation, congestion in the vessels, and an increase in osteoclast cells in the defect area. We also observed that new osteocyte cells, increase in connective tissue fibers, and new bone trabeculae. Osteopontin expression was positive in osteoblast cells and lacunated osteocyte cells were located in the periphery of the new bone trabeculae. Osteopontin expression was also positive in osteoblasts and osteocytes cells of new bone trabeculae in the graft site. Conclusion: It has been shown that allopurinol treatment in rat calvaria defects may induce osteoblastic activity, matrix development, mature bone cell formation and new bone formation when used with autogenous grafts.

Effect of local application of alendronate and parathyroid hormone on craniofacial bone repair - a preliminary study

Abstract This study aimed to evaluate the effect of two methods of local application of alendronate and parathyroid hormone (PTH) on bone repair and the systemic implications. A critically sized defect (5 mm) was created in the cranial region of twenty-five male Wistar rats, and the bone removed was particulated, and grafted back to the defect with different treatments. The animals were randomly divided into five groups: A1- bone graft immersion in alendronate solution (3 mg/kg) for 5 minutes; P1- bone graft immersion in PTH solution (20 µg); A2- weekly local applications of alendronate 1 mg/kg; P2- weekly local applications of PTH (20 µg); C- no drugs were used. The animals were euthanized 60 days after surgery. Cranial bone blocks were removed for histological, histomorphometric, and immunohistochemical analyses. MMP-2 and MMP-9 were used for immunolabeling. The kidneys, liver, and brain were also removed from all the rats for histological analysis. The data were submitted for statistical analysis with a level of significance of 0.05 (One-way ANOVA). The group C and group P2 presented a higher quantity of viable bone particles than the remaining groups. Groups A1, A2, and P1 presented with fewer viable bone particles than the control group, with a predominance of non-mineralized connective tissue. The histomorphometric analysis revealed no differences in relative bone area or MMP-2 or MMP-9 immunolabeling between the groups (p>0.05). Group A2 showed presence of fat in the liver consistent with hepatic steatosis. Changes in brain tissue were observed in groups A1 and P1.

Resumo Este estudo visou avaliar o efeito de dois métodos de aplicação local de alendronato e de paratormônio (PTH) no reparo ósseo e avaliar as implicações sistêmicas. Um defeito de tamanho crítico (5 mm) foi criado na calota craniana de vinte e cinco ratos Wistar machos, e o osso removido foi particulado e enxertado de volta no defeito com diferentes tratamentos. Os animais foram divididos aleatoriamente em cinco grupos: A1: imersão do enxerto ósseo em solução de alendronato (3 mg/kg) durante 5 min; P1- imersão do osso em solução de PTH (20 μg); A2- aplicações locais semanais de alendronato 1 mg/kg; P2- aplicações locais semanais de PTH 20 μg; C: não foram utilizados medicamentos. Os animais foram eutanasiados 60 dias após a cirurgia. Foram removidos os blocos ósseos envolvendo a região do defeito para realização das análises histológica, histomorfométrica e imuno-histoquímica. MMP2 e MMP9 foram as imunomarcações utilizadas. Os rins, fígado e cérebro também foram removidos de todos os ratos para análise histológica. Os dados foram submetidos à análise estatística com um nível de significância de 0,05 (One-way ANOVA). A análise histológica revelou que o grupo C e o grupo P2 apresentaram maior quantidade de partículas ósseas viáveis do que as apresentadas pelos demais grupos. Os grupos A1, A2 e P1 apresentaram menos partículas ósseas viáveis em comparação com o grupo controle com predominância de tecido conjuntivo não mineralizado. A análise histomorfométrica não revelou diferenças entres os grupos na área óssea relativa ou em MMP2 e MMP9 (p>0,05). O grupo A2 mostrou presença de gordura no fígado consistente com esteatose hepática. Alterações no tecido cerebral foram observadas nos grupos A1 e P1.

Demineralized bone matrix and calcium-phosphate cement in bone regeneration in rats

Abstract Purpose: To compare bone regeneration in critical-sized defects in rat calvarium using demineralized bone matrix and calcium phosphate cement. Methods: Thirty Wistar rats were divided into 3 groups of 10 animals each. Two defects of 5-mm were made in the parietal bones of each animal. Group I had calcium phosphate cement placed in the experimental defect, Group II had filled with demineralized bone matrix and Group III had with the combination of the matrix and cement in equal parts. All animals had one defect left unfilled to serve as controls. Five animals in each group were sacrificed at 4 and 8 weeks. Histomorphometric analysis was used to quantify the amount of new bone within the defects. Results: The results showed that demineralized bone matrix-treated defects had significantly more new bone at 4 weeks compared to calcium phosphate cement-treated defects (p=0.03) and also had significantly more new bone at 8 weeks compared to unfilled defects (p=0.04). Conclusions: The demineralized bone matrix was superior to calcium phosphate cement in bone regeneration. It seems that calcium phosphate cement acted by inhibiting the osteogenesis when associated with a demineralized bone matrix and this combination should not be recommended.

