Eric Gershwin

The Potential Adverse Health Effects of Dental Amalgam

There is significant public concern about the potential health effects of exposure to mercury vapour (Hg0) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg0, evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects.Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg0 is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg0 released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg0 and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg0 levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20–30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.

Autoantibody Profile of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease of unknown etiology. It has been suggested that genetic and immunological factors are important in its pathogenesis. The present study examined the prevalence of 23 different autoantibodies in 25 PSC sera, by ELISA, in order to better define the autoimmune profile of PSC. The results indicate that 88% of PSC patients produced at least 1 autoantibody, and 36% had reactivity to multiple autoantibodies. Moreover, 35% of the PSC patients produced anti-endothelial-cell antibodies (AECA) and 75% of the sera contained perinuclear antineutrophil cytoplasmic antibodies (pANCA), detected by indirect immunofluorescence. The prominent ANCA autoantibody was anti-cathepsin-G, demonstrated in 35% of the patients. The multiplicity of the autoantibody profile, revealed in the present study, points to the autoimmune characteristics of PSC. In addition, the association of ANCA and of AECA in PSC may suggest a pathogenic role for these antibodies in PSC.

Crosstalk among IL-23 and DNAX Activating Protein of 12 kDa–Dependent Pathways Promotes Osteoclastogenesis

IL-23 has been well studied in the context of T cell differentiation; however, its role in the differentiation of myeloid progenitors is less clear. In this paper, we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human PBMCs, IL-23 induces the expression of MDL-1, a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DNAX activating protein of 12 kDa and its ITAMs. The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on spleen tyrosine kinase and phospholipase Cγ2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor NFATc1. IL-23–elicited osteoclastogenesis is independent of the receptor activator of NF-κB ligand pathway and uses a unique myeloid DNAX activating protein of 12 kDa–associated lectin-1+/DNAX activating protein of 12 kDa+ cell subset. Our data define a novel pathway that is used by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis.

Macrophage-Mediated Inhibition of Melanoma Cell Growth in Nude Mice

The effects of macrophages or sera from tumor-transplanted or control syngeneic and allogeneic mice on the latency and growth rate of P51 murine melanoma cells were determined after transplantation into congenitally athymic (nude) mice (tumor neutralization test). Syngeneic macrophages from tumor-bearing mice (TBM) inhibited melanoma growth in the nude mouse more than control macrophages, additionally macrophages from sensitized allogeneic mice inhibited melanoma growth to a greater degree than did allogeneic control macrophages. Sera from TBM inhibited melanoma growth as compared to control cells alone. Macrophages obtained after 14 days were also cytolytic towards the melanoma target in vitro. Despite the growth of large local masses, no evidence of distant metastases was found. The nude mouse thus provides an appropriate model for this tumor to portray in vivo immunotherapy.

Xenobiotic Induced Model of Primary Biliary Cirrhosis

Abstract Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver that is, characterised by destruction of the intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMAs). Several murine models of PBC, with similar serological, biochemical, and histological features to human PBC, have been developed in recent years. These animal models enable investigators to study the etiology and pathophysiologic mechanism of PBC. Immune response in PBC is directed towards E2 components of the 2-oxo-acid dehydrogenase family of enzymes, which is in located in mitochondria and is an immunodominant epitope (a lipoylated peptide sequence shared by enzymes). Immunisation of mice with 2-octynoic acid coupled to bovine serum albumin (2-OA-BSA) (which is an antigen that is structurally related to the E2 subunit of the pyruvate dehydrogenase complex [PDC-E2]) produces histologic features similar to those found in human PBC. Th is model of xenobiotic induced PBC is suitable for studying the early events in PBC pathogenesis and for developing new therapeutics in PBC. Sažetak Primarna bilijarna ciroza (PBC) je autoimunska bolest jetre koju karakteriše destrukcija intrahepatičnih žučnih kanalića i prisistvo antimitohondrijalnih antitela (AMAs). Poslednjih godina je razvijeno nekoliko mišjih modela PBC koji imaju slične serološke, biohemijske i histološke karakteristike kao i humana PBC. Ovi animalni modeli su omogućili ispitivanje etiologije i mehanizama uključenih u patogenezu PBC. U PBC imunski odgovor je usmeren na E2 komponentu 2-okso-kiseline dehidrogenaza familije enzima koji su locirani u mitohondrijama, a imunodominantni epitop je peptidna sekvenca sa lipidima koja je zajednička za ove enzime. Imunizacija miševa 2-oktinoičnom kisleinom vezanom za goveđi serumski albumin (2-OA-BSA), antigenom koji je strukturno sličan E2 subjedinici kompleksa piruvat dehidrogenaze (PDC-E2), omogućava razvoj histoloških promena koje karakterišu PBC kod ljudi. Ovaj model PBC indukovan ksenobiotikom je pogodan za ispitivanje početnih događaja u patogenezi PBC i za razvoj novih lekova za PBC.

Crosstalk among IL-23 and DNAX Activating Protein of 12 kDa-Dependent Pathways Promotes Osteoclastogenesis - eScholarship

IL-23 has been well studied in the context of T cell differentiation; however, its role in the differentiation of myeloid progenitors is less clear. In this paper, we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human PBMCs, IL-23 induces the expression of MDL-1, a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DNAX activating protein of 12 kDa and its ITAMs. The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on spleen tyrosine kinase and phospholipase Cγ2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor NFATc1. IL-23–elicited osteoclastogenesis is independent of the receptor activator of NF-κB ligand pathway and uses a unique myeloid DNAX activating protein of 12 kDa–associated lectin-1+/DNAX activating protein of 12 kDa+ cell subset. Our data define a novel pathway that is used by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis.