The evolution of women as physicians and surgeons.

Women have played an active role as physicians and surgeons from earliest history. In the United States, medical education for women began in 1847 and flourished as medical schools proliferated to meet the growing population demand. The Flexner Report in 1910 resulted in about half the medical schools in the U.S. closing; many of them had admitted women. The number of women medical students increased beginning in the 1970s, until now, 43% of medical school graduates are women. The number of women residents has increased concomitantly from 22% in 1980 to 36% in 1997. Women residents in surgical training programs lag behind. Thoracic surgery has the lowest percent of women residents, at 5%. Unless an attempt is made to actively recruit women, thoracic surgery training programs are in danger of drawing from an increasingly smaller portion of medical school graduates.

The liberal arts physician.

The United States is in the midst of the second revolution in American health care to occur during this century, as Kenneth Ludmerer makes clear in his book Time to Heal: American Medical Education from the Turn of the Century to the Era of Managed Care. The "Flexnerian revolution" eventually led to the closing of a third of the medical schools. Although such closures are not likely this time, familiar arrangements are collapsing, without a clear picture of the shape of things to come. Whatever the outcome of the current revolution, well-trained physicians will be needed to care for the sick. Academic medical centers truly are at risk and increasingly require public support to flourish or even to survive, but medical schools and their teaching hospitals must demonstrate that they deserve this support. These institutions have responded by focusing on the business aspects of medicine, perhaps to the detriment of medical education. Lost in this focus is teaching time, and perhaps even more important, the time for mentoring. Often lacking too is a clear vision of the preparation needed by the student to practice medicine successfully in the future: different specialty mixes, interdisciplinary group practice; vastly increased use of information technologies, and overwhelming amounts of relevant and interrelated information. Yet the answer is the same as it was 75 years ago when Yale introduced the first radical medical curricular reform--the "liberal arts physician," trained in science, the values of medicine, and particularly for uncertainly and with the capacity to adapt.

Hyperthyroidism in pregnancy: diagnosis and treatment.

Hyperthyroidism due to autoimmune Graves' disease is the leading cause of thyrotoxicosis in pregnant women. The peak incidence of the disease is in the second through the fourth decade of life, which encompasses the reproductive years for women. Although menstrual irregularity is frequent in women with mild to moderate hyperthyroidism, convincing evidence that fertility is impaired is lacking. In general, 2 of every 1000 pregnancies have been reported to be complicated by hyperthyroidism. Hyperthyroidism associated with pregnancy may pose a challenging diagnostic and therapeutic dilemma. The current review focuses on the discussion of symptomatology and diagnosis of the disease, on therapeutic options available to women presenting with hyperthyroidism during gestation, and on the controversy surrounding maternal and fetal outcome in pregnancies complicated by thyrotoxicosis.

Effects of thyroid-stimulating hormone on the replicative cycle of vesicular stomatitis virus in primary cultured sheep thyroid cells.

Sheep thyroid cells in primary culture are highly sensitive to thyroid stimulating hormone (TSH). We infected thyroid cells with vesicular stomatitis virus (VSV) in the course of studies on cell polarity, and we found that TSH augmented the speed of the replicative cycle of VSV but did not affect the final yield of the virus. Three hours post-infection, at a multiplicity of infection of 10, the virus was detected in the cell layer of the cultures incubated with TSH but not in those without TSH. Five hours post-infection, there was a 100-fold increase in the medium in the yield of VSV and a 60-fold increase in the cell-associated virus in the TSH-treated cells compared with the cells without TSH. We found that the early stages of infection were accelerated by TSH. This effect appears to be due, at least in part, to increased processing in the lysosomes, thus allowing deposition of the transcriptionally-active nucleocapsid into the cytoplasm. These studies show that TSH is critically involved in the infectivity of VSV and that by manipulating cell culture conditions, an increased rate of virus production can be achieved.

Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease.

PURPOSE: Detection of mRNA transcripts for thyroglobulin (TG), thyroid peroxidase (TPO) and RET/PTC1 in the peripheral blood of patients with thyroid disease. PATIENTS AND METHODS: TG, TPO, and RET/PTC1 mRNA were analyzed in 52 peripheral-blood samples from 44 patients diagnosed with thyroid carcinoma (24 patients), adenoma (five patients), and nodular hyperplasia (15 patients) by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: TG and TPO were identified in 13 patients (54.2%) with thyroid carcinoma, which includes five of eight patients with no clinical evidence of disease at the time of blood collection. Four of 5 patients had cervical lymph node metastases and/or extrathyroid extension at the time of the initial surgery. RET/PTC1 mRNA was detected in the peripheral blood of only one patient with papillary thyroid carcinoma. This sample was also positive for TG and TPO. TG and TPO were detected in two patients (10%) with benign thyroid nodules. All positive samples from patients with benign thyroid lesions were collected before surgery, whereas all samples collected after surgery were negative. RET/PTC1 mRNA was not detected in any of the patients with benign thyroid nodules. RT-PCR positivity for TG and TPO mRNA was higher in patients with carcinoma than in patients with benign lesions (P = .002). CONCLUSION: TG, TPO, and RET/PTC1 mRNA are detectable in the peripheral blood of patients with thyroid disease, which correlates with a diagnosis of carcinoma.