Bone repair access of BoneCeramic™ in 5-mm defects: study on rat calvaria

Abstract Objective: The aim of this study was to evaluate the osteoconductive potential of BoneCeramic™ on bone healing in rat calvaria 5-mm defects. Material and Methods: A 5-mm calvaria bone defect was induced in three groups and the defect was not filled with biomaterial [Clot Group (CG)], autogenous bone (AG), or Bone Ceramic Group (BCG). Animals were euthanized after 14 or 28 days and the bone tissue within the central area of the bone defect was evaluated. Results were compared using ANOVA and Tukey test (p<0.05). Immunohistochemistry was performed using primary antibodies against osteocalcin, RUNX-2, TRAP, VEGF proteins, and 3-dimensional images of the defects in μCT were obtained to calculate bone mineral density (BMD). Results: In BCG, the defect was completely filled with biomaterial and new bone formation, which was statistically superior to that in the GC group, at both time-points (p<0.001 for 14 days; p=0.002 for 28 days). TRAP protein showed weak, RUNX-2 showed a greater immunolabeling when compared with other groups, VEGF showed moderate immunostaining, while osteocalcin was present at all time-points analyzed. The μCT images showed filling defect by BCG (BMD= 1337 HU at 28 days). Conclusion: Therefore, the biomaterial tested was found to be favorable to fill bone defects for the reporting period analyzed.

To what extent does hyaluronic acid affect healing of xenografts? A histomorphometric study in a rabbit model

ABSTRACT Among the many graft materials that have been used for the treatment of bone defects in oral and maxillofacial regions is xenograft. To improve osteoconductive effects of xenografts, they have been combined with various biocompatible materials, such as hyaluronic acid and bone morphogenetic protein. Objective: To determine bone-healing capacity of high molecular weight hyaluronic acid (HA) combined with xenograft in rabbit calvarial bone defects. Material and methods: Ten adult male New Zealand rabbits (mean weight 3 kg) were included in the study. Three 6-mm-diameter bicortical cranial defects were created on calvarial bone of all rabbits. These defects were filled as follows: a) xenograft; b) HA+xenograft; c) autograft. One month after the first operation, rabbits were sacrificed. Specimens were evaluated histomorphometrically. Results: Considering multiple comparisons, differences regarding new bone were statistically significant between all groups (p<0.05). The volume of residual graft was significantly decreased in HA group compared to xenograft group (p=0.035). Marrow space, trabecular thickness (TbTh), trabecular width (TbWi), trabecular separation (TbSp), and number of node: number of terminus (NNd:NTm) in the autograft group were significantly better than xenograft and HA groups (p<0.05). However, regarding marrow space, TbTh, TbWi, TbSp, and NNd:NTm values, xenograft and HA groups showed similar results and the difference were not significant (p>0.05). Conclusion: These results support that high molecular weight hyaluronic acid could contribute to the healing of xenograft by improving the percentage of new bone formation and reducing the percentage of residual graft. However, HA did not significantly affect the quality of newly formed bone assessed by microarchitectural parameters.

Simvastatin and biphasic calcium phosphate affects bone formation in critical-sized rat calvarial defects

ABSTRACT PURPOSE: To investigate the effects of locally applied simvastatin plus biphasic calcium phosphate (BoneCeramic(r)) or collagen sponge on bone formation in critical-sized bone defects. METHODS: Thirty defects of 5mm in diameter were created bilaterally with a trephine bur in the calvariae of fifteen Wistar rats. The defects were divided into five groups: group 1 - control, no treatment; group 2 (BoneCeramic(r)); group 3 (BoneCeramic(r) + 0.1mg simvastatin); group 4 (collagen sponge); and group 5 (collagen sponge + 0.1mg simvastatin). After eight weeks the animals were euthanized and their calvariae were histologically processed. Hematoxylin and eosin-stained sections were subjected to histological and histomorphometrical analyses. The area of newly formed bone was calculated and compared between groups. RESULTS: The greater amount of a bone-like tissue was formed around the carrier in group 3 (BoneCeramic(r) + 0.1mg simvastatin) followed by group 2 (BoneCeramic(r)), and almost no bone was formed in the other groups. Group 3 was significantly different compared to group 2, and both groups were significantly different compared to the other groups. CONCLUSION: Simvastatin combined with BoneCeramic(r) induced significantly greater amounts of newly formed bone and has great potential for the healing of bone defects.

