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1.
Am J Surg Pathol ; 44(8): 1040-1049, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32282346

RESUMO

Prostatic-type differentiation in the lower female genital tract is encountered rarely and its causes and clinical associations are not well established. Within the vagina, reports to date have invariably described ectopic prostatic-type differentiation as restricted to the lamina propria. We recently encountered a patient receiving testosterone for gender dysphoria whose vaginectomy specimen showed a prostatic glandular proliferation within the surface epithelium. To elucidate its potential association with androgen exposure, we sought similar lesions, resected over a 26-year period, from patients with exogenous or endogenous androgen excess. Thirteen cases were identified, involving the vagina (n=12) and exocervix (n=1). The most common clinical context was gender dysphoria with long-term testosterone therapy; the lesion was present in 7 of 8 gender-dysphoric patients examined. Four other patients had congenital disorders of sexual development associated with endogenous androgen excess (congenital adrenal hyperplasia, 46,XY disorder of sexual development, and ovotesticular disorder of sexual development). Two had no known exposure to androgen excess. Immunohistochemically, glands stained for NKX3.1 (100% of cases), androgen receptor (100%), CK7 (92%), and prostate-specific antigen (69%). Follow-up (median duration, 11 mo) showed no masses or neoplasia. We propose the designation "androgen-associated prostatic metaplasia" for this form of prostate tissue with distinctive clinical, histologic and immunohistochemical features. It is novel and previously unrecognized within the vagina. It is strikingly prevalent among patients undergoing gender-affirming surgery, an increasingly common procedure. Recognition is important to distinguish it from other potentially neoplastic glandular lesions and facilitate accrual of more follow-up data to better understand its natural history.


Assuntos
Diferenciação Celular , Coristoma/patologia , Células Epiteliais/patologia , Próstata , Doenças do Colo do Útero/patologia , Doenças Vaginais/patologia , Adolescente , Adulto , Androgênios/administração & dosagem , Androgênios/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Criança , Coristoma/induzido quimicamente , Células Epiteliais/efeitos dos fármacos , Feminino , Disforia de Gênero/tratamento farmacológico , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Masculino , Metaplasia , Fatores de Risco , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Transexualidade/tratamento farmacológico , Doenças do Colo do Útero/induzido quimicamente , Doenças Vaginais/induzido quimicamente , Adulto Jovem
2.
Saudi J Kidney Dis Transpl ; 30(2): 517-519, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031389

RESUMO

Accessory breast tissue is a relatively common congenital condition in which abnormal accessory breast tissue is seen as a mass anywhere along the course of embryologic mammary streak in addition to the presence of normal breast tissue. Ciclosporin therapy has been associated with benign breast disease in women. However, to the best of our knowledge, there are no reported cases of accessory breast tissue growth associated with ciclosporin therapy and regression after adjusting the dose. A 48-year-old woman had renal transplantation in 2009 with her brother as the donor. Her transplant follow-up over eight years had been unremarkable. She presented to our transplant follow-up clinic with bilateral painful axillary masses approximately 3 cm × 3 cm in diameter, not attached to the skin or underlying structures with no skin changes and no lymphadenopathy. Breast examination did not reveal any abnormalities. Her ciclosporin levels over the previous three years ranged between 130 and 150 ng/mL. These levels were within the acceptable recommended level of 100-150 ng/mL at that time (currently reduced to 80-120 ng/ml). Ultrasound of both axilla showed well-defined hypoechoic smooth outline masses in both axillary regions 3 cm × 4 cm. Fine-needle aspiration showed lesions consisting of cohesive ductal cells. The findings were consistent with accessory breast tissue with no evidence of inflammatory infiltrate or malignant changes. Her ciclosporin dose was reduced with the subsequent follow-up visits levels ranging between 90 and 110 ng/mL. Clinical examination four months later showed dramatic reduction in the axillary masses on both sides. Ultrasound confirmed the regression in the size of both masses. We conclude that ciclosporin was probably responsible for the formation of accessory breast tissue and reduction in the dose of ciclosporin resulted in substantial reduction in the tissue size.


Assuntos
Axila , Coristoma/induzido quimicamente , Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Glândulas Mamárias Humanas , Ciclosporina/administração & dosagem , Feminino , Humanos , Imunossupressores/administração & dosagem , Transplante de Rim , Pessoa de Meia-Idade
3.
J Mater Sci Mater Med ; 24(5): 1201-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23392969

RESUMO

The possibility to affect bone formation by using crushed versus solid hydrogels as carriers for bone morphogenetic protein 2 (BMP-2) was studied. Hydrogels, based on chemical crosslinking between hyaluronic acid and poly(vinyl alcohol) derivatives, were loaded with BMP-2 and hydroxyapatite. Crushed and solid forms of the gels were analyzed both in vitro via a release study using ¹²5I radioactive labeling of BMP-2, and in vivo in a subcutaneous ectopic bone model in rats. Dramatically different morphologies were observed for the ectopic bone formed in vivo in the two types of gels, even though virtually identical release profiles were observed in vitro. Solid hydrogels induced formation of a dense bone shell around non-degraded hydrogel, while crushed hydrogels demonstrated a uniform bone formation throughout the entire sample. These results suggest that by crushing the hydrogel, the construct's three-dimensional network becomes disrupted. This could expose unreacted functional groups, making the fragment's surfaces reactive and enable limited chemical fusion between the crushed hydrogel fragments, leading to similar in vitro release profiles. However, in vivo these interactions could be broken by enzymatic activity, creating a macroporous structure that allows easier cell infiltration, thus, facilitating bone formation.