Divergent patterns of immediate early gene expression in response to thyroid-stimulating hormone and insulin-like growth factor I in Wistar rat thyrocytes.

The rapid and transient induction of immediate early gene expression accompanies growth factor stimulation. TSH and insulin-like growth factor I (IGF-I) are important regulators of the thyroid follicular cell and stimulate both proliferation and differentiation. The signaling pathways induced by TSH and IGF-I are at least partially distinct. TSH uses cAMP as a second messenger, whereas the IGF-I receptor possesses protein tyrosine kinase activity. Although both agents stimulate DNA synthesis and proliferation in Wistar rat thyroid cells, they induce dramatically different patterns of immediate early gene expression. IGF-I stimulates the expression of c-fos, c-jun, junB, and egr1. In contrast, TSH stimulates c-fos and junB but not egr1 expression. TSH inhibits basal levels of c-jun expression in quiescent cells and represses serum and IGF-I-stimulated c-jun, c-fos, and egr1 expression. Consistent with these results, TSH represses serum- and phorbol ester-stimulated AP-1 activity. Although TSH and IGF-I individually stimulate DNA synthesis in thyroid cells, they exert opposing effects on the expression of some immediate early genes, including c-jun and egr1.

Diagnosis, treatment, and outcome of follicular thyroid carcinoma.

BACKGROUND: There have been numerous studies concerning the diagnosis, treatment, and prognosis of patients with papillary thyroid carcinoma, but relatively few addressing patients with follicular carcinoma. METHODS: The authors analyzed their experience with 65 patients who underwent 96 thyroid operations for pure follicular thyroid carcinoma from 1956 to 1990. RESULTS: The patients were 43 women and 22 men with a mean age of 45 years who were followed postoperatively for a mean of 10.4 years. Fifty-two patients (80%) were seen initially with a solitary thyroid nodule, and 24 (37%) had symptoms at presentation. Median tumor size was 2.2 cm. Fine-needle aspiration biopsy was performed in 20 patients, revealing a follicular neoplasm in 18 patients (90%) and an inadequate specimen in 2 patients. Nineteen patients received thyroid-stimulating hormone (TSH)-suppressive thyroid hormone therapy for an average of 4.5 months before surgery; tumor size remained the same in 10 patients (53%), increased in 5 (26%), and decreased in 2 (11%). At presentation, six patients had lymph node involvement, three had locally invasive tumors, and two had distant metastases. Initial operative treatment was lobectomy in 32 patients (49%), total thyroidectomy in 15 patients (23%), lobectomy plus contralateral partial or subtotal lobectomy in 11 patients (17%), and lesser procedures in 7 patients (11%). Twenty-nine patients had a completion total thyroidectomy, so that final surgical treatment consisted of total thyroidectomy in 44 patients (68%). Among 39 patients having intraoperative frozen section, only 3 (8%) were correctly diagnosed as having cancer. Permanent complications occurred during 3 of the 96 operations. Three patients (5%) have died of thyroid cancer (one with anaplastic transformation) since thyroidectomy, and two are living with distant metastatic disease. CONCLUSIONS: Patients with follicular thyroid cancer, when first examined, usually have solitary thyroid nodules that are follicular neoplasms by aspiration cytology, and these nodules fail to regress in response to TSH-suppressive therapy. Frozen section rarely aids in management. The preferred treatment for follicular neoplasms is lobectomy followed by completion total thyroidectomy for histologically proven carcinomas larger than 1.0 cm. Total thyroidectomy allows use of thyroglobulin and radioiodine scanning to detect and treat metastatic disease. Complications of thyroidectomy were uncommon, and the mortality rate in treated patients was relatively low.

Tensions within the academic health center.