Effect of collagen sponge and fibrin glue on bone repair

ABSTRACT The ability of hemostatic agents to promote bone repair has been investigated using in vitro and in vivo models but, up to now, the results are inconclusive. Objective In this context, the aim of this study was to compare the potential of bone repair of collagen sponge with fibrin glue in a rat calvarial defect model. Material and Methods Defects of 5 mm in diameter were created in rat calvariae and treated with either collagen sponge or fibrin glue; untreated defects were used as control. At 4 and 8 weeks, histological analysis and micro-CT-based histomorphometry were carried out and data were compared by two-way ANOVA followed by Student-Newman-Keuls test when appropriated (p≤0.05). Results Three-dimensional reconstructions showed increased bone formation in defects treated with either collagen sponge or fibrin glue compared with untreated defects, which was confirmed by the histological analysis. Morphometric parameters indicated the progression of bone formation from 4 to 8 weeks. Additionally, fibrin glue displayed slightly higher bone formation rate when compared with collagen sponge. Conclusion Our results have shown the benefits of using collagen sponge and fibrin glue to promote new bone formation in rat calvarial bone defects, the latter being discreetly more advantageous.

Tridax procumbens flavonoids promote osteoblast differentiation and bone formation

BACKGROUND: Tridaxprocumbens flavonoids (TPFs) are well known for their medicinal properties among local natives. Besides traditionally used for dropsy, anemia, arthritis, gout, asthma, ulcer, piles, and urinary problems, it is also used in treating gastric problems, body pain, and rheumatic pains of joints. TPFs have been reported to increase osteogenic functioning in mesenchymal stem cells. Our previous study showed that TPFs were significantly suppressed the RANKL-induced differentiation of osteoclasts and bone resorption. However, the effects of TPFs to promote osteoblasts differentiation and bone formation remain unclear. TPFs were isolated from Tridax procumbens and investigated for their effects on osteoblasts differentiation and bone formation by using primary mouse calvarial osteoblasts. RESULTS: TPFs promoted osteoblast differentiation in a dose-dependent manner demonstrated by up-regulation of alkaline phosphatase and osteocalcin. TPFs also upregulated osteoblast differentiation related genes, including osteocalcin, osterix, and Runx2 in primary osteoblasts. TPFs treated primary osteoblast cells showed significant upregulation of bone morphogenetic proteins (BMPs) including Bmp-2, Bmp-4, and Bmp-7. Addition of noggin, a BMP specific-antagonist, inhibited TPFs induced upregulation of the osteocalcin, osterix, and Runx2. CONCLUSION: Our findings point towards the induction of osteoblast differentiation by TPFs and suggested that TPFs could be a potential anabolic agent to treat patients with bone loss-associated diseases such as osteoporosis.

Use of a New Fibrin Sealant and Laser Irradiation in the Repair of Skull Defects in Rats

This study evaluated the osteogenic capacity of a new fibrin sealant (FS) combined with bone graft and laser irradiation in the bone repair. Defects were created in the skull of 30 rats and filled with autogenous graft and FS derived from snake venom. Immediately after implantation, low-power laser was applied on the surgical site. The animals were divided in: control group with autogenous graft (G1), autogenous graft and laser 5 J/cm2 (G2), autogenous graft and laser 7 J/cm2 (G3), autogenous graft and FS (G4), autogenous graft, FS and laser 5 J/cm2 (G5), autogenous graft, FS and laser 7 J/cm2 (G6). The animals were sacrificed 6 weeks after implant. Results showed absence of inflammatory infiltrate in the bone defect. New bone formation occurred in all groups, but it was most intense in G6. Thus, the FS and laser 7 J/cm2 showed osteoconductive capacity and can be an interesting resource to be applied in surgery of bone reconstruction.