Assuntos
Proteína Morfogenética Óssea 2/farmacologia , Ácido Hialurônico/farmacologia , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacologia , Osteogênese/efeitos dos fármacos , Animais , Densidade Óssea/efeitos dos fármacos , Proteína Morfogenética Óssea 2/farmacocinética , Coristoma/induzido quimicamente , Coristoma/patologia , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacocinética , Masculino , Tamanho do Órgão/efeitos dos fármacos , Porosidade , Ratos , Ratos Sprague-Dawley , Dermatopatias/induzido quimicamente , Dermatopatias/patologia , Propriedades de Superfície
4.
Calcif Tissue Int ; 91(2): 139-48, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22752619

RESUMO

Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma activators, and insulin sensitizers represent drugs used to treat hyperglycemia in diabetic patients. Type 2 diabetes mellitus (T2DM) is associated with a twofold increase in fracture risk, and TZDs use increases this risk by an additional twofold. In this study, we analyzed the effect of systemic administration of the TZD rosiglitazone on new bone formation in two in vivo models of bone repair, a model of drilled bone defect regeneration (BDR) and distraction osteogenesis (DO) and a model of extended bone formation. Rosiglitazone significantly inhibited new endosteal bone formation in both models. This effect was correlated with a significant accumulation of fat cells, specifically at sites of bone regeneration. The diminished bone regeneration in the DO model in rosiglitazone-treated animals was associated with a significant decrease in cell proliferation measured by the number of cells expressing proliferating cell nuclear antigen and neovascularization measured by both the number of vascular sinusoids and the number of cells producing proangiogenic vascular endothelial growth factor at the DO site. In summary, rosiglitazone decreased new bone formation in both BDR and DO models of bone repair by mechanisms which include both intrinsic changes in mesenchymal stem cell proliferation and differentiation and changes in the local environment supporting angiogenesis and new bone formation. These studies suggest that bone regeneration may be significantly compromised in T2DM patients on TZD therapy.


Assuntos
Tecido Adiposo , Doenças Ósseas/induzido quimicamente , Regeneração Óssea/efeitos dos fármacos , Coristoma/induzido quimicamente , Osteogênese/efeitos dos fármacos , Tiazolidinedionas/efeitos adversos , Animais , Doenças Ósseas/diagnóstico por imagem , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteogênese/fisiologia , Rosiglitazona , Tiazolidinedionas/farmacologia , Microtomografia por Raio-X
5.
J Spinal Disord Tech ; 23(1): 78, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20134288

Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Reabsorção Óssea/induzido quimicamente , Coristoma/induzido quimicamente , Hiperostose/induzido quimicamente , Vértebras Lombares/efeitos dos fármacos , Proteínas Recombinantes/efeitos adversos , Fusão Vertebral/efeitos adversos , Fator de Crescimento Transformador beta/efeitos adversos , Implantes Absorvíveis/efeitos adversos , Proteína Morfogenética Óssea 2 , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/fisiologia , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Coristoma/patologia , Coristoma/fisiopatologia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Colágeno/uso terapêutico , Humanos , Hiperostose/patologia , Hiperostose/fisiopatologia , Doença Iatrogênica/prevenção & controle , Vértebras Lombares/patologia , Vértebras Lombares/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Polirradiculopatia/induzido quimicamente , Polirradiculopatia/patologia , Polirradiculopatia/fisiopatologia , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/fisiopatologia , Reoperação/estatística & dados numéricos , Reprodutibilidade dos Testes , Canal Medular/efeitos dos fármacos , Canal Medular/patologia , Canal Medular/fisiopatologia , Fusão Vertebral/métodos , Resultado do Tratamento , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia
6.
Spine (Phila Pa 1976) ; 34(22): 2363-8, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19829249

