A case study of translating ACGME practice-based learning and improvement requirements into reality: systems quality improvement projects as the key component to a comprehensive curriculum.

BACKGROUND: In 2002, the Accreditation Council for Graduate Medical Education (ACGME) introduced a new requirement: residents must demonstrate competency in Practice-Based Learning and Improvement (PBLI). Training in this domain is still not consistently integrated into programmes, with few, if any, adequately going beyond knowledge of basic content and addressing all components of the requirement. AIM: To summarise the implementation of a PBLI curriculum designed to address all components of the requirement and to evaluate the impact on the practice system. METHODS: A case-study approach was used for identifying and evaluating the steps for delivering the curriculum, along with the Model for Improvement's successive Plan-Do-Study-Act (PDSA) cycles (July 2004-May 2006). DATA SOURCE: Notes from curriculum development meetings, notes and presentation slides made by teams about their projects, resident curriculum exit evaluations curriculum and interviews. RESULTS: Residents reported high levels of comfort by applying PBLI-related knowledge and skills and that the curriculum improved their ability to do various PBLI tasks. The involvement of multiple stakeholders increased. Twelve of the 15 teams' suggestions with practical systems-relevant outcomes were implemented and sustained beyond residents' project periods. While using the traditional PDSA cycles was helpful, there were limitations. CONCLUSION: A PBLI curriculum that is centred around practice-based quality improvement projects can fulfil the objectives of this ACGME competency while accomplishing sustained outcomes in quality improvement. A comprehensive curriculum is an investment but offers organisational rewards. We propose a more realistic and informative representation of rapid PDSA cycle changes.

Cushing's syndrome: problems in management.

CS comprises a group of disorders characterized by hypercortisolism. The variety of causes--pituitary-dependent CS (CD), adrenal tumor, and the ectopic ACTH syndrome--necessitates a variety of therapies--surgical, radiotherapeutic, and medical. Once a specific diagnosis is made, specific therapy can be instituted. Although some controversy persists regarding treatment, particularly that of CD, for most patients it is straightforward. However, in our experience with more than 60 patients, therapeutic dilemmas can arise in a number of circumstances, e.g. the patient with the radiologically normal sella or recurrent CD after adrenalectomy. In addition, the treatment of such conditions as the large ACTH-producing pituitary tumor, Nelson's syndrome, the malignant ectopic ACTH syndrome, and adrenal carcinoma is not entirely satisfactory. Our approach to these problems is illustrated by seven cases, and we emphasize that the proper management of CS requires both correct diagnosis and the logical application of all available therapies.

Secretion of insulinlike growth factor I and insulinlike growth factor-binding proteins by murine bone marrow stromal cells.

Insulin-like growth factor I (IGF-I) stimulates hematopoiesis. We examined whether bone marrow stromal cells synthesize IGF-I. Secretion of IGF-I immunoreactivity by cells from TC-1 murine bone marrow stromal cells was time-dependent and inhibited by cycloheximide. Gel filtration chromatography under denaturing conditions of TC-1 conditioned medium demonstrated two major peaks of apparent IGF-I immunoreactivity with molecular weights of approximately 7.5-8.0 kD, the size of native IGF-I, and greater than 25 kD. Expression of IGF-I mRNA was identified by both RNase protection assay and reverse transcription/polymerase chain reaction. To determine whether the greater than 25-kD species identified by RIA possessed IGF-binding activity, a potential cause of artifactual IGF-I immunoreactivity, charcoal adsorption assay of these gel filtration fractions was performed. The peak of IGF-binding activity coeluted with apparent IGF-I immunoreactivity suggesting that TC-1 cells secrete IGF-binding protein(s). Unfractionated conditioned medium exhibited linear dose-dependent increase in specific binding of [125I]-IGF-I with a pattern of displacement (IGF-I and IGF-II much greater than insulin) characteristic of IGF-binding proteins. Western ligand analysis of conditioned medium showed three IGF-I binding species of approximately 31, 38, and 40 kD. These data indicate that TC-1 bone marrow stromal cells synthesize and secrete IGF-I and IGF-binding proteins and constitute a useful model system to study their regulation and role in hematopoiesis.

