Biomedical subjects
J Feder
Publications and source records attributed to J Feder.
Young physicians most and least likely to have second thoughts about a career in medicine.
To identify factors associated with apparent disaffection with medicine as a career, the authors analyzed data for 4,931 young physicians surveyed in 1987. Using survey responses, the authors classified 932 of the physicians (18.9%) as most likely to have second thoughts about their career choices and 1,094 (22.2%) as least likely to have second thoughts. The group with the greatest reservations included significantly higher proportions of white women, blacks, and Hispanics. This group reported significantly lower incomes, higher educational debt, and more hours and patients' visits per week. Among employee physicians, those most disaffected were significantly more likely to report inappropriate use of tests and procedures and lack of autonomy in their practices. The authors conclude that it is important to reexamine the heavy reliance on debt financing of medical education, especially for minority students, and to explore the equality of career opportunities for women and minorities in medicine.
Comparison of uninsured and privately insured hospital patients. Condition on admission, resource use, and outcome.
To investigate the association between insurance status and condition on admission, resource use, and in-hospital mortality, we analyzed discharge abstracts for 592,598 patients hospitalized in 1987 in a national sample of hospitals. In 13 of 16 age-sex-race-specific cohorts, the uninsured had a 44% to 124% higher risk of in-hospital mortality at the time of admission than did the privately insured. After controlling for this difference, the actual in-hospital death rate was 1.2 to 3.2 times higher among uninsured patients in 11 of 16 cohorts. The uninsured also were 29% to 75% less likely to undergo each of five high-cost or high-discretion procedures and 50% less likely to have normal results on tissue pathology reports for biopsies performed during five of seven different endoscopic procedures. Our results suggest that insurance status is associated with a broad spectrum of aspects of hospital care.
Free bone graft reconstruction of irradiated facial tissue: experimental effects of basic fibroblast growth factor stimulation.
A study was undertaken to evaluate the potential utility of basic fibroblast growth factor in the induction of angiogenesis and osseous healing in bone previously exposed to high doses of irradiation. Thirty New Zealand rabbits were evaluated by introducing basic fibroblast growth factor into irradiated mandibular resection sites either prior to or simultaneous with reconstruction by corticocancellous autografts harvested from the ilium. The fate of the free bone grafts was then evaluated at 90 days postoperatively by microangiographic, histologic, and fluorochrome bone-labeling techniques. Sequestration, necrosis, and failure to heal to recipient osseous margins was observed both clinically and histologically in all nontreated irradiated graft sites as well as those receiving simultaneous angiogenic stimulation at the time of graft placement. No fluorescent activity was seen in these graft groups. In the recipient sites pretreated with basic fibroblast growth factor prior to placement of the graft, healing and reestablishment of mandibular contour occurred in nearly 50 percent of the animals. Active bone formation was evident at cortical margins adjacent to the recipient sites but was absent in the more central cancellous regions of the grafts.
Assignment of eight human genomic DNA sequences detecting high frequency restriction fragment length polymorphisms.
From a lambda Charon 4A library digested with EcoRI, eight human genomic clones have been isolated, each detecting a high frequency RFLP. These phage clones have been assigned to eight different human chromosomes using Southern blot analysis and human-rodent somatic cell hybrids.
Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor.
Rodent and human tumor cell lines secrete a potent vascular permeability factor (VPF) which causes a rapid and substantial increase in microvascular permeability to plasma proteins without causing mast cell degranulation, or endothelial cell damage or without exciting an inflammatory cell infiltrate [D. R. Senger, S. J. Galli, A. M. Dvorak, C. A. Perruzzi, V. S. Harvey, and H. F. Dvorak. Science (Wash. DC), 219: 983-985, 1983; D. R. Senger, C. A. Perruzzi, J. Feder, and H.F. Dvorak. Cancer Res., 46: 5629-5632, 1986]. VPF now has been purified to homogeneity from guinea pig tumor cell culture medium; it is a Mr 34,000-43,000 protein, and a NH2-terminal amino acid sequence has been derived. A synthetic peptide corresponding to amino acid residues 1-24 of the native protein was used to raise rabbit antibodies which bind all of the vessel permeability-increasing activity secreted by guinea pig tumor cells and which stain purified VPF on immunoblots. These findings establish that this NH2-terminal amino acid sequence was derived from the permeability factor. Homology searches found no identity or close similarity between VPF NH2-terminal sequence and database sequences, indicating that VPF is distinct from other proteins for which sequence data are available. In particular, no sequence similarity was found between tumor-secreted VPF and other mediators of increased vessel permeability including plasma and glandular kallikreins.