RESUMO

STUDY DESIGN: Animal experiment using a rabbit posterolateral intertransverse process fusion model. OBJECTIVE: To explore the temporal and spatial distribution of sensory nerve fibers expressing calcitonin-gene related peptide (CGRP) during spinal fusion induced by recombinant human bone morphogenetic protein-4 and the role of the CGRP innervation in ectopic bone formation and remodeling. SUMMARY OF BACKGROUND DATA: Sensory neuropeptide CGRP involved in local bone turnover has been evidenced but its underlying mechanism is poorly understood. Knowledge in the CGRP innervation in ectopic bone induced by bone morphogenetic proteins can help us to understand its role in bone turnover. METHODS: Twenty-seven New Zealand white rabbits underwent single level posterolateral intertransverse process fusion of the lumbar vertebrae with implantation of porous poly-d,l-lactic acid blocks loaded with 1.25 microg recombinant human bone morphogenetic protein-4 solution. Animals were killed and the operated lumbar vertebrae were harvested for histomorphological evaluation at 3 days (n = 3), 1 week (n = 6), 3 weeks (n = 6), 7 weeks (n = 6), and 12 weeks (n = 6) following surgery, respectively. RESULTS: New cartilage presented at 1 week postimplantation adjacent to the implant, reached a peak volume at week 3 followed by a drop till week 12 after its ossification. Trabeculae-like woven bone structure presented at week 3. CGRP-positive nerve fibers regenerated already at 3 days postimplantation, reached its peak density at week 3. The CGRP-positive fibers presented both in fibrous tissues adjacent to proliferating cartilages and in bone marrow of newly formed trabecular bone. CONCLUSIONS: The observed spatial and temporal regeneration of CGRP-positive nerve fibers in ectopic bone formation suggested CGRP innervation is associated with ectopic osteogenesis.


Assuntos
Proteína Morfogenética Óssea 1/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Receptoras Sensoriais/metabolismo , Fusão Vertebral/métodos , Coluna Vertebral/cirurgia , Animais , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/fisiologia , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Condrogênese/efeitos dos fármacos , Condrogênese/fisiologia , Coristoma/induzido quimicamente , Coristoma/patologia , Coristoma/fisiopatologia , Modelos Animais de Doenças , Humanos , Ácido Láctico/química , Ácido Láctico/uso terapêutico , Vértebras Lombares/inervação , Vértebras Lombares/fisiopatologia , Vértebras Lombares/cirurgia , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Poliésteres , Polímeros/química , Polímeros/uso terapêutico , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/fisiopatologia , Coelhos , Proteínas Recombinantes de Fusão/efeitos adversos , Coluna Vertebral/inervação , Coluna Vertebral/fisiopatologia , Fatores de Tempo
7.
Fertil Steril ; 92(5): 1748.e5-7, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19744650

RESUMO

OBJECTIVE: To present an unusual side effect of therapy for adolescent menorrhagia, with commentary on management options. DESIGN: Case report. SETTING: Tertiary gynecologic center. PATIENT(S): A 13-year-old girl presenting with profuse uterine bleeding. INTERVENTION(S): Dysfunctional uterine bleeding was diagnosed, and pharmacologic therapy with a monophasic oral contraceptive (OC) pill was introduced. MAIN OUTCOME MEASURE(S): A large decidual cast occurred during treatment. RESULT(S): After finishing therapy with OC followed by three cycles of cyclic progestogen, the patient experienced regular menses. CONCLUSION(S): A large decidual cast may occur during treatment of adolescent menorrhagia with OCs; patients should be informed about this possibility, to reduce stress connected with the appearance of this side effect.


Assuntos
Coristoma/induzido quimicamente , Decídua , Menorragia/tratamento farmacológico , Progestinas/efeitos adversos , Doenças Uterinas/induzido quimicamente , Adolescente , Coristoma/patologia , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepcionais Orais Hormonais/uso terapêutico , Feminino , Humanos , Progestinas/administração & dosagem , Doenças Uterinas/patologia
8.
Epilepsia ; 48(1): 158-68, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17241223

RESUMO

PURPOSE: Brain malformations are a common cause of intractable epilepsy and cognitive dysfunction in children. Prenatal exposure to the teratogen methylazoxymethanol (MAM) is a rodent model of brain malformation featuring loss of lamination, clusters of displaced hippocampal cells, and pharmaco-resistance to antiepileptic drugs. In a normotopic hippocampus, expression of postsynaptic glutamate receptors and the transporters regulating neurotransmitter reuptake are critical factors modulating excitation and synaptic communication. Alterations in this system can have profound effects on overall excitability, cognitive function, and seizure thresholds. METHODS: Immunohistochemical techniques were used to analyze the expression of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5 methylisoxazole-4-proprionic acid (AMPA) receptor subunits in rats exposed to MAM in utero (25 mg/kg, intraperitoneal injection). We also examined the expression of several glutamate transporters (EAAC1, vGLUT1, and vGLUT2). A video-electroencephalographic (video-EEG) system was used for long-term monitoring of adult MAM-exposed rats. RESULTS: Heterotopic hippocampal neurons exhibited striking reductions in GluR1 and EAAC1 expression; vGlut2 expression was prominent in these regions. Spontaneous electrographic seizures were verified in two animals. CONCLUSIONS: We conclude that glutamate receptor subunit and transporter expression are altered in animals exposed to MAM in utero. Further studies in the MAM model may provide greater insight into the potential disruptions in excitatory synaptic neurotransmission that can occur in a malformed brain.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Córtex Cerebral/anormalidades , Hipocampo/anormalidades , Troca Materno-Fetal , Acetato de Metilazoximetanol/análogos & derivados , Receptores de Glutamato/efeitos dos fármacos , Convulsões/induzido quimicamente , Teratogênicos/farmacologia , Sistema X-AG de Transporte de Aminoácidos/efeitos dos fármacos , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Coristoma/induzido quimicamente , Coristoma/metabolismo , Modelos Animais de Doenças , Eletrodos Implantados , Eletroencefalografia/estatística & dados numéricos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imuno-Histoquímica , Acetato de Metilazoximetanol/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
9.
Neurobiol Dis ; 24(3): 429-42, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17027274

