Transferrin is an insulin-like growth factor-binding protein-3 binding protein.

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) possesses both growth-inhibitory and -potentiating effects on cells that are independent of IGF action and are mediated through specific IGFBP-3 binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix. We have here characterized transferrin (Tf) as one of these IGFBP-3 binding proteins. Human serum was fractionated over an IGFBP-3 affinity column, and a 70-kDa protein was eluted, sequenced, and identified (through database searching and Western immunoblot) as human Tf. Tf bound IGFBP-3 but had negligible affinity to the other five IGFBPs, and iron-saturated holo-Tf bound IGFBP-3 more avidly than unsaturated Tf. Biosensor interaction analysis confirmed that this interaction is specific and sensitive, with a high association rate similar to IGF-I, and suggested that binding occurs in the vicinity of the IGFBP-3 nuclear localization site. As an independent confirmation of this interaction, using a yeast two-hybrid system, we cloned Tf from a human liver complementary DNA library as an IGFBP-3 protein partner. Tf treatment blocked IGFBP-3-induced cell proliferation in bladder smooth muscle cells, and IGFBP-3-induced apoptosis in prostate cancer cells. In summary, we have employed a combination of techniques to demonstrate that Tf specifically binds IGFBP-3, and we showed that this interaction has important physiological effects on cellular events.

Identification of novel high molecular weight insulin-like growth factor-binding protein-3 association proteins in human serum.

The insulin-like growth factor (IGF)-binding proteins (IGFBPs) carry IGFs in serum and regulate their activity and bioavailability. The main IGFBP in serum, IGFBP-3, is known to form a 150-kDa complex with IGFs and the acid-labile subunit (ALS). We investigated the binding of IGFBP-3 to additional association proteins in human serum (IGFBP-3 APs). Ligand blots, column chromatography, and affinity cross-linking experiments revealed the specific binding of IGFBP-3 to at least three novel serum proteins. These techniques demonstrated the presence of proteins with molecular masses of 70, 100, and 150 kDa that bind IGFBP-3 with high affinity. Serum ALS migrated separately (at 88 kDa) from the novel IGFBP-3 APs (as evident by Western immunoblot), and bound IGFBP-3 weakly (by reverse ligand blots). We also demonstrated that large amounts of one of the IGFBP-3 APs and small amounts of ALS were coimmunoprecipitated with IGFBP-3 from human serum. Similar to ALS, these IGFBP-3 APs are acid labile and lose their IGFBP-3 binding capacity after exposure to low pH. We conclude that there are several serum proteins in addition to ALS and IGFs that bind IGFBP-3 with high affinity. These IGFBP-3 APs may serve as an additional reservoir of IGFBP-3 or modulate its functions.

Drug kinetics and artificial kidneys.

The factors affecting solute movement across the membrane during haemodialysis are well understood. Likewise the mathematics of drug kinetics are well described. However, studies of the effects of artificial kidneys on drug kinetics have often been limited by a lack of attention to proper methods of calculating solute clearance by the artificial kidney.

Developing episodes of care for adult asthma patients: a cautionary tale.

An episodes of care methodology examines the contiguous cluster of services related to a particular health condition. We developed an episodes methodology for evaluating the quality of health care delivery to privately insured adult asthma patients. Computer algorithms were used for episode construction beginning with an index asthma diagnosis and ending with a final clinical event, yielding a sample of 30,553 episodes. Only service claims with an asthma diagnosis were assigned to an episode. We used a database of private insurance claims from 1992 to 1993. Disease staging served as the framework for evaluating episodes with similar severity and resource use. We found that episodes of care can be constructed from claims data and have the potential for use in physician profiling and as quality screens. Certain limitations in using this methodology suggest that caution needs to be exercised in applying this approach to evaluation of health care services.

Multifacility utilization by the chronically mentally ill in the Department of Veterans Affairs.

The objectives of this research are (1) to quantify the multifacility utilization patterns ("shared care") for a selected subset of patients with a chronic mental disorder, (2) to examine the patient characteristics correlated with several observed utilization patterns, and (3) to determine facility groups through cluster analysis, based on multifacility readmissions. Patients were identified from the VA's hospital discharge abstract system based on a diagnosis of schizophrenia in any discharge during the two-year study period. All discharges for this cohort during the period were analyzed. Essentially, three different groups of patients from this cohort were found. The vast majority have one or two hospitalizations and in the process are seen at one or maybe two facilities. However, two small minorities are hospitalized many times. One small group confines these hospitalizations to relatively few facilities while the other travels from facility to facility around the country. These two groups present very different clinical management problems from each other as well as from the majority. Since the distribution of travel distance between facilities remained similar for all types of patients (median distance was about 120 miles), facilities were clustered based on the number of linkages they shared. By use of six different measures of the disjointedness of shared care, clustering produced a reasonable number of meaningful groups which account for a majority of possibly uncoordinated shared care. We feel that these results and this approach can be useful for administrators, policymakers, and researchers. By looking simultaneously at the utilization patterns of its clients and their characteristics (e.g., age) as well as the utilization patterns within groups of facilities, any multifacility health system can characterize its shared care and identify those clients and facilities most in need of intervention, resources, and future study.