Bone marrow- or vessel wall-derived osteoprotegerin is sufficient to reduce atherosclerotic lesion size and vascular calcification.

OBJECTIVE: Osteoprotegerin (OPG) is a decoy receptor for the osteoclast differentiation factor receptor activator of NF-κB ligand. OPG regulates bone homeostasis, and its inactivation in mice results in severe osteoporosis. OPG deficiency in apolipoprotein E (ApoE)(-/-) mice results in increased atherosclerotic lesion size and calcification. Furthermore, receptor activator of NF-κB ligand enhances macrophage-dependent smooth muscle cell calcification in vitro. Here, we hypothesized that reconstitution of ApoE(-/-)OPG(-/-) mice with ApoE(-/-)OPG(+/+) bone marrow (BM) would be sufficient to rescue lesion progression and vascular calcification. Conversely, reconstitution of ApoE(-/-)OPG(+/+) mice with ApoE(-/-)OPG(-/-) BM may accelerate lesion progression and vascular calcification. APPROACH AND RESULTS: ApoE(-/-)OPG(-/-) mice transplanted with ApoE(-/-)OPG(+/+) BM developed smaller atherosclerotic lesions and deposited less calcium in the innominate artery than that of ApoE(-/-)OPG(-/-) mice transplanted with ApoE(-/-)OPG(-/-) BM. There were no differences in lesion size and calcification in ApoE(-/-)OPG(+/+) mice transplanted with BM from ApoE(-/-)OPG(-/-) or ApoE(-/-)OPG(+/+) mice. The large lesions observed in the ApoE(-/-)OPG(-/-) mice transplanted with OPG(-/-) BM were rich in chondrocyte-like cells, collagen, and proteoglycans. Importantly, the ApoE(-/-)OPG(-/-) mice transplanted with OPG(+/+) BM remained osteoporotic, and the ApoE(-/-)OPG(+/+) mice did not show signs of bone loss regardless of the type of BM received. In coculture experiments, macrophages and mesenchymal stem cells derived from ApoE(-/-)OPG(-/-) BM induced more vascular smooth muscle cell calcification than cells derived from ApoE(-/-)OPG(+/+) mice. CONCLUSIONS: These results indicate that OPG derived either from the BM or from the vessel wall is sufficient to slow down lesion progression and vascular calcification independent of bone turnover.

Development of a lipoprotein based molecular imaging MR contrast agent for the noninvasive detection of early atherosclerotic disease.

INTRODUCTION: Currently there are no clinically available means of noninvasively detecting early atherosclerotic disease because these lesions are characterized by an accumulation of extracellular lipid and foam cells, but a lack of significant wall thickening or architectural distortion. OBJECTIVE: We hypothesize that a paramagnetically labeled low density lipoprotein (LDL) could serve as a functional probe to detect sites of abnormal lipid metabolism in the vessel wall that represent sites of early disease. METHODS: Isolated LDL was first incubated with manganese-mesoporphyrin, a hydrophobic MR contrast agent (MnMeso). Size exclusion chromatography and absorption mass spectroscopy were performed on the resulting samples to prove that an association between the two occurred. Subsequently, foam cell cultures (n=7) were incubated (10-30 microg/ml for 48 h) with these labeled lipoproteins and the T1 relaxivity of centrifuged pellets of these cells was determined by using an inversion recovery sequence on a 1.5T scanner. These results were compared to control measurements made from foam cell cultures fed unlabeled lipoproteins (n=7). RESULTS: Measured T1 relaxation times of the cells fed the MnMeso-LDL (443.3 +/- 51.8 ms) was significantly different from the T1 relaxivity obtained from cells fed unlabeled lipoproteins (661.3 +/- 60.9 ms). These findings indicate that the amount of contrast bound to the constructed lipoproteins is sufficient to produce measurable MR signal changes noninvasively. CONCLUSIONS: The study results support the feasibility of future in vivo MR experiments with labeled lipoproteins to assess lipoprotein kinetics in the vessel wall, which will hopefully provide a means of detecting early atherosclerotic disease.

Laryngeal cancer cost analysis: association of case-mix and treatment characteristics with medical charges.

OBJECTIVES: To examine the relationship of various pretreatment case-mix characteristics and treatment modalities with medical charges incurred during diagnosis, treatment, and 2-year follow-up for patients with laryngeal cancer. DESIGN: Retrospective chart review and billing record analysis. METHODS: The charts and billing records of patients diagnosed with laryngeal cancer at the University of Iowa Hospitals and Clinics (UIHC) between January 1, 1991 and December 31, 1994 were reviewed. The independent variables included various pretreatment patient-mix and tumor characteristics (age, AJCC TNM clinical stage, smoking history, ASA class, and comorbidity as defined by Kaplan-Feinstein grade) as well as type of treatment. The dependent variables included total physician, office, and university hospital-based charges incurred during the pretreatment evaluation and 0- to 3-, 3- to 12, and 12- to 24-month billing periods after the initiation of cancer-directed therapy. Total 1-year and 2-year charges were also evaluated. Univariate and multivariate analyses were used to investigate the relationships between dependent and independent variables and to develop models predictive of management charges during the individual and total billing periods. RESULTS: Pretreatment charges showed no significant associations (P < .05) with any of the independent variables. Multiple regression analyses indicated that comorbidity, stage, and initial treatment modality were significant variables in one or more of the models predicting charges incurred during the 0- to 3-month, 3- to 12-month, total 1-year, and total 2-year billing periods. The models yielded R2 values for the total 1- and 2-year billing periods of 0.5246 and 0.5055, respectively. CONCLUSIONS: This work supports continued study of measures that may result in earlier detection of laryngeal cancer as a potential means of reducing management charges. These results also indicate that a more accurate method of stratifying the disease severity of laryngeal cancer patients for reimbursement purposes would include measurements of the severity of the index disease as well as comorbid diseases.