Health care of the disadvantaged: the elderly.
This paper explores threats to the maintenance and expansion of public commitment to financing health care for the elderly. Threats come from rising costs that increase financial burdens, especially on low-income elderly; efforts to contain costs that may undermine benefits; and financing initiatives that treat the elderly as the sole revenue source for addressing problems in that age group. A review of these threats provides lessons not only for sustaining and improving health care for the elderly, but also for policy toward equally or more disadvantaged groups.
Vascular permeability factor, an endothelial cell mitogen related to PDGF.
Vascular permeability factor (VPF) is a 40-kilodalton disulfide-linked dimeric glycoprotein that is active in increasing blood vessel permeability, endothelial cell growth, and angiogenesis. These properties suggest that the expression of VPF by tumor cells could contribute to the increased neovascularization and vessel permeability that are associated with tumor vasculature. The cDNA sequence of VPF from human U937 cells was shown to code for a 189-amino acid polypeptide that is similar in structure to the B chain of platelet-derived growth factor (PDGF-B) and other PDGF-B-related proteins. The overall identity with PDGF-B is 18%. However, all eight of the cysteines in PDGF-B were found to be conserved in human VPF, an indication that the folding of the two proteins is probably similar. Clusters of basic amino acids in the COOH-terminal halves of human VPF and PDGF-B are also prevalent. Thus, VPF appears to be related to the PDGF/v-sis family of proteins.
Human vascular permeability factor. Isolation from U937 cells.
Human vascular permeability factor (hVPF) is a glycoprotein that promotes fluid and protein leakage from blood vessels. The function of hVPF is at present unknown, but the potent bioactivities of this protein suggest that it could act during inflammation, wound healing, and tumor angiogenesis. hVPF was purified from serum-free conditioned medium of the human histiocytic lymphoma cell line U937 as a disulfide-linked dimeric 40-kDa protein that promoted dermal blood vessel leakage in guinea pigs at a dose of 20 ng (3 x 10(-9) M) and promoted in vitro endothelial cell growth at concentrations as low as 50 PM. Multiple forms of hVPF with apparent pI values greater than 7.5 were resolved using pH gradient electrophoresis. Antibodies against guinea pig vascular permeability factor were found to cross-react with hVPF. The N-terminal amino acid sequence of hVPF was similar to, but not identical with, the N-terminal sequence of guinea pig vascular permeability factor.
Effects of N-glycosylation on in vitro activity of Bowes melanoma and human colon fibroblast derived tissue plasminogen activator.
Tissue-type plasminogen activator (t-PA), when isolated from human colon fibroblast (hcf) cells, is N-glycosylated differently than when isolated from the Bowes melanoma (m) cell line (Parekh et al., 1988). Both hcf- and m-t-PA can be separated into type I t-PA (with three occupied N-glycosylation sequons, at Asn-117, -184, and -448) and type II t-PA (with two occupied sequons, at Asn-117 and -448). Oligosaccharide analysis of each of these types of t-PA indicates that hcf-t-PA and m-t-PA have no glycoforms in common, despite having the same primary amino acid sequence. We have therefore compared in vitro the enzymatic activities and fibrin binding of type I and type II hcf- and m-t-PA with those of aglycosyl t-PA isolated from tunicamycin-treated cells. Plasminogen activation kinetics were determined by using an indirect amidolytic assay with Glu-plasminogen and a chromogenic plasmin substrate. In the absence of stimulator, there was little difference in activity between type I and type II t-PA, but the activity of aglycosyl t-PA was 2-4-fold higher than that of the corresponding glycosylated t-PA. In the presence of a fibrinogen fragment stimulator, the Kcat value of type II t-PA was approximately 5-fold that of type I t-PA from the same cell line, while the Km values for activation of Glu-plasminogen were similar (0.13-0.18 microM). The stimulated activity of glycosyl t-PA was similar to that of type II t-PA.(ABSTRACT TRUNCATED AT 250 WORDS)
Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.