Endocrine complications of the acquired immunodeficiency syndrome.

Acquired immunodeficiency syndrome (AIDS) is a multisystem disorder characterized by defects in the immune system that result in opportunistic infections and neoplasms. While endocrine dysfunction has not been a prominent clinical feature of AIDS, all endocrine glands may be affected by the opportunistic infections and neoplasms or by agents used in their treatment. Adrenal cortical insufficiency related to cytomegalovirus and ketoconazole therapy, hypoglycemia related to pentamidine therapy, and hyponatremia secondary to diverse causes are the most serious endocrine abnormalities that commonly occur. As the numbers of patients with AIDS increase, the development of these and other endocrine complications will occur more often. Because the clinical manifestations of endocrine dysfunction may be nonspecific or subtle, they may be overlooked, particularly in the setting of chronically and severely ill patients. Recognition and prompt therapy for endocrine dysfunction is essential for optimal treatment of these patients.

Pheochromocytoma of the broad ligament. Localization by computerized tomography and ultrasonography.

Computerized tomography (CT) and ultrasonography demonstrated a pheochromocytoma of the broad ligament of the uterus in a patient in whom arteriographic findings had been negative. We suggest that either or both of these techniques be used initially because, although they are not histologically specific, they are noninvasive and sensitive. An additional advantage of CT is its ability to evaluate sites of extra-adrenal pheochromocytomas above the diaphragm.

Management of gallstones in diabetic patients.

The management of gallstones in diabetic patients has traditionally been considered problematic. Autopsy findings and uncontrolled studies have documented a higher prevalence of cholelithiasis in diabetics, and early reports showed dramatically increased perioperative morbidity and mortality for treatment of diabetics with acute cholecystitis. As a result, some authorities have recommended prophylactic cholecystectomy for diabetic patients with asymptomatic gallstones, which is in contrast to recommendations for nondiabetics. More recent investigators have shown comparable rates of operative morbidity and mortality for biliary surgery in diabetics when compared with the general population. Recent studies have questioned whether diabetes is an independent risk factor for gallstone formation. Decision analyses using these new data have shown that prophylactic cholecystectomy is not of clear benefit and should not be routinely recommended for diabetics with asymptomatic gallstones. We believe that available data, although limited, indicate that asymptomatic patients with diabetes do not benefit from screening for gallstones and that cholecystectomy should only be performed in cases of symptomatic cholelithiasis, as is the case in the general population.

Nonsomatostatin secretory peptide(s) derived from prosomatostatin's amino terminus in a rat medullary thyroid carcinoma cell line.

We have established a system, the CA77 rat medullary thyroid carcinoma cell line, for studying the products of somatostatin (SS) gene expression. Based on the amino acid sequence of proSS, we developed a RIA for the amino terminus of proSS (proSS-NTP) and demonstrated in acidic cell extracts two major proSS-NTP-containing species of 8000 and 4000 daltons. Studies were then performed on species secreted into culture medium. Serial dilutions of culture medium showed tracer displacement curves parallel to serial dilutions of synthetic proSS-NTP standard. Analysis by gel filtration chromatography of 24-h culture medium showed the major proSS-NTP-containing species to have an estimated mol wt of 8000 daltons. No 4000-dalton species was observed. The acute effects of calcium and glucagon, known secretagogues of SS, on secretion of immunoreactive (i) proSS-NTP were investigated in 3-h experiments. Basal (0.5 mM calcium) secretory rates (mean +/- SE) of iproSS-NTP and iSS were 1.29 +/- 0.36 and 7.38 +/- 1.51 ng/mg acid-extractable protein, respectively. High calcium (3 mM) stimulated iproSS-NTP and iSS secretion 302 +/- 100% and 363 +/- 105%, respectively. High calcium plus 10(-6) M glucagon also stimulated secretion of iproSS-NTP and iSS in a coordinate fashion. Analyses by gel filtration chromatography of 3-h culture medium revealed that high calcium markedly increased the 8000