RESUMO

We examined the blood-brain barrier (BBB) function in methylazoxymethanol acetate (MAM)-treated rats, a model of human developmental brain malformations. We found aberrant vessels morphology and serum albumin leakage in the heterotopic (malformed) hippocampus; these changes were associated with a significant increase in endothelial P-glycoprotein (P-gp) expression. Seizures exacerbated BBB leakage and greatly augmented P-gp expression in vessels and additionally in perivascular/parenchymal astrocytes. The effects of seizures were observed to a much larger extent in malformed than in normal brain tissue. The intrinsic changes in BBB function in MAM-exposed rats were associated with increased blood-to-brain penetration of ondansetron, a P-gp substrate. However, a marked reduction in drug brain levels was provoked by seizures, and this effect was reversed by selective blockade of P-gp activity with tariquidar. Changes in BBB function may critically contribute to determine the brain uptake and distribution of P-gp substrates in epileptic tissue associated with developmental malformations.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Epilepsia/metabolismo , Hipocampo , Convulsões/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Anticonvulsivantes/farmacocinética , Astrócitos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/anormalidades , Encéfalo/irrigação sanguínea , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Coristoma/induzido quimicamente , Modelos Animais de Doenças , Resistência a Medicamentos/fisiologia , Células Endoteliais/efeitos dos fármacos , Epilepsia/patologia , Feminino , Masculino , Análise por Pareamento , Acetato de Metilazoximetanol , Ondansetron/farmacocinética , Gravidez , RNA Mensageiro/análise , Ratos , Convulsões/patologia , Albumina Sérica/metabolismo
10.
Brain Res ; 1089(1): 55-66, 2006 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-16638609

RESUMO

Primary microcephaly can be accompanied by numerous migration anomalies. This experiment was undertaken to examine the pathogenesis of gray matter heterotopia and microcephaly that is produced after administering cytosine arabinoside (Ara-C) to mice. Pregnant mice were intraperitoneally injected with Ara-C at 30 mg/kg body weight on days 13.5 and 14.5 of gestation, and then their offspring were examined. On embryonic day 15.5, in the ventricular zone of the cingulate cortex, the neuroepithelial cells lacked BrdU immunoreactivity. Nestin-immunoreactive radial glial fibers and calretinin-positive subplate fibers were disrupted. TUNEL reaction was remarkable throughout the cerebral hemisphere. Subcortical heterotopia in the cingulate cortex and subependymal nodular heterotopia in the dorsolateral part of the lateral ventricles became detectable by the first day after birth. Thirty-two days after birth, microcephaly was apparent; subcortical heterotopia was observed to have increased in size while it was still located in the frontal and cingulate cortices. This experiment demonstrated that Ara-C induces neuronal apoptosis throughout the cerebral hemisphere. The immunohistochemical characteristics in the gray matter heterotopia suggest that both the subcortical and the subependymal heterotopias were formed by neurons originally committed to the neocortex. We conclude that the gray matter heterotopia that accompanies the microcephaly was produced by a disturbance of radial, tangential, and interkinetic neuronal migrations due to the toxicity of Ara-C in the immature developing brain.


Assuntos
Córtex Cerebral/anormalidades , Córtex Cerebral/efeitos dos fármacos , Coristoma/induzido quimicamente , Citarabina/efeitos adversos , Microcefalia/induzido quimicamente , Malformações do Sistema Nervoso/induzido quimicamente , Animais , Animais Recém-Nascidos , Antimetabólitos Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Biomarcadores/metabolismo , Bromodesoxiuridina , Calbindina 2 , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Coristoma/diagnóstico , Coristoma/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos ICR , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Proteínas Associadas aos Microtúbulos/metabolismo , Degeneração Neural/induzido quimicamente , Degeneração Neural/fisiopatologia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteína G de Ligação ao Cálcio S100/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/patologia
11.
Am J Pathol ; 168(4): 1227-40, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16565497

