Health System Creation and Integration at a Health Sciences University: A Five-Year Follow-up.

EXECUTIVE SUMMARY: Shifting healthcare market forces and regulation have exerted near-constant pressure on U.S. academic health centers (AHCs) attempting to successfully execute their traditional tripartite mission. A governance structure and organizational alignment that works well under one set of conditions is rarely optimal when conditions change. Thus, the degree and type of alignment of an AHC's clinical, educational, and faculty practice organizations have changed regularly within the sector, typically landing near one end or the other on a continuum from fully aligned with centralized governance to largely independent with separate governance. The authors examine the case of Georgia Regents University and Health System in this context. In step with industry trends, the institution's governance structure swung from fully aligned/centralized governance in the early 1990s to essentially separate and decentralized by 2000. In 2010, the Georgia Regents University organizations achieved rapid realignment by creating a governance structure of sufficient strength and flexibility to absorb and adjust to continuing external upheaval. The hospitals, clinics, and physician-faculty practice group were combined into one integrated health system, then aligned with the university to form the state's only public AHC under aligned, but distinct, corporate and management structures. The years since reorganization have seen significant growth in patient volumes and complexity, improved service quality, and enhanced faculty physician satisfaction, while also significantly increasing economic contributions from the health system to the academic mission. This case study offers observations and lessons learned that may be useful to other higher education institutions considering reorganization.

Effects of sub-toxic concentrations of camphorquinone on cell lipid metabolism.

The biological effects of camphorquinone (CQ), an initiator for light-polymerized resins, have been reported to relate to its ability to generate free radicals and cause radical-induced membrane damage via lipid peroxidation. However, the effects of CQ on lipids other than peroxidation may result in unfavorable tissue responses especially at concentrations that are not overtly toxic to cells. The purpose of the current study was to examine the effects of CQ on cell lipid metabolism at subtoxic concentrations, with or without visible light irradiation. HCP and THP-1 cells were exposed to CQ with or without light irradiation under clinically relevant conditions and lipid metabolism was analyzed using 14C-labeling and thin-layer chromatography. We found that CQ increased synthesis of neutral lipids, such as triglycerides, from 7 to nearly 15% of the total and diglycerides from 2% to about 3% of the total in HCP cells, while synthesis of phospholipids, such as sphingomyelin, was decreased by 1-1.5%. In THP-1 cells cholesterol synthesis increased more than 2-fold and cholesterol ester synthesis increased more than 5-fold. Light-activated CQ did not differ significantly in terms of its bioactivity compared to no-light conditions. We conclude that CQ significantly altered the metabolism of several important structural lipids in two cell types at sub-toxic concentrations that are clinically relevant. These changes in lipid metabolism may in turn affect membrane integrity and permeability and possibly lead to significant changes in cell responses.

Mercury (II) alters mitochondrial activity of monocytes at sublethal doses via oxidative stress mechanisms.

The perennial controversy about the safety of mercury in dental amalgams has adversely affected the availability and the quality of dental care. Chronic Hg(II) blood concentrations above 300 nM are known to alter function of the nervous system and the kidney. However, the effects of blood concentrations of 10 to 75 nM, far more common in the general population, are not clear and mechanisms of any effects are not known. The monocyte is an important potential target of Hg(II) because of its critical role in directing inflammatory and immune responses. In the current study we tested the hypothesis that concentrations of Hg(II) of 10 to 300 nM alter monocyte activity via a redox-dependent mechanism. Mitochondrial activity was used to establish inhibitory concentrations of Hg(II) following 6 to 72 h of exposures to THP1 human monocytic cells. Then subinhibitory concentrations were applied, and total glutathione levels and reactive oxygen species (ROS) were measured. Antioxidants [N-acetyl cysteine, (NAC); Na2SeO3, (Se)] and a pro-oxidant (tert-butylhydroquinone, tBHQ) were used to support the hypothesis that Hg(II) effects were redox-mediated. After 72 h of exposure, 20 microM of Hg(II) inhibited monocytic mitochondrial activity by 50%. NAC mitigated Hg(II)-induced mitochondrial suppression only at concentrations of greater than 10 microM, but Se had few effects on Hg-induced mitochondrial responses. tBHQ significantly enhanced mitochondrial suppression at higher Hg(II) concentrations. Hg(II) concentrations of 75 and 300 nM (0.075 and 0.30 microM, respectively) significantly increased total glutathione levels, and NAC mitigated these increases. Se plus Hg(II) significantly elevated Hg-induced total cellular glutathione levels. Increased ROS levels were not detected in monocytes exposed to mercury. Hg(II) acts in monocytic cells, at least in part, through redox-mediated mechanisms at concentrations below those commonly associated with chronic mercury toxicity, but commonly occurring in the blood of some dental patients.

