E-Cadherin, beta -Catenin and cadmium carcinogenesis.

Cadmium (Cd(2+)) is an important industrial and environmental pollutant that has been classified as a human carcinogen. Studies reported in the literature indicate that cadmium may play a role in both the initiation of cancer, by activating oncogenes, and in the progression of cancer, by increasing the metastatic potential of existing cancer cells. However, the mechanisms underlying these effects have yet to be elucidated. Recent studies from our laboratory have shown that cadmium can disrupt the tight junctions between many types of epithelial cells by interfering with the normal function of E-cadherin, a Ca(2+)-dependent cell adhesion molecule that plays a key role in epithelial cell-cell adhesion. This finding may be especially significant because a large volume of evidence indicates that the disruption of E-cadherin-mediated cell adhesion can trigger the beta-catenin-mediated activation of oncogenes in epithelial cells and increase the invasive potential of existing epithelial-derived cancers. The hypothesis that we are proposing is that the cadmium-induced disruption of E-cadherin dependent cell-cell junctions may represent a pivotal step in both the initiation of cancer by cadmium and in the tumor promoting actions of cadmium.

The role of district hospitals and the action in international medicine network.

As the first-referral hospitals for the primary health care (PHC) services, district hospitals providing secondary health care (SHC) have a peculiar importance in the developing world. The World Health Organization has led the way in defining their functions and adopting the concept of the district health system linking PHC and SHC in a vital relationship. The author's personal experience in this area over many years in Nigeria is presented in this article. The need for postgraduate training programs to encourage physicians to pursue a career at the district level is becoming widely recognized as an extension of the discipline of general practice/family medicine.

Function associated with IL-2 receptor-beta on human neutrophils. Mechanism of activation of antifungal activity against Candida albicans by IL-2.

Polymorphonuclear neutrophils (PMN) are essential components of the host defense system against a wide variety of pathogens. We report here the novel finding that freshly isolated human PMN constitutively express detectable surface levels of IL-2R beta, but not IL-2R alpha, as analyzed by flow cytometry. Northern blot analysis confirmed the constitutive expression of mRNA for IL-2R beta in PMN. Scatchard analysis using 125I-labeled IL-2 demonstrated the presence of approximately 600 intermediate binding IL-2R per PMN, with a dissociation constant of 1.1 x 10(-9) M, similar to that of IL-2 binding to YT-1 tumor cells that specifically express IL-2R beta. More importantly, PMN were able to respond functionally to IL-2 by enhanced growth-inhibitory activity against an opportunistic fungal pathogen, Candida albicans. IL-2 activation of antifungal activity was dose-dependent, with some functional activation detected at 1 U/ml of rIL-2 and maximal activation at 1000 U/ml. The action of IL-2 was rapid, with maximal PMN activation after 30-min incubation with IL-2. The IL-2 enhancement of antifungal activity could be blocked by a specific antibody against IL-2R beta, but not by anti-IL-2R alpha. Analysis of the mechanism of IL-2 activation of PMN indicated that oxidative metabolism, as measured by superoxide anion production, was not involved. Instead, PMN release of lactoferrin appeared to be responsible for the heightened activity against C. albicans in IL-2-treated PMN. Not only was lactoferrin detected in the supernatants of IL-2-treated PMN, but also the antifungal activity of PMN activated by IL-2 could be blocked in the presence of antilactoferrin. These results, taken together, indicate that normal PMN are capable of functionally responding to IL-2 via expression of the IL-2R beta chain.

Lactoferrin release and interleukin-1, interleukin-6, and tumor necrosis factor production by human polymorphonuclear cells stimulated by various lipopolysaccharides: relationship to growth inhibition of Candida albicans.

Lipopolysaccharides (LPSs) from Escherichia coli, Serratia marcescens, and Salmonella typhimurium, at doses from 1 to 100 ng/ml, strongly enhanced growth inhibition of Candida albicans by human polymorphonuclear leukocytes (PMN) in vitro. Flow cytometry analysis demonstrated that LPS markedly augmented phagocytosis of Candida cells by increasing the number of yeasts ingested per neutrophil as well as the number of neutrophils capable of ingesting fungal cells. LPS activation caused augmented release of lactoferrin, an iron-binding protein which itself could inhibit the growth of C. albicans in vitro. Antibodies against lactoferrin effectively and specifically reduced the anti-C. albicans activity of both LPS-stimulated and unstimulated PMN. Northern (RNA blot) analysis showed enhanced production of mRNAs for interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 and in neutrophils within 1 h of stimulation with LPS. The cytokines were also detected in the supernatant of the activated PMN, and their synthesis was prevented by pretreatment of LPS-stimulated PMN with protein synthesis inhibitors, such as emetine and cycloheximide. These inhibitors, however, did not block either lactoferrin release or the anti-Candida activity of LPS-stimulated PMN. These results demonstrate the ability of various bacterial LPSs to augment neutrophil function against C. albicans and suggest that the release of a candidastatic, iron-binding protein, lactoferrin, may contribute to the antifungal effect of PMN. Moreover, the ability to produce cytokines upon stimulation by ubiquitous microbial products such as the endotoxins points to an extraphagocytic, immunomodulatory role of PMN during infection.

Differential release of interleukin (IL)-1 alpha, IL-1 beta, and IL-6 from normal human monocytes stimulated with a virulent and an avirulent isogenic variant of Mycobacterium avium-intracellulare complex.

Members of the Mycobacterium avium-intracellulare complex (MAC) can exist in a transparent or opaque colonial morphology when cultured on synthetic medium. An opaque variant was developed from a transparent strain of a clinical MAC isolate. Comparison of the two variants showed a greater ability of the transparent colonial variant to infect normal human monocytes as measured by growth in monocyte-bacteria cocultures. Further analyses indicated diminished ability of the transparent variant to induce extracellular secretion of interleukin (IL)-1 and IL-6, as well as membrane-associated IL-1 when compared with the opaque isotype. At the molecular level, induction of specific IL-1 alpha, IL-1 beta, and IL-6 mRNAs was consistent with the protein results. These results suggest that the virulent transparent MAC, as opposed to the avirulent opaque type, may escape host defenses by failing to induce IL-1 and IL-6, key factors in the initiation of a normal immune response.