RESUMO

Lymphoid neogenesis is associated with antibody-mediated autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. Although systemic lupus erythematosus is the prototypical B-cell-mediated autoimmune disease, the role of lymphoid neogenesis in its pathogenesis is unknown. Intraperitoneal injection of 2,6,10,14-tetramethyl-pentadecane (TMPD, pristane) or mineral oil causes lipogranuloma formation in mice, but only TMPD-treated mice develop lupus. We report that lipogranulomas are a form of lymphoid neogenesis. Immunoperoxidase staining of lipogranulomas revealed B cells, CD4(+) T cells, and dendritic cells and in some cases organization into T- and B-cell zones. Lipogranulomas also expressed the lymphoid chemokines CCL21, CCL19, CXCL13, CXCL12, and CCL22. Expression of the type I interferon (IFN-I)-inducible genes Mx1, IRF7, IP-10, and ISG-15 was greatly increased in TMPD- versus mineral oil-induced lipogranulomas. Dendritic cells from TMPD lipogranulomas underwent activation/maturation with high CD86 and interleukin-12 expression. Magnetic bead depletion of dendritic cells markedly diminished IFN-inducible gene (Mx1) expression. We conclude that TMPD-induced lupus is associated with the formation of ectopic lymphoid tissue containing activated dendritic cells producing IFN-I and interleukin-12. In view of the increased IFN-I production in systemic lupus erythematosus, these studies suggest that IFN-I from ectopic lymphoid tissue could play a role in the pathogenesis of experimental lupus in mice.


Assuntos
Granuloma/metabolismo , Interferon Tipo I/biossíntese , Tecido Linfoide/metabolismo , Terpenos , Animais , Linhagem Celular , Quimiocina CXCL10 , Quimiocinas/biossíntese , Quimiocinas CXC/biossíntese , Coristoma/induzido quimicamente , Coristoma/metabolismo , Coristoma/patologia , Citocinas/biossíntese , Células Dendríticas/metabolismo , Feminino , Proteínas de Ligação ao GTP/biossíntese , Granuloma/induzido quimicamente , Granuloma/patologia , Fator Regulador 7 de Interferon/biossíntese , Interleucina-12/biossíntese , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/patologia , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/patologia , Camundongos , Camundongos Endogâmicos BALB C , Óleo Mineral , Proteínas de Resistência a Myxovirus , Peritônio , Ubiquitinas/biossíntese
12.
J Comp Neurol ; 495(1): 133-48, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16432901

RESUMO

While there are many recent examples of single gene deletions that lead to defects in cortical development, most human cases of cortical disorganization can be attributed to a combination of environmental and genetic factors. Elucidating the cellular or developmental basis of teratogenic exposures in experimental animals is an important approach to understanding how environmental insults at particular developmental junctures can lead to complex brain malformations. Rats with prenatal exposure to methylazoxymethanol (MAM) reproduce many anatomical features seen in epilepsy patients. Previous studies have shown that heterotopic clusters of neocortically derived neurons exhibit hyperexcitable firing activity and may be a source of heightened seizure susceptibility; however, the events that lead to the formation of these abnormal cell clusters is unclear. Here we used a panel of molecular markers and birthdating studies to show that in MAM-exposed rats the abnormal cell clusters (heterotopia) first appear postnatally in the hippocampus (P1-2) and that their appearance is preceded by a distinct sequence of perturbations in neocortical development: 1) disruption of the radial glial scaffolding with premature astroglial differentiation, and 2) thickening of the marginal zone with redistribution of Cajal-Retzius neurons to deeper layers. These initial events are followed by disruption of the cortical plate and appearance of subventricular zone nodules. Finally, we observed the erosion of neocortical subventricular zone nodules into the hippocampus around parturition followed by migration of nodules to hippocampus. We conclude that prenatal MAM exposure disrupts critical developmental processes and prenatal neocortical structures, ultimately resulting in neocortical disorganization and hippocampal malformations.


Assuntos
Córtex Cerebral/anormalidades , Coristoma/patologia , Epilepsia/fisiopatologia , Hipocampo/anormalidades , Malformações do Sistema Nervoso/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Coristoma/induzido quimicamente , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/patologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Acetato de Metilazoximetanol/análogos & derivados , Malformações do Sistema Nervoso/induzido quimicamente , Malformações do Sistema Nervoso/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Teratogênicos
13.
Cereb Cortex ; 14(10): 1071-80, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15166098

RESUMO

Abnormalities in the migration of cortical neurons to ectopic sites can be caused by prenatal exposure to ethanol. In extreme cases, cells migrate past the pial surface and form suprapial heterotopias or 'warts'. We used organotypic slice cultures from 17-day-old rat fetuses to examine structural and molecular changes that accompany wart formation. Cultures were exposed to ethanol (0, 200, 400 or 800 mg/dl) and maintained for 2-32 h. Fixed slices were sectioned and immunolabeled with antibodies directed against calretinin, reelin, nestin, GFAP, doublecortin, MAP-2 and NeuN. Ethanol promoted the widespread infiltration of the marginal zone (MZ) with neurons and the focal formation of warts. The appearance of warts is time- and concentration-dependent. Heterotopias comprised migrating neurons and were not detected in control slices. Warts were associated with breaches in the array of Cajal-Retzius cells and with translocation of reelin-immunoexpression from the MZ to the outer limit of the wart. Ethanol also altered the morphology of the radial glia. Thus, damage to the integrity of superficial cortex allows neurons to infiltrate the MZ, and if the pial-subpial glial barrier is also compromised these ectopic neurons can move beyond the normal cerebral limit to form a wart.


Assuntos
Córtex Cerebral , Coristoma/induzido quimicamente , Coristoma/patologia , Etanol/toxicidade , Animais , Relação Dose-Resposta a Droga , Proteína Duplacortina , Embrião de Mamíferos , Feminino , Técnicas de Cultura de Órgãos , Gravidez , Ratos , Proteína Reelina
14.
J Child Neurol ; 19(2): 107-15, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15072103

RESUMO

To investigate the mechanisms of radial and tangential neuronal migration disorders, immunohistochemical expressions of reelin, vimentin, and calretinin were examined in brain lesions induced by ibotenate (an agonist of the N-methyl-D-aspartate [NMDA] complex receptor) in hamsters. Thirty-four newborn hamsters were subjected to intracerebral injections of ibotenate, and 12 animals served as the control. These hamsters were examined at 1, 2, 3, 5, and 7 days after injections. The cortical lesions observed after ibotenate injections had a strong resemblance to the following neuronal migration disorders: (1) microgyria, (2) focal subcortical heterotopia, and (3) leptomeningeal glioneuronal heterotopia. In microgyria, the radial glial fibers were sparsely distributed, but in leptomeningeal glioneuronal heterotopia, vimentin-positive fibers extended into this abnormal neural tissue. Calretinin-immunoreactive neurons and fibers were present along the lesion forming the microgyria and abnormal neuronal arrangement. Focal subcortical heterotopia also included a small number of calretinin-expressing neurons originating from the subplate neuronal population. These results imply that the neuronal migration disorders produced by ibotenate show not only the migrational arrest of neurons but also interference from the termination of the migration process. We also suggest that the heterotopic neurons constituting the focal subcortical heterotopia originate in the lateral or medial ganglionic eminence of the ventral telencephalon, probably caused by the abnormal tangential neuronal migration.


Assuntos
Encefalopatias , Moléculas de Adesão Celular Neuronais/metabolismo , Movimento Celular/fisiologia , Córtex Cerebral , Coristoma , Proteínas da Matriz Extracelular/metabolismo , Ácido Ibotênico/efeitos adversos , Neurônios , Vimentina/metabolismo , Animais , Animais Recém-Nascidos , Encefalopatias/induzido quimicamente , Encefalopatias/metabolismo , Encefalopatias/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Coristoma/induzido quimicamente , Coristoma/metabolismo , Coristoma/patologia , Cricetinae , Ácido Ibotênico/administração & dosagem , Imuno-Histoquímica , Injeções , Mesocricetus , Proteínas do Tecido Nervoso , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteína Reelina , Serina Endopeptidases
15.
J Control Release ; 95(2): 249-56, 2004 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-14980773

RESUMO

The osteoinductive potential of growth factors leads not only to a stimulated bone formation in bony tissue but also in extra skeletal tissue. This potential depends on the dosage and potentially on the application method and may limit the clinical use. The aim of the present study was to investigate the potential of IGF-I, TGF-beta1 and BMP-2 released from a newly developed application systems of orthopaedic implants to induce ectopic bone formation in muscles. This bioactive coating showed a stimulating effect on fracture healing in several experimental studies before. Titanium discs were coated on one side with the drug carrier poly(d,l-lactide) (PDLLA), with the carrier plus IGF-I and TGF-beta1 or with the carrier plus BMP-2. The discs were implanted in the Musculus cleidomastoideus of sheep and followed up for 3 months. X-rays were taken after the operation and the day of sacrifice. The muscles plus implant were harvested and prepared for histology. Neither the radiology nor the histology revealed any signs of ectopic ossification in the implant/muscle interface or in a distance to the plate in any group. An influence of the locally applied growth factor, however, was seen in the formation of a soft tissue capsule. Histomorphometric analysis revealed a significantly larger capsule area over the growth factor coated side in comparison to the uncoated side or the pure titanium plate, indicating an effect of the applied growth factors on cells, however, not resulting in osteoinduction in muscle. The result showed that the local and controlled release of growth factors from PDLLA coated implants does not induce ectopic bone formation in sheep muscle and could be used in orthopaedic surgery to increase healing without the risk of ectopic bone formation in the surrounding soft tissue.


Assuntos
Proteínas Morfogenéticas Ósseas/administração & dosagem , Proteínas Morfogenéticas Ósseas/efeitos adversos , Osso e Ossos , Coristoma/induzido quimicamente , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/efeitos adversos , Músculo Esquelético/fisiologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/patologia , Osteogênese/efeitos dos fármacos , Próteses e Implantes , Titânio , Fator de Crescimento Transformador beta/administração & dosagem , Fator de Crescimento Transformador beta/efeitos adversos , Animais , Proteína Morfogenética Óssea 2 , Coristoma/diagnóstico por imagem , Coristoma/patologia , Materiais Revestidos Biocompatíveis , Excipientes , Feminino , Doenças Musculares/diagnóstico por imagem , Poliésteres , Radiografia , Ovinos , Fator de Crescimento Transformador beta1
16.
Epileptic Disord ; 5 Suppl 2: S51-8, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14617421