Cost-identification analysis in oral cavity cancer management.

The objectives of this study were to investigate potential relationships between pretreatment patient-mix characteristics, treatment modalities, and costs generated during the pretreatment work-up, treatment, and 1-year follow-up periods for patients with oral cavity cancer (OCC). Another objective was to identify potential areas for cost reduction and improved resource allocation in the management of OCC patients. Using a retrospective cohort of 73 patients with OCC, pretreatment patient-mix characteristics and treatment modalities were evaluated in relation to university-based charges incurred during the pretreatment evaluation, treatment, and 1-year follow-up periods. Simple regression and stepwise multiple regression analyses were used to develop predictive models for cost based on independent variables, including age, AJCC TNM clinical stage, smoking history, American Society of Anesthesiologists (ASA) class, comorbidity as defined by the Kaplan-Feinstein grade and treatment modality. The dependent measurements included all physician, office, and hospital charges incurred at the University of Iowa Hospitals and Clinics during the pretreatment evaluation, treatment, and follow-up periods, as well as the total pretreatment through 1-year follow-up management costs. Independent variables that were identified as being significantly associated with treatment costs included T classification, N classification, TNM stage, unimodality versus multimodality treatment, and the Kaplan-Feinstein comorbidity grade. Age, smoking status, and ASA class were not significantly associated with costs. The majority of the OCC management costs were incurred during the treatment period. The most substantial decreases in management costs for OCC will be realized through measures that allow identification and treatment of disease at an early stage, in which single-modality treatment may effectively be used. Resource allocation for OCC should support the investigation of measures through which the diagnosis and treatment of OCC at the earliest possible stage is facilitated. The presence of comorbid illness is a significant component in the determination of management costs for OCC and should be included in analyses of resource allocation for OCC. The singular diagnosis of OCC encompasses a wide range of patient illness severity, and diagnosis-related reimbursement schemes for OCC treatment should optimally differentiate between early and advanced stage disease.

Assessment of glutaraldehyde crosslinking efficiency with an amine-specific fluorescent probe.

BACKGROUND: Crosslinking of heart valves with glutaraldehyde involves the binding of amine groups. We have developed a technique that provides an inverse measure of the degree of tissue fixation by quantifying the amount of unbound amines. METHODS: Whole aortic valves were exposed to 0.5% glutaraldehyde solution for 0, 1, 15, and 60 minutes, 6 hours, and 1 and 7 days. Frozen sections were exposed to carboxyfluorescein succinimidyl ester, a fluorescent amine-reactive probe. Images were acquired from each section and processed to separate pixels representing tissue from those representing background. An average fluorescent intensity for each image was calculated and related to the number of unbound amines by comparing with standards. RESULTS: The amount of uncrosslinked amines was observed to decrease exponentially with fixation time and achieved a plateau at 1 day of fixation. A significant difference in the amount of unbound amines also exists between valve leaflets fixed while connected to the root and those excised from the root before fixation. CONCLUSIONS: This amine measurement technique, being sensitive to spatially varying differences in chemical fixation, should be useful in evaluating the efficacy of new fixation protocols.

Cell cycle analysis in the cardiac and neuroepithelial tissues of day 10 rat embryos and the effects of phosphoramide mustard, the major teratogenic metabolite of cyclophosphamide.

Using the autoradiographic technique of percent labeled mitoses (PLM), total cell cycle length (Tc) and length of the cell cycle phases G1, S, G2, and M have been estimated for the neuroepithelium and heart of day 10 rat embryos. The Tc for the neuroepithelium was estimated to be 9.45 hr, consisting of G1 of 1.24 hr, S of 6.15 hr, G2 of 1.34 hr, and M of 0.72 hr. The Tc for the heart was estimated to be 13.37 hr, consisting of G1 of 4.30 hr, S of 7.01 hr, G2 of 1.81 hr, and M of 0.25 hr. Comparison of cell cycle parameters in these two tissues indicates that the longer cell cycle in heart tissue is related primarily to an increase in G1. If embryos are exposed to the major teratogenic metabolite of cyclophosphamide, phosphoramide mustard, cell cycle analysis reveals that the S phase of the neuroepithelial cell cycle is lengthened and cells are either slowed or arrested in G2.

Radio, social support, and mental health.

The author discusses the rise of "interactive radio" and its potential as a form of social support. Ranging from music request shows to on-air counselling, interactive radio reduces isolation, allows listeners to participate in various kinds of networking and dialogue, and conveys information and advice that may be helpful in promoting mental health. Based in part on his own experience with a weekly program, the author identifies characteristics of interactive radio that will be to interest or professionals who want to use the medium for community mental health promotion.

Eccentric pericardial effusion after radiation therapy of left breast carcinoma.

Pericardial damage is one of the consequences of cardiac radiation and may lead to chronic pericarditis and/or tamponade. In three patients treated with radiation for carcinoma of the left breast, the effusions were loculated on the right side of the pericardium resulting in a peculiar cardiac silhouette. The importance of recognizing this entity and possible treatment is stressed.