Este estudo avaliou a capacidade osteogênica de um novo selante de fibrina (FS) associado com enxerto ósseo e irradiação laser no reparo ósseo. Defeitos foram criados no crânio de 30 ratos e preenchidos com enxerto autógeno e FS derivado do veneno de cobra. Imediatamente após implantação, foi aplicado laser de baixa potência na área cirúrgica. Os animais foram divididos em grupo controle com autógeno (G1), autógeno e laser 5 J/cm2 (G2), autógeno e laser 7J/cm2 (G3), autógeno e FS (G4), autógeno, FS e laser 5J/cm2 (G5), autógeno, FS e laser 7J/cm2 (G6). Os animais foram sacrificados 6 semanas após implante. Resultados mostraram ausência de infiltrado inflamatório no defeito ósseo. Neoformação óssea ocorreu em todos os grupos, entretanto, foi mais intenso em G6. Desta maneira, o FS e laser 7J/cm2 mostraram capacidade osteocondutiva e podem ser um interessante recurso a ser aplicado nas cirurgias de reconstrução óssea.

Influence of the association between simvastatin and demineralized bovine bone matrix on bone repair in rats

Simvastatin, a drug used to lower blood cholesterol, has been reported to have an anabolic effect on bone. The purpose of this study was to evaluate the influence of simvastatin and demineralized bovine bone matrix (DBBM) on the repair of rat calvarial defects. Defects of 5 mm were created in 64 rats, divided into four groups: no local treatment (control); treatment with DBBM (DBBM); treatment with a combination of simvastatin solution (2.2 mg/50 μl) and DBBM (DBBMSIM-1); and treatment with simvastatin solution (0.5 mg/50 μl) and DBBM (DBBMSIM-2). Animals were sacrificed on postoperative day 30 or 60, after which the calvariae were X-rayed and prepared for histomorphometric evaluation. The data were submitted to statistical analysis (p < 0.05). X-rays revealed that, on postoperative day 30, animals treated with a lower dose of simvastatin presented the lowest bone density, whereas on postoperative day 60 the use of simvastatin, regardless of the dose, resulted in lower density than that observed in control and DBBM group samples. Histomorphometric analysis revealed that, on postoperative day 30, both DBBM and DBBMSIM-1 had a negative impact on bone formation. On postoperative day 60, none of the combinations tested impaired bone repair. These results showed that the association between DBBM and simvastatin had a negative impact on bone repair.

Inhibitory effect of (-)-epigallocatechin gallate on titanium particle-induced TNF-alpha release and in vivo osteolysis

Tumor necrosis factor-alpha (TNF-alpha) and inflammatory cytokines released from activated macrophages in response to particulate debris greatly impact periprosthetic bone loss and consequent implant failure. In the present study, we found that a major polyphenolic component of green tea, (-)-epigallocatechin gallate (EGCG), inhibited Ti particle-induced TNF-alpha release in macrophages in vitro and calvarial osteolysis in vivo. The Ti stimulation of macrophages released TNF-alpha in a dose- and time-dependent manner, and EGCG substantially suppressed Ti particle-induced TNF-alpha release. Analysis of signaling pathway showed that EGCG inhibited the Ti-induced c-Jun N-terminus kinase (JNK) activation and inhibitory kappaB (IkappaB) degradation, and consequently the Ti-induced transcriptional activation of AP-1 and NF-kappaB. In a mouse calvarial osteolysis model, EGCG inhibited Ti particle-induced osteolysis in vivo by suppressing TNF-alpha expression and osteoclast formation. Therefore, EGCG may be a potential candidate compound for osteolysis prevention and treatment as well as aseptic loosening after total replacement arthroplasty.

McCune-albright syndrome and acromegaly: hormonal control with use of cabergoline and long-acting somatostatin - case report / Síndrome de McCune-albright associada à acromegalia: controle hormonal com cabergolina e somatostatina de longa duração - relato de caso

OBJECTIVES: The use of drug therapy based on cabergoline, octreotide and long-acting release (LAR) octreotide has presented varying results in the treatment of GH excessive production in patients with McCune-Albright Syndrome. METHODS: We report the case of a 29 year-old female patient presenting McCune-Albright Syndrome and complaint of excessive bone growth. RESULTS: The patient presented a pituitary adenoma involving the right internal carotid artery and excessive secretion of growth hormone (no GH suppression was observed after the oral glucose tolerance test). Due to the presence of diffuse thickness in skull base bones, surgical approach was not considered effective and the patient was submitted to drug therapy with octreotide LAR and cabergoline. At the one year follow-up, GH and IGF-1 levels were normal and no adverse effects were present. CONCLUSION: The use of drug therapy based on the association of cabergoline and octreotide is safe and able to achieve complete hormonal control in the treatment of acromegaly for McCune-Albright patients.