RESUMO

The pre-natal administration of methylazoxymethanol acetate (MAM) in rats is able to induce cerebral heterotopia that share striking similarities with those observed in human periventricular nodular heterotopia, a cerebral dysgenesis frequently associated with drug-resistant focal seizures. In the present study, we investigated the mode of neurogenesis in cerebral heterotopia of MAM-treated rats, by analyzing post-natal cytoarchitectural features and time of neurogenesis using bromodeoxyuridine immunocytochemistry. The cytoarchitectural analysis demonstrated the existence, in the early post-natal period, of white matter cellular bands in close anatomical relationship with the heterotopia, which most likely serve as a reservoir of young, migrating neurons for the newly forming heterotopia. The birth dating analysis demonstrated that the period of generation of neurons within the heterotopia and adjacent white matter bands, was extended in comparison to corticogenesis in normal rat brains. In addition, it demonstrated that the heterotopia were formed through a rather precise outside-in (for cortical and periventricular heterotopia) and dorso-ventral (for intra-hippocampal heterotopia) neurogenetic pattern. We hypothesize that the MAM-induced ablation of an early wave of cortical neurons is sufficient to alter per se the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different types of heterotopia. On this basis, we suggest a neurogenetic scheme for MAM-induced heterotopia that can also explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in humans.


Assuntos
Encefalopatias/complicações , Encefalopatias/patologia , Coristoma/complicações , Coristoma/patologia , Epilepsia/etiologia , Animais , Encefalopatias/induzido quimicamente , Movimento Celular/fisiologia , Coristoma/induzido quimicamente , Feminino , Imuno-Histoquímica , Acetato de Metilazoximetanol/administração & dosagem , Acetato de Metilazoximetanol/efeitos adversos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/efeitos adversos , Ratos , Ratos Sprague-Dawley
17.
Food Chem Toxicol ; 41(12): 1739-47, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14563399

RESUMO

Modulating effects of high fat fish oil (HFFO) and high fat corn oil (HFCO) diets on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were studied in male F344 rats following 8 weeks of dietary treatment. The incidence of AOM-induced ACF was significantly lower in the proximal colon of rats fed the HFFO diets compared with rats fed the HFCO diets. No differential effects were found on enzyme activities that are involved in metabolic activation and detoxification of AOM. Activities of hepatic P450 IAI and P450 IIBI and hepatic and feacal levels of lipid peroxidation were increased by feeding the HFFO diet. Hepatic GST activity and plasma levels of PGE(2) were significantly lower in rats fed the HFFO diets compared with those fed the HFCO diets. These observations demonstrate that HFFO diets with high levels of n-3 PUFAs are also protective against preneoplastic lesions in the early stages of chemically induced colon carcinogenesis. It seems unlikely from our results that the inhibitory effect of a HFFO diet can be attributed to an altered metabolic activation and detoxification of AOM. Other mechanisms such as oxidative stress or reduction of PGE(2) levels may play an important role in the anticarcinogenic effects of n-3 PUFAs.


Assuntos
Azoximetano/antagonistas & inibidores , Azoximetano/toxicidade , Carcinógenos/antagonistas & inibidores , Carcinógenos/toxicidade , Coristoma/induzido quimicamente , Doenças do Colo/induzido quimicamente , Óleo de Milho/farmacologia , Dieta/efeitos adversos , Óleos de Peixe/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Ceco/efeitos dos fármacos , Ceco/enzimologia , Coristoma/patologia , Doenças do Colo/patologia , Dinoprostona/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Células Epiteliais/patologia , Fezes/química , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344
18.
J Neuropathol Exp Neurol ; 62(6): 662-75, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12834111

RESUMO

Double intraperitoneal injections of methylazoxymethanol (MAM) in pregnant rats induce developmental brain dysgenesis with nodular heterotopia similar to human periventricular nodular heterotopia (PNH) and composed of hyperexcitable neurons. Here we analyzed the NMDA receptor complex and associated proteins in the heterotopic neurons of 2- to 3-month-old MAM-treated rats by means of a combined immunocytochemical/molecular approach. Our data demonstrated a clear reduction of p286-active form of alphaCaMKII and a selective impairment of both the targeting and the CaMKII-dependent phosphorylation of NR2A/B subunits in the postsynaptic membranes of the MAM-induced heterotopia. The reduced NR2A/B immunofluorescence of the cellular membrane was not due to reduced expression since it was decreased only in postsynaptic fractions but not in the homogenate. NMDA-NR1 and AMPA-GluR2/3 subunits, as well as PSD-95 and total alphaCaMKII protein levels, were not affected in MAM-treated rats, thus revealing that the overall composition of the postsynaptic fraction was not altered. These data clearly suggest that the molecular organization of the NMDA/alphaCaMKII complex is selectively altered in the postsynaptic compartment of heterotopic neurons. This alteration can play a role in determining the hyperexcitability of brain heterotopia in MAM rats as well as in human patients affected by PNH.


