Changing structure to improve function: one academic health center's experience.

Academic health centers (AHCs) have been under siege for the past few years, with decreased federal and state funding for educational and research programs and increasing competition in the health care marketplace. In addition, many AHCs are burdened with the bureaucratic red tape of large educational institutions, which makes agility in responding to a demanding health care market difficult. The authors describe the response to these threats by Oregon Health Sciences University (OHSU), an approach that has been different from those of most similar institutions. OHSU chose to change its structure from being part of the state system of higher education to being an independent public corporation. The authors outline the political process of building widespread support for the legislation passed in 1995, the key features of the restructuring, the challenges faced before and after the transition to a public corporation, and lessons learned in this metamorphosis to a new form.

Specialists/primary care professionals: striking a balance.

Even before the recent movement toward managed care, there was mounting evidence of excessive numbers of many medical and surgical specialists. Generalist physicians are now in short supply, as are nonphysician providers. The ideal correction for the current problems of specialty surplus and total physician excess would be based on economics or the marketplace. However, a rapid correction is unlikely in a voluntary system. A national commission has been suggested by several bodies. This commission could make recommendations for the total number of training positions and, subsequently, the subspecialty trainees needed. Implementation of the recommendations could be through large multistate regional consortia.

Giant invasive prolactinomas.

Two of the largest prolactinomas ever documented that have been followed for nine and 10 years, respectively, demonstrate how aggressive prolactinomas may become and how difficult invasive prolactinomas are to treat. One of these prolactinomas invaded both internal auditory canals and simultaneously grew inferiorly, reducing the bony support of the skull and necessitating the patient to utilize both hands to hold his head up. The second patient's prolactinoma invaded the sphenoidal, ethmoidal, and cavernous sinuses. Both of these patients had neurosurgical debulking of their tumors followed by radiation therapy. Neither patient's prolactin levels decreased significantly during their first five years post-surgically, at which time bromocriptine was added. Since then, there has been a gradual lowering of serum prolactin levels and a decrease in the size of these tumors. These cases demonstrate that prolonged treatment and very large doses of bromocriptine may be necessary for tumor reduction in patients with invasive prolactinomas.

Glucocorticoid induction of beta-adrenergic receptors in the DDT1 MF-2 smooth muscle cell line involves synthesis of new receptor.

We have shown that glucocorticoids induce the appearance of beta 2-adrenergic receptors in membranes of the ductus deferens smooth muscle cell line (DDT1 MF-2). A concomitant increase in isoproterenol stimulated adenylate cyclase activity in the absence of exogenously applied GTP was observed as was a significantly increased (p less than 0.05) sensitivity of the adenylate cyclase system to exogenously applied GTP. However, no significant difference in the maximal velocity of adenylate cyclase between control and steroid treatment was measurable in the presence of sodium fluoride. Induction of beta 2-adrenergic receptors in DDT1 MF-2 cells is correlated with the presence of steroid receptors (androgen and glucocorticoid) in the cells since estrogens and progesterones had no effect on receptor levels. Finally, utilizing dense amino acid labeling of cells to measure old versus newly synthesized receptor sites by a density shift method, we have documented that glucocorticoid induction of beta 2-adrenergic receptors involves synthesis of new receptor protein.

Human prolactin heterogeneity in pituitary effluent blood.

We have used column chromatography to study prolactin (PRL) heterogeneity in plasma obtained from the inferior petrosal vein, a sampling site very close to the anterior pituitary gland. Blood specimens were obtained from four hyperprolactinemic subjects over varying time intervals during inferior petrosal vein venography. All patients demonstrated an increase in PRL secretion during the sampling period which was presumably secondary to the mild stress of the procedure. In each study subject there was an increase in the percent and amount of PRL secreted as small PRL (peak III) as the PRL concentration in the inferior petrosal vein increased to a maximum. The percent secreted as intermediate PRL (peak II) fell while the amount either remained constant or increased slightly. The percent and amount eluting as large PRL (peak I) was small and unchanging in patients 1, 2 and 3, despite the increase in total PRL concentration. Patient 4 had an unusual elution pattern in which the 0 minute specimen contained predominantly large PRL. As the total PRL concentration increased the percent and amount eluting as small PRL dramatically increased while the percent eluting as large PRL fell in proportion to the increase of small PRL. Intermediate PRL was virtually absent in this patient. Thus, this study indicates that the increase in PRL concentration during a secretory pulse is primarily from small PRL while the contributions of large and intermediate PRL are modest and variable.

Hyperalimentation as cause of markedly worsened metabolic control in a patient with autoantibodies to the insulin receptor.

Patients with type B insulin resistance and acanthosis nigricans have autoantibodies to their insulin receptors and usually have signs and symptoms of other autoimmune diseases. The first case demonstrating that hyperalimentation markedly disturbs blood glucose control in type B insulin-resistant patients is described. Neither prednisone, insulin (up to 240 units per hour), nor tolbutamide appeared to help this patient's metabolic control. After the addition of cyclophosphamide for one week, the anti-insulin receptor autoantibody titer dropped from greater than 1:1,000 to 1:1. Six months later, the patient had a complete remission, which is rare, with only three other reported remissions in these patients with type B insulin resistance.