A variety of forces are converging to unbalance the internal environment of the academic health center, and the dean of the medical school sits uneasily in the resulting vortex of conflicting needs and demands. For example, the introduction of Medicare in 1965 profoundly changed the size and complexity of medical school departments and greatly stimulated the growth of hospitals. More stresses have come from rising health care expectations of the public; the replacement of free-for-service indemnity health care by managed care and vertically integrated health care systems; the proliferation of academic specialties and subspecialties; and the recent growth in the academic medical center, which is seen as a threat to the academic integrity of the university. Within the medical school there are tensions between basic and clinical research, between education and research, between education and clinical practice, and between the dean and department chairs over allocation of resources. Perhaps the most complex tensions exist between the medical school dean and the academic hospital director. The overarching tension in the academic health center results from striving to balance the need to fulfill academic goals with the need to fill hospital beds to maintain financial solvency. This tension will not lessen so long as there is no common vision for the academic health center as a whole, and will probably increase with the forthcoming changes in health care reform. The dean and the hospital director must forge a strong alliance, and the hospital must realize that for its continuing success, it must support the academic program.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of thyrotropin-induced DNA synthesis in thyroid follicular cells by microinjection of an antibody to the stimulatory G protein of adenylate cyclase, Gs.

Thyrotropin (TSH) is an important regulator of thyroid follicular cells. While its role in the maintenance of differentiated functions is undisputed, its role as a mitogen is less clear. TSH induces DNA synthesis and cell proliferation in some cells, while in others, TSH is mitogenic only in the presence of additional growth factors such as insulin-like growth factor-1. TSH causes elevations in intracellular cAMP and is thought to utilize this second messenger system in its mitogenic action. We studied TSH as a mitogen in Wistar rat thyroid cells (WRT) (Brandi, M. L., Rotella, C. M., Mavilia, C., Franceschelli, F., Tanini, A., and Toccafondi, R. (1987) Mol. Cell. Endocrinol. 54, 91-103) and examined the role of the guanine nucleotide binding protein, Gs, in its mitogenic action. WRT cells synthesized DNA in response to TSH and elevations in cAMP. In addition, TSH caused a rapid stimulation of an indicator gene whose expression is regulated by cAMP response elements. Following microinjection of an inhibitory polyclonal antibody raised against the Gs protein, both TSH-induced changes in gene expression and DNA synthesis were significantly reduced. These results demonstrate that virtually all of the mitogenic action of TSH is transduced through the Gs protein in WRT cells, presumably through the regulation of adenylate cyclase. Whether all or only part of TSH action is mediated by cAMP and the cAMP-dependent protein kinase remains to be determined.

Control of thyroid secretion: effects of stimulators of protein kinase C, thyrotropin, and calcium mobilization on secretion of iodinated compounds from sheep thyroid cells.

We have compared and contrasted the abilities of TSH and agents capable of discretely activating the cAMP-dependent protein kinase, protein kinase C, or calcium mobilization to influence the secretion of iodinated compounds from cells prelabeled with iodide and blocked from further organification with methimazole. We found that calcium mobilization induced by A23187, protein kinase C activation induced by 12-O-tetradecanoyl phorbol 13-acetate (TPA) and TSH all stimulated the secretion of iodinated compounds. The effects of TSH were mimicked by forskolin and those of TPA by a synthetic diacylglycerol, sn-1,2-dioctanoylglycerol. The effects of TPA were partially inhibited by staurosporine whereas those of TSH were not. Epidermal growth factor and norepinephrine were without effect on thyroid secretion. The effects of A23187 and TPA were synergistic. The effects of TSH and TPA were not and the increased secretion induced by either agent was partially prevented by the combination. Preincubation of cells with TSH desensitized the cells to further stimulation by TSH but the stimulatory effects of TPA were unaffected. Exposure of cells to medium without calcium also induced loss of iodinated compounds which was partially prevented by TSH or forskolin but not TPA. TSH did not stimulate the rapid production of inositol trisphosphate production. We conclude that the mechanisms by which TSH (through stimulation of cAMP) and stimulators of other intracellular pathways exert their effects on secretion of iodocompounds, differ. Activation of protein kinase C and acute production of inositol trisphosphate do not appear to be involved in the mechanism of action of TSH in stimulating thyroid secretion but calcium mobilization is implicated.

Iodide induces transforming growth factor beta 1 (TGF-beta 1) mRNA in sheep thyroid cells.

We examined TGF-beta mRNA levels in primary sheep thyroid cell cultures to determine whether the inhibitory effects of iodide on thyroid cells could be explained by an induction of TGF-beta mRNA and if this induction was mediated by iodine organification. Thyroid cells were incubated with TSH and five additives (insulin, somatostatin, growth hormone, transferrin, and glycyl-L-histidyl-L-lysin) for 2-3 weeks and then were exposed to sodium iodide (NaI) or 1-methylimidazole-2-thiol (methimazole, MMI), or both for 72 h. Iodide at 10(-6) M and 10(-4) M significantly increased the amount of TGF-beta mRNA as determined by Northern blot analysis with a rat TGF-beta 1 cDNA probe. This increase in TGF-beta 1 mRNA was abolished by the addition of methimazole, an inhibitor of organification. These data indicate that the effects of iodide on thyroid growth and function may be mediated by a process that involves organification of iodide and increases in TGF-beta 1 mRNA levels.