Assuntos
Córtex Cerebral , Coristoma/patologia , Acetato de Metilazoximetanol/análogos & derivados , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Animais Recém-Nascidos , Autorradiografia/métodos , Western Blotting , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Carcinógenos/toxicidade , Membrana Celular/metabolismo , Membrana Celular/patologia , Coristoma/induzido quimicamente , Coristoma/metabolismo , Clonagem Molecular/métodos , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Análise por Pareamento , Proteínas de Membrana , Acetato de Metilazoximetanol/toxicidade , Microscopia Confocal/instrumentação , Microscopia Confocal/métodos , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Gravidez , Ratos , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/classificação , Frações Subcelulares/metabolismo
19.
Cereb Cortex ; 13(7): 736-48, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12816889

RESUMO

We have previously demonstrated that the antiproliferative agent methylazoxymethanol acetate (MAM) is able to induce in rats cerebral heterotopia that share striking similarities with those observed in human periventricular nodular heterotopia (PNH), a cerebral dysgenesis frequently observed in human patients affected by drug-resistant focal epilepsy. In this study, we investigated the time-course of neurogenesis in the cerebral heterotopia of MAM-treated rats, with the idea of understanding why PNH develop in human patients. For these goals, we analyzed the cytoarchitectural features, the time of neurogenesis and the cellular phenotype of the heterotopia, by means of BrdU immunocytochemistry and confocal immunofluorescence experiments. Our data demonstrate that the different types of heterotopia in MAM-treated rats are formed through the same altered neurogenetic process, which follows quite organized neurogenetic gradients. The MAM-induced ablation of an early wave of cortical neurons is sufficient to alter per se the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different heterotopic structures. The neurogenesis of MAM-induced heterotopia may explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in human patients.


Assuntos
Encefalopatias/embriologia , Encefalopatias/patologia , Córtex Cerebral , Coristoma/embriologia , Coristoma/patologia , Acetato de Metilazoximetanol/análogos & derivados , Animais , Encefalopatias/induzido quimicamente , Encefalopatias/genética , Bromodesoxiuridina , Coristoma/induzido quimicamente , Coristoma/genética , Modelos Animais de Doenças , Feminino , Microscopia Confocal , Morfogênese , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fenótipo , Gravidez , Ratos , Ratos Sprague-Dawley
20.
Epilepsia ; 44(3): 315-21, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12614386

RESUMO

PURPOSE: To study voltage-dependent calcium currents (VDCCs) on hippocampal heterotopic neurons by using whole-cell patch-clamp techniques in brain slices prepared from methylaxozymethanol (MAM)-exposed rats. METHODS: Whole-cell voltage-clamp recordings were obtained from visually identified neurons in acute brain slices by using an infrared differential interference contrast (IR-DIC) video microscopy system. Heterotopic neurons were compared with normotopic pyramidal cells in hippocampal slices from MAM-exposed rats or CA1 pyramidal neurons in slices from controls. RESULTS: Heterotopic neurons expressed a prominent VDCC, which exhibited a peak current maximum around -30 mV (holding potential, -60 mV) and an inactivation time constant of 48.2 +/- 2.4 ms (n = 91). VDCC peak current and inactivation time constants were similar for normotopic (n = 92) and CA1 pyramidal cells (n = 40). Pharmacologic analysis of VDCC, on heterotopic, normotopic, and CA1 pyramidal cells, revealed an approximately 70% blockade of peak Ca2+ current with nifedipine and amiloride (L- and T-type channel blockers, respectively). Inhibition of VDCC, for all three cell types, also was similar when more specific Ca2+ channel antagonists were used [e.g., omega-conotoxin GVIA (N-type), omega-agatoxin KT (P/Q-type), and sFTX-3.3 (P-type)]. VDCC modulation by norepinephrine (NE) or adrenergic receptor-specific agonists [clonidine (alpha2), isoproterenol (beta), and phenylephrine (alpha1)] was similar for heterotopic and CA1 pyramidal cells. CONCLUSIONS: Heterotopic neurons do not appear to exhibit Ca2+ channel abnormalities that could contribute to the reported hyperexcitability associated with MAM-exposed rats.


Assuntos
Canais de Cálcio/fisiologia , Coristoma/induzido quimicamente , Coristoma/fisiopatologia , Epilepsia/fisiopatologia , Hipocampo/anormalidades , Hipocampo/fisiopatologia , Acetato de Metilazoximetanol , Acetato de Metilazoximetanol/análogos & derivados , Malformações do Sistema Nervoso/induzido quimicamente , Malformações do Sistema Nervoso/fisiopatologia , Neurônios/fisiologia , Teratogênicos , Animais , Cálcio/fisiologia , Canais de Cálcio/efeitos dos fármacos , Modelos Animais de Doenças , Eletrofisiologia , Epilepsia/induzido quimicamente , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Técnicas In Vitro , Acetato de Metilazoximetanol/farmacologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Canais de Potássio/fisiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiopatologia , Ratos , Ratos Sprague-Dawley , Teratogênicos/farmacologia
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