ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force.

Nitric oxide (NO), a diffusible gas, plays an important role in many physiological and diverse pathophysiological conditions (1, 2). At low concentrations NO has been shown to play a unique role in neurotransmission and vasodilation, whereas at higher concentrations it is neurotoxic (1, 2). Consistently, NO, which is derived in excessive amounts from the activation of inducible nitric-oxide synthase (iNOS) 1 in glial cells (microglia and astrocytes), is assumed to contribute to oligodendrocyte degeneration in demyelinating diseases and neuronal death during neurodegenerative diseases (3-7). Evidence from several laboratories emphasizes the involvement of NO in the pathophysiology of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), the animal model of MS (4, 8, 9). Analysis of cerebrospinal fluid from MS patients has shown increased levels of nitrite and nitrate compared with normal controls (11). The reaction of NO with O 2 Ϫ forms peroxynitrite (ONOO Ϫ ), a strong nitrosating agent capable of nitrosating tyrosine residues of a protein to nitrotyrosine. Increased levels of nitrotyrosine have been found in demyelinating lesions of MS brains as well as in spinal cords of mice with EAE (12, 13). Subsequently, a semiquantitative reverse transcription-PCR for iNOS mRNA in MS brains also shows a markedly higher expression of iNOS mRNA in MS brains than in normal brains (6,14).CD40, a 45-50-kDa receptor, is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed in a wide range of both immune and non-immune cell types (16 -18). Recently, several investigators have shown that enhanced CD40-CD40 ligation can be dangerous to the host as it is involved in the pathogenesis of a number of autoimmune inflammatory diseases (e.g. MS, arthritis, insulin-dependent diabetes) (19 -21). High levels of CD40 ligand (CD40L)-expressing cells co-localize with CD40-positive cells in both MS and EAE; most of these CD40-positive cells are of the monocytic lineage (macrophages or microglia) (19,20). Furthermore, the importance of CD40-CD40L interaction in the disease process of EAE/MS has been highlighted by the fact that administration of anti-CD40L monoclonal antibody attenuates the development of EAE (20,21) and that EAE cannot be induced in CD40L(Ϫ/Ϫ) mice (19). However, the molecular events surrounding the marked increase of CD40 ligation in neural tissues of MS patients and EAE animals are not completely understood.

Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia. Expression of the tat gene as RSV-tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the

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