Vascular permeability factor (VPF) is an Mr 40-kD protein that has been purified from the conditioned medium of guinea pig line 10 tumor cells grown in vitro, and increases fluid permeability from blood vessels when injected intradermally. Addition of VPF to cultures of vascular endothelial cells in vitro unexpectedly stimulated cellular proliferation. VPF promoted the growth of new blood vessels when administered into healing rabbit bone grafts or rat corneas. The identity of the growth factor activity with VPF was established in four ways: (a) the molecular weight of the activity in preparative SDS-PAGE was the same as VPF (Mr approximately 40 kD); (b) multiple isoforms (pI greater than or equal to 8) for both VPF and the growth-promoting activity were observed; (c) a single, unique NH2-terminal amino acid sequence was obtained; (d) both growth factor and permeability-enhancing activities were immunoadsorbed using antipeptide IgG that recognized the amino terminus of VPF. Furthermore, 125I-VPF was shown to bind specifically and with high affinity to endothelial cells in vitro and could be chemically cross-linked to a high-molecular weight cell surface receptor, thus demonstrating a mechanism whereby VPF can interact directly with endothelial cells. Unlike other endothelial cell growth factors, VPF did not stimulate [3H]thymidine incorporation or promote growth of other cell types including mouse 3T3 fibroblasts or bovine smooth muscle cells. VPF, therefore, appears to be unique in its ability to specifically promote increased vascular permeability, endothelial cell growth, and angio-genesis.
Case-mix payment for nursing home care: lessons from Maryland.
Even before Medicare adopted case-based payments for hospitals, some state Medicaid programs employed case-mix payment systems for nursing home care. Their purpose was less to promote cost containment than to improve access to nursing homes for the most costly patients. This paper evaluates one such system, adopted by the state of Maryland in 1983 as part of an overall reimbursement reform. Using data on nursing home patient characteristics, costs, and staffing, as well as interviews with officials and various providers of care, the article shows that Maryland's system was successful in shifting nursing home service away from light-care and toward heavy-care patients. Furthermore, the shift occurred without inducing readily measurable declines in quality of care and with little additional administrative cost (partly because the state built its case-mix system on preexisting patient review activities). Although states could learn from and improve upon Maryland's experience--most notably in offering incentives to improve quality of care and in targeting community care on the light-care patients that nursing homes become less willing to serve--Maryland demonstrates that case-mix payment can change nursing home behavior in desired directions without substantial negative consequences.
Profits and fiscal pressure in the prospective payment system: their impacts on hospitals.
For hospitals that were under Medicare's Prospective Payment System (PPS) for one and two years in their 1985 fiscal year, this paper examines how variation in the fiscal pressure PPS imposed affected expenditures and other aspects of behavior. The analysis shows that in hospitals' second as well as first year on PPS, hospitals under greater pressure experienced greater behavioral change. However, second year changes were far smaller than changes in the system's first year. Evidence that variation in pressure reflects factors in addition to hospitals' relative efficiency and may undermine rather than promote appropriate cost containment leads the authors to propose modifications in PPS methods.
Photon correlation spectroscopy of human IgG.
The translational diffusion coefficient D020,w, of monomeric human immunoglobulin G (IgG) has been studied by photon-correlation spectroscopy as a function of pH and protein concentration. At pH 7.6, we find D020,w = 3.89 x 10(-7) cm2/sec, in good agreement with the value determined by classic methods. This value corresponds to an effective hydrodynamic radius R, of 55.1 +/- 0.3 A. As pH is increased to 8.9; with the same ionic strength, the molecule appears to expand slightly (3.5% increase in hydrodynamic radius). The concentration dependence of the IgG diffusion constant is interpreted in terms of solution electrostatic effects and shows that long-range repulsive interactions are negligible in the buffer used. The diffusion coefficient for dimeric IgG has also been determined to be D20,w = 2.81 x 10(-7) +/- 0.04 cm2/sec at 1.6 mg/ml, which corresponds to a hydrodynamic radius of 75 A. For light-scattering studies of protein molecules in the dimension range of 5-10 nm (Mr approximately 10(5)-10(7] we find monomeric horse spleen ferritin well suited as a reference standard. Ferritin is a spherical molecule with a hydrodynamic radius R of 6.9 +/- 0.1 nm and is stable for years in our standard Tris-HCl-NaCl buffer even at room temperature.