Effect of vascular stent alloys on expression of cellular adhesion molecules by endothelial cells.

OBJECTIVE: Nickel and cobalt ions activate ICAM1 expression on endothelial cells and keratinocytes. Furthermore, these ions are released in vitro and in vivo from the types of alloys used for vascular stents, but the full biological consequences of this release is not known. In the current study, we determined if release of elements from vascular stent alloys that contained nickel and cobalt was sufficient to activate expression of key cellular adhesion molecules (CAMs) by endothelial cells. Expression of these CAMs is a critical step in the long-term inflammatory response to stent materials and possibly to in-stent restenonsis. METHODS: Stainless steel, NiTi, CoCrNi, and NiCr alloys were placed in direct contact with primary human microvascular endothelial cells for 72 hours after preparation at three roughnesses (120, 320, and 1200 grit). Expression of three CAMs--ICAM1, VCAM1, and e-selectin--was assessed using a modified ELISA procedure. Cytotoxicity of the alloys was assessed by measuring succinate dehydrogenase (SDH) activity and total protein content of the cells, and nickel release was measured by atomic absorption spectroscopy. RESULTS: None of the alloys suppressed SDH activity or total cellular protein significantly at any surface roughness, indicating little or no cytotoxicity. Ni release was measurable from all alloys, was greatest from the rougher surfaces, and was significantly different for the different alloy types. NiTi alloys exhibited the lowest nickel release. However, none of the alloys activated expression of the CAMs, regardless of surface roughness or nickel release level. Supplemental experiments using nickel ions alone confirmed that ICAM1 was inducible on the endothelial cells by Ni(II) concentrations above 100 microM. CONCLUSIONS: In this in vitro system, nickel or other elemental release from several common types of stent alloys was not sufficient to activate expression of CAMs on endothelial surfaces. Although these results indicate a low risk for direct activation of endothelial cells by ions released from stent alloys, other mechanisms, such as modulation of CAM expression by monocytes or smooth muscle cells, must be considered before ion-mediated influence on CAM expression can be dismissed.

Blue light differentially alters cellular redox properties.

Blue light (lambda = 380-500 nm) historically has been used to initiate polymerization of biomaterials and recently has been proposed as a therapeutic agent. New evidence suggests that cell-type-specific responses result from redox changes induced by exposure to blue light. Cultured cells were exposed to defined doses of blue light, equivalent to exposure times of 10 s and 2 min, to achieve energies of 5 J/cm2 and 60 J/cm2, respectively, after which (a) viable cell number, (b) cellular protein profiles, (c) mitochondrial succinate dehydrogenase (SDH) activity, (d) total reactive oxygen species (ROS), and (e) induction of apoptosis were compared to that of nonexposed control cultures. Results showed that blue-light exposure arrested monocyte cell growth and increased levels of peroxiredoxins. SDH activity of normal epidermal keratinocytes (NHEK) was slightly enhanced by blue light, whereas identical treatment of OSC2 oral tumor cells resulted in significant suppression of SDH activity. Blue-light exposure generally induced higher levels of total ROS in OSC2 cells than in NHEK. Finally, only OSC2 cells exhibited signs of apoptosis via Annexin V staining following exposure to blue light. These data support the central hypothesis that blue light induces an oxidative stress response in cultured cells resulting in cell-type-specific survival outcomes. The identification of oxidative stress as a mediator of the effects of blue light is a critical first step in defining its biological risks and therapeutic opportunities.

Alterations of cell lipids by metal salts.