OBJETIVO: O uso de terapia medicamentosa, como cabergolina, octreotide e octreotide de longa duração, tem apresentado resultados variados no tratamento da produção excessiva de hormônio de crescimento (GH) em pacientes com síndrome de McCune-Albright. MÉTODOS: Foi relatado o caso de uma paciente de 29 anos apresentando síndrome de McCune-Albright com queixas de crescimento ósseo excessivo. RESULTADOS: A paciente apresentava adenoma pituitário com envolvimento da artéria carótida interna direita e produção excessiva de GH (sem supressão de GH após o teste de supressão com glicose). Por causa do aumento importante da espessura dos ossos da base do crânio, a abordagem cirúrgica foi considerada pouco efetiva e a paciente foi submetida à terapia medicamentosa com octreotide de longa duração e cabergolina. No seguimento de um ano, os níveis de GH e IGF-1 estavam normais e os efeitos adversos não eram presentes. CONCLUSÃO: A terapia medicamentosa fundamentada na associação de cabergolina e octreotide é segura e capaz de alcançar controle hormonal completo no tratamento de acromegalia na síndrome de McCune-Albright.

Efeitos do tratamento neonatal com inibidor seletivo de recaptura da 5-HT sobre o desenvolvimento anatômico crânio-encefálico / Neonatal treatment effect with selective inibitor of 5-HT recapture over the cranium-encephalic anatomic development

Pesquisadas repercussões neonatais do tratamento crônico com inibidores seletivos de recaptura da serotonina (ISRS) sobre crescimento somático, do encéfalo e crânio. Ratos machos foram divididos em grupos: controle (NaCl) e Cit (10 æL/Kg citalopram 10 mg). Durante 21 dias pós-natais, foram aferidos peso corporal, eixo látero-lateral, ântero-posterior e circunferência do crânio. Aos 8, 15 e 22 dias pós-natais, os animais foram sacrificados para retirada do encéfalo para avaliar as medidas citadas acima. A utilização de ISRS provocou déficit de crescimento corporal, diminuição das medidas craniais e do encéfalo. O retardo é possivelmente decorrência de alteração na magnitude da ação trófica da serotonina sobre morfogênese crânio-facial, reforçando a participação do sistema serotoninérgico sobre o crescimento somático e ontogenético. O possível efeito hipofágico dos ISRS não é descartado.

Neonatal repercussion researched of the serotonin selective recapture inibitor (SSRI) chronic treatment about the somatic growth, of the encephalon and skull. Male rats were divided into groups: control (NaCl) and Cit (10 æL/Kg citalopram 10 mg). In 21 post birth days were measured body weight, side axle , front and rear and skull circle. At 8, 15, 22 days after birth, animals were sacrified for the encephalon withdrawal to evaluate the measurements mentioned above. SSRI use caused body growth deficit, skull and encephalon reduction. The retard is possibly caused by the magnitude change of the trophic serotonin action over the skull-facial morphogenesis, reinforcing the serotoninergic system participation over the somatic and ontogenic growth. The SSRI possible hypophagic effects are not discarded.

Efecto de las hormonoas gonadales sobre el dimorfismo sexual en substrato de desnutrición / Effect of gonodal hormones on the sexual dimorphism in malnutrition substrate

El efecto ambiental sobre el crecimiento y el dimorfismo sexual es mediado por disfunciones endócrinas. Se ha comprobado que la desnutrición compromete al eje hipotalámico-hipofisario-glandular. Se realizó una experiencia en ratas Wistar con objeto de determinar el efecto de la administración de hormonas gonadales sobre componentes craneanos funcionales cuyo dimorfismo sexual fue alterado por desnutrición postnatal y analizar el tipo de efecto que estas hormonas tienen sobre el dimorfismo sexual. Se constituyeron cuatro tratamientos: control con consumo de dieta stock ad-libitum; subnutrición (50 por ciento del consumo promedio control); subnutrición+hormonas con inyecciones periódicas de testosterona y estradiol a machos y hembras respectivamente y sham-operado, en el cual la hormona fue sustituida por el vehículo oleoso. Se realizó un estudio radiológico longitudinal entre los 20 y 80 días de edad. Sobre cada radiografía se relevaron longitud, ancho y altura neuro y esplacnocraneanas. Con los datos obtenidos se realizó análisis de varianza y test de Mann-Whitney por medio del programa SYSTAT7.0. Los resultados obtenidos indicaron que ambas hormonas restituyeron el dimorfismo craneano sexual ya sea estimulando (testosterona) o inhibiendo (estradiol) el crecimiento de los componentes craneanos.