Enhancement of angiogenesis by bFGF in mandibular bone graft healing in the rabbit.
The effectiveness of basic fibroblast growth factor (bFGF) as an in vivo angiogenic factor was evaluated in autogeneic bone grafts to the rabbit mandible. Block cortical grafts harvested from the ilium were implanted into sites in the mandibular ramus or body. The basic fibroblast growth factor was continuously introduced over a period of 14 days through subcutaneous osmotic pumps. Increased vascularity, as assessed by vessel number and depth of penetration into the grafts, was noted at 10 days postoperatively in the bFGF stimulated side as compared to contralateral control grafts. At the fourteenth postoperative day, bFGF administration was discontinued and a decrease in angiogenesis was noted over the ensuing 2 weeks so that after 1 postoperative month, little difference could be detected between the stimulated and nonstimulated grafts. Assessment of osseous healing at the 1 month postoperative interval using triple fluorochrome labeling did not reveal evidence of accelerated osteogenesis on the previously stimulated side.
The development of large-scale animal cell perfusion culture systems.
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Purification and characterization of a tissue plasminogen activator-inhibitor complex from human umbilical vein endothelial cell conditioned medium.
Tissue plasminogen activator-inhibitor complexes were purified from the conditioned medium of human umbilical vein endothelial cells by affinity chromatography followed by gel filtration. It was found that a single complex was isolated which can exist in two distinct interconvertible conformations. These may be separated by electrophoresis into a form with a 105,000 apparent molecular weight and a form with an 88,000 apparent molecular weight. The particular conformation which predominates may be altered by changing the pH at which preparations are incubated or by including dithiothreitol in incubation buffers. Plasminogen activator enzymatic activity may be partially recovered from purified complexes by incubation in the presence of fibrin. Incubation in 1.5 M NH4OH results in the dissociation of the complex into two major polypeptides of 67 and 40 kilodaltons (kDa). The 40-kDa protein was isolated by gel filtration high-pressure liquid chromatography. N-Terminal amino acid analysis of this protein revealed three distinct sequences. Two of these were nearly identical and matched the N-terminal sequence recently reported for the native plasminogen activator inhibitor from endothelial cells. The third sequence exactly matched an internal portion of the same protein. The results suggest that the internal sequence is located at the site where the inhibitor is cleaved by tissue plasminogen activator.
How did Medicare's prospective payment system affect hospitals?
Using data from 1982 and 1984, we examined how Medicare's prospective payment system affected hospitals. The study showed that hospitals paid through the prospective payment system had significantly lower increases in Medicare costs and greater declines in Medicare use than did other hospitals. Unlike these other hospitals, for which Medicare costs approximately equaled Medicare revenues, hospitals receiving prospective payment kept Medicare costs from rising as fast as Medicare revenues, earning the profit that the prospective payment system allowed. The opportunity to earn a profit led hospitals to slow increases in Medicare costs, regardless of the level of revenue constraint. However, the more the prospective payment system constrained hospitals' revenues, the more hospitals slowed increases in Medicare costs. In the most constrained hospitals, slower increases in Medicare costs were accompanied by slower increases in total hospital spending. The least constrained hospitals slowed Medicare cost increases the least and did not show their overall spending. These hospitals nevertheless increased their profit margins the most, since the prospective payment system's federal rate paid them the highest rates relative to base-year costs. Since federal rates produced extra profits, not extra cost containment, their appropriateness is questionable. The prospective payment system should be modified to eliminate windfalls while continuing to promote cost containment.