Metallic medical devices undergo degradation in vivo and the degradation products affect the chemistry and biological responses of cells and tissues in the immediate vicinity. The responses vary with the metal and cell type. In the current study, we examined the effects of several metals on a human monocytic cell line. Monocytes are important effector cells capable of responding rapidly to inflammatory and immune stimuli in a variety of ways, including production of inflammatory proteins, differential expression of surface adhesion molecules, enhanced phagocytic activity, and activation and differentiation to macrophages. Cells were exposed in the presence of (14)C-acetate to titanium, nickel, chromium, copper, or cobalt or vanadium at concentrations that were subinhibitory or inhibitory based on cellular mitochondrial dehydrogenase activity. Cell lipids were then extracted, separated by thin layer chromatography, and quantitated by liquid scintillation spectrometry. Total cell protein also was measured. Titanium reduced cell protein content at concentrations that were noninhibitory to mitochondrial dehydrogenase activity, whereas neither chromium nor cobalt affected protein amounts at dehydrogenase-inhibitory concentrations. In cells exposed to vanadium, the protein- and dehydrogenase-inhibitory concentrations were similar. The major effects on cell lipids appeared to occur in the neutral lipids, although chromium, cobalt, and titanium produced changes in some major phospholipids. These results suggest that metals differentially affect various metabolic pathways in THP-1 cells, perhaps related to their abilities to enter the cells or interact with the membrane. These alterations to the cells may affect the cells' abilities to respond to various stimuli that can damage the tissues.

Chemoprevention of oral cancer by green tea.

Green tea has been a popular beverage for many centuries. Only recently, however, has the anti-cancer power of green tea constituents been unveiled. Green tea polyphenols are found to induce apoptosis (programmed cell death) in many types of tumor cells, including oral cancer cells. However, mechanisms that enable normal cells to evade the apoptotic effect still are not understood. In this study, cell growth and invasion assays combined with apoptosis assays were used to examine the effects of green tea extracts, green tea polyphenols, and the most potent green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), on normal human keratinocytes and oral carcinoma cells. The results showed that green tea and its constituents selectively induce apoptosis only in oral carcinoma cells, while EGCG was able to inhibit the growth and invasion of oral carcinoma cells. These differential responses to green tea and its constituents between normal and malignant cells were correlated with the induction of p57, a cell cycle regulator. These data suggest that the chemopreventive effects of green tea polyphenols may involve a p57 mediated survival pathway in normal epithelial cells, while oral carcinoma cells undergo an apoptotic pathway. Therefore, regular consumption of green tea could be beneficial in the prevention of oral cancer.

Nicotine modulation of in vitro human gingival fibroblast beta1 integrin expression.

BACKGROUND: Smoking is clearly a high-risk behavior for the development of periodontal disease, and nicotine is the major vasoactive component in tobacco. Integrins are a large family of homologous transmembrane adhesion proteins serving as the principal receptors on animal cells to bind and communicate with many extracellular matrix proteins such as collagen, fibronectin, and laminin. This study's aim was to evaluate nicotine's effects on beta1 integrin expression as a function of either 1) the generalized effects on RNA/protein synthesis or 2) as a specific modulation of beta1 integrin synthesis. METHODS: Pooled human gingival fibroblasts (HGFs) were cultured in nicotine concentrations commonly seen in smokers (0.025 to 0.8 microM), and relative incorporation of [35S]methionine into newly synthesized protein or [3H]uridine into newly synthesized RNA was measured. Cultures were harvested at various times, and duplicate cell aliquots were homogenized and fractionated to obtain cell membrane-enriched preparations or solubilized to obtain whole cell lysates. Radiolabeled RNA and proteins were quantitated by trichloroacetic acid (TCA) precipitation and liquid scintillation spectrometry. Beta1 integrin subunits were detected by SDS-PAGE and Western blotting, and the relative intensities of reactive bands were quantitated by scanning densitometry. RESULTS: After 17 hours of exposure, 0.4 and 0.8 microM nicotine resulted in a dose-dependent increase in beta1 integrin in whole cell lysates, and a decrease in beta1 integrin in the corresponding membrane-enriched fractions. There was also a statistically significant decrease (P < or = 0.05) in radiolabeled proteins in culture. Although there appeared to be a mild, generalized reduction in radiolabeled RNA in nicotine-treated cultures compared to controls, a 1-way analysis of variance showed no statistical significance between values. CONCLUSIONS: Our results suggest that nicotine may induce an altered compartmentalization process in which beta1 integrin molecules are produced, but are not appropriately transferred to the membrane. Nicotine effects on cellular protein synthesis and its modulation of beta1 integrin expression may impair gingival fibroblast ability to adhere to and communicate with one another and with the extracellular matrix, which could impair wound healing and/or exacerbate periodontal disease.