Medication-related osteonecrosis of the jaw associated with bisphosphonates and denosumab in osteoporosis.

OBJECTIVE: To describe the clinical characteristics and evolution of our series of medication-related osteonecrosis of the jaws (MRONJ) associated with denosumab in osteoporotic patients. MATERIAL AND METHODS: We present 10 new cases of MRONJ in patients receiving denosumab for osteoporosis. We describe the mean doses of denosumab, previous bisphosphonate intake, and the clinical characteristics associated with the osteonecrosis, such as local contributing factors, symptoms, and evolution after treatment. RESULTS: The mean number of denosumab doses was 3.4 ± 2.2. In 90% of patients, there was a prior history of oral bisphosphonate intake, with a mean duration of 46.78 ± 25.11 months. The most common local factor was dental extraction (6 cases; 60%), and most cases had necrotic bone exposure (9/10, 90%). Sclerosis of the bone was the most common radiographic finding. Stage 1 was the most common ONM stage, found in 80%. 'Cure' after conservative treatments was obtained in 71.4%. CONCLUSIONS: Most of our cases were in the early stages of MRONJ, and the success rate after conservative treatment was high.

Ultrastructural patterns of human dentinal tubules, odontoblasts processes and nerve fibres.

The structure of the dentin, consists of the following elements: the odontoblastic processes, dentinal tubules and their periodontoblastic spaces. The odontoblasts are aligned in a single layer in the periphery of the dental pulp and secrete the organic components of dentin. The vitality of dentin is mediated too by the nerve fibres. The ultrastructure of the trigeminal sensory nerves in dentin, especially in relation to odontoblasts remains to be clarified. We studied the third molars and young premolars. The specimens were fixed in glutaraldehyde immediately after extraction. Our investigations give evidence to prove that the distribution of the dentinary tubules is homogeneous, containing a principal odontoblastic prolongation in the regions of the inner dentine, and only in special cases more than one. The area of the dentinary tubules and the odontoblastic prolongations' area were studied. The nervous fibres appeared accompanying 30-70% of the odontoblastic prolongations and their synapsis-like relation with the odontotoblastic processes was demonstrated. The existence of very few periodontoblastic spaces, and intradentinal sensory axons, as well as the intercellular connections will allow us to discover more about the mechanisms of the dentinary permeability, and its significance in maintenance and repair of the human pulpodentinal complex.

Osteoprotegerin (OPG) and RANKL expression and distribution in developing human craniomandibular joint.

During embryogenesis the bone tissue of craniomandibular joint (CMJ) is formed through two pathways: intramembranous ossification and endochondral ossification. The development process is under the control of regulatory factors. The osteoprotegerin (OPG) and the receptor activator of nuclear factor (NF)-kappaB ligand are key regulators of osteoclastogenesis. The aim of this study is the localization of OPG and RANKL mRNA and protein in the foetal CMJ by immunohistochemistry (IHC) and in situ hybridization (ISH). The main results were: OPG and RANKL mRNA and protein were co-localized in the same cell types; OPG and RANKL were specially immunolocated in osteogenic cells; immunolabeling was often seen in the nucleus and cytoplasm of otherwise negative hypertrophic chondrocytes; IHC and ISH labeling decreased from proliferative to hypertrophic chondrocytes; early osteocytes showed dual protein expression and some of the mature osteocytes were ISH-negative; periosteal osteoclasts and chondroclasts were mostly stained by IHC and variably labeled by ISH; the new bone matrix and trabecular borders showed intense immunolabeling. The co-expression of OPG and RANKL in the same bone cell types confirms their strictly coupled action in the regulation of bone metabolism in the CMJ development and their extracellular presence in the new bone matrix and trabecular borders suggests a local regulatory role.

Hydrodynamic liver gene transfer mechanism involves transient sinusoidal blood stasis and massive hepatocyte endocytic vesicles.

The present study contributes to clarify the mechanism underlying the high efficacy of hepatocyte gene transfer mediated by hydrodynamic injection. Gene transfer experiments were performed employing the hAAT gene, and the efficacy and differential identification in mouse plasma of human transgene versus mouse gene was assessed by ELISA and proteomic procedures, respectively. By applying different experimental strategies such as cumulative dose-response efficacy, hemodynamic changes reflected by venous pressures, intravital microscopy, and morphological changes established by transmission electron microscopy, we found that: (a) cumulative multiple doses of transgene by hydrodynamic injection are efficient and well tolerated, resulting in therapeutic plasma levels of hAAT; (b) hydrodynamic injection mediates a transient inversion of intrahepatic blood flow, with circulatory stasis for a few minutes mainly in pericentral vein sinusoids; (c) transmission electron microscopy shows hydrodynamic injection to promote massive megafluid endocytic vesicles among hepatocytes around the central vein but not in hepatocytes around the periportal vein. We suggest that the mechanism of hydrodynamic liver gene transfer involves transient inversion of intrahepatic flow, sinusoidal blood stasis, and massive fluid endocytic vesicles in pericentral vein hepatocytes.

Primary triple teeth: histological and CT morphological study of two case reports.

The macromorphology and micromorphology of two specimens of primary triple teeth using histological and CT analysis approach is analyzed. A single morphological pattern of triple teeth has been found and described: three nearly separate crowns with three separate pulp chambers, and three joined roots with three connected root canals. The characteristic triple teeth appearance occurred because a labial supernumerary tooth is the junction element between two teeth of normal series: the central incisor on the mesial side and the lateral incisor on the distal side. Primary triple teeth suggest an idiopathic abnormality in the distribution of the dental material originated very soon in the dental development. They can be considered as an early double fusion between three tooth germs, initially separate but in close proximity and developing synchronically.

Erythrophagocytic tumour cells in melanoma and squamous cell carcinoma of the skin.

AIMS: Erythrophagocytosis is a characteristic feature of tumour cells in malignant histiocytosis, some leukaemias, lymphomas, and also reactive histiocytes in the haemophagocytic syndrome associated with a variety of infections and neoplasms. It has also been found exceptionally in metastatic malignant epithelial cells in bone marrow and lymph nodes. We present two cases, a cutaneous malignant melanoma and an acantholytic squamous cell carcinoma, in which erythrophagocytosis by tumour cells was demonstrable by both light and electron microscopy. METHODS AND RESULTS: The melanocytic and squamous nature of these cells was supported by the immunohistochemical detection of HMB45, S100, and NKI-C3 in the former, and cytokeratin and EMA in the latter, and at ultrastructural level by the presence of melanosomes and tonofilaments, respectively. CONCLUSIONS: This is, to our knowledge, the first documented report of erythrophagocytic tumour cells in human melanomas and primary carcinomas. Biological considerations apart, this unusual feature can prove to be of value to avoid a misdiagnosis of a variety of haematopoietic malignancies.

[Oral hairy leukoplakia. A study of 5 cases]. / Leucoplasia vellosa oral. Estudio de cinco casos.

Oral hairy leukoplakia (HL) is a newly described lesion (1984) in human immunodeficiency virus infected patients. Patients with HL show a high probability of developing an acquired immunodeficiency syndrome (AIDS). The results of histopathological, microbiological, immunological and ultrastructural studies in five patients with HL and AIDS are reported. The histopathological exam revealed in all cases acanthosis, parakeratosis, koilocytosis and keratin projections on the surface. Dermis was normal. Herpes type virus were seen in four cases and in one of them papilloma virus was also present in electron microscopic examination. There was immunocytochemical evidence of papilloma virus in one lesion. Candida albicans was found in 5 lesions by culture but only in two ones by periodic acid Schiff stain. Virus cultures for herpes virus were negative. Immunocytochemical search of Langerhans cells (S-100, HLA-DR, OKT4, OKT6) showed nearly absence of these cells in HL lesions. These results favour the viral etiology hypothesis of hairy leukoplakia.

Verrucous carcinoma of the oral cavity.

The clinical course and morphologic (light and ultrastructural) characteristics of a case of verrucous carcinoma of the lower gingival mucosa are presented. Clinical course of the patient was unfavorable following surgery (supposedly incomplete) and radiotherapy (6,000 R) of the tumor. The therapeutic factors that may influence an unfavourable prognosis are commented upon, especially in regard to a slow-growing neoplasm with a generally good course.

Malignant mixed osteogenic tumours of the breast. An ultrastructural study of two cases.

Two cases of malignant mesodermic tumours of the human mammary gland with osteogenic and chondrogenic structures were analysed by optical and electronic microscopical means. One of them was associated with an adenocarcinoma of the gland. The histological pattern was similar to that of those cases previously examined under the optical microscope in the mammary gland and in extraskeletal osteogenic sarcomas of soft tissues. When investigated under the electron microscope, the chondroblasts possessed a highly developed RER in active synthesis with an amorphous material which contributed to the building up of the ground substance matrix of the tumorous cartilage. Osteoid fields with scattered osteoblasts appear throughout the tumorous stroma and were associated with calcium deposits. They were continuous with fibroblasts and mesenchymal undifferentiated cells of a very immature character. Giant cells of osteoclastic type were included within the mononucleated mesenchymal cells mimicking bone osteoclastoma. The presence of all these cell types suggests the existence of a common malignant origin, the stem cell being differentiated into epithelial carcinomatous and mesenchymal sarcomatous chondral and osteogenic tissues.