Glucocorticoids induce a 29 000 Mr protein in DDT1 MF-2 smooth muscle cells but not in the DDT1 MF-2 GR glucocorticoid resistant variant.

We have demonstrated that glucocorticoids induce in DDT1 MF-2 cells by a glucocorticoid mediated mechanism the synthesis of a methionine-cysteine rich protein of 29 000 Mr (p29). Induction of p29 is not observed in DDT1 MF-2 GR glucocorticoid resistant variants which have only 7% of glucocorticoid receptor site per cell compared to wild type cells. Increased synthesis of p29 is specific to glucocorticoids since neither androgens, estrogens, progesterone nor the glucocorticoid antagonist dexamethasone mesylate are effective inducers. Stimulation of p29 synthesis in wild type cells is observed at 10(-10) M triamcinolone acetonide, reaching a maximum at a concentration of 1 X 10(-8) M. The induction of p29 is not a function of glucocorticoid arrest of DDT1 MF-2 cells since DDT1 MF-2 cells promoted to re-enter the cell cycle by 50 ng/ml platelet derived growth factor (PDGF) continue synthesis of p29. Finally, increased levels of p29 translation products are observed in cell free translation assays carried out utilizing poly A+ RNA transcripts isolated from glucocorticoid treated cells. These data suggest that the glucocorticoid stimulation of p29 synthesis is a transcriptional and/or RNA processing event controlled by glucocorticoid receptor complexes.

Autocrine regulation of growth: II. Glucocorticoids inhibit transcription of c-sis oncogene-specific RNA transcripts.

The ductus deferens smooth muscle tumor cell line (DDT1MF-2) expresses c-sis proto-oncogene poly A+ RNA transcripts which are thought to encode at least one subunit of the potent mitogen platelet derived growth factor (PDGF). We have previously demonstrated that glucocorticoids block DDT1MF-2 cells in G0/G1 stage of the cell cycle, and that exogenously applied PDGF reinitiates cell cycle progression. In this paper we document that glucocorticoids act to inhibit cell cycle progression by inhibiting the expression of c-sis poly A+ transcripts, which we suggest are encoding a PDGF-like molecule for DDT1MF-2 cells.

The chorionic gonadotropin alpha-subunit gene is on human chromosome 18 in JEG cells.

The gene for the alpha subunit of human chorionic gonadotropin (hCG) has been tentatively assigned to human chromosome 18. This localization was accomplished through the use of Southern blot analysis. A full-length cDNA probe for the hCG alpha subunit and DNA isolated from a series of somatic hybrids between mouse and human cells were utilized to make this assignment. In addition, in situ hybridization with normal human peripheral blood lymphocytes as a source of human chromosomes and with the same cDNA probe confirmed this result. The presence of human chromosome 18 was required for the detection of DNA fragments characteristic of the alpha-hCG gene. These results are consistent with our previous observation that human chromosomes 10 and 18 are required for the production of hCG in cultured cells.

Somatomedin C in treated acromegaly: poor correlation with growth hormone and clinical response.

To determine the usefulness of commercially available somatomedin C levels in the evaluation of the treatment of acromegaly, 15 patients were tested at 0.25-15.4 yr after onset of therapy. Clinical response, as determined by a numerical scoring system, was compared with RIA of GH and somatomedin C. Symptomatic response was poorly correlated with somatomedin C (r = 0.033) as well as with GH (r = 0.24). The correlation of GH and somatomedin C was also poor (r = 0.46, P greater than 0.05). Eighty-three percent of patients with clinical improvement had GH less than or equal to 10 ng/ml, 50% had GH less than or equal to 5 ng/ml, while 42% had somatomedin C less than or equal to 3.0 U/ml. All patients who were evaluated at 1 yr or less after therapy had elevated somatomedin C levels with normal or near normal GH values. In contrast only 2 of 11 patients evaluated at more than 1 yr after therapy had a mild persistence of somatomedin C elevation with normal GH levels. Determination of somatomedin c costs more than GH determinations and appears to offer no apparent advantage over GH in following patients treated for acromegaly.

Recent advances in the control and function of the anterior pituitary.

Major advances in our understanding of the synthesis and release of anterior pituitary hormones have been made over the past several years. Neurons of the hypothalamus have been found to serve as "neuroendocrine transducers" in that they have both electrical and secretory functions. Peptidergic neurons respond to appropriate stimuli with a release of hypothalamic factors into the hypophyseal-portal system. These factors or hormones ultimately control the endocrine function of anterior pituitary cells. Three hormones, Thyrotropin Releasing Hormone (TRH), Gonadotropin Releasing Hormone (GnRH or LHRH) and somatostatin have been identified, synthesized and tested for clinical applications. The clinical assessment of pituitary function has been greatly improved by new and improved radioimmunoassays. One of the recent clinical advances in the area of pituitary disease has been the determination of the relatively high frequency of prolactinomas. Prolactin secreting microadenomas are an important and treatable cause of amenorrhea and infertility in young women. In addition, many pituitary tumors previously believed to be non-functional or "chromophobe adenomas" appear to be prolactinomas. Many new diagnostic and therapeutic techniques are continuing to be developed to improve our management of patients with hypothalamic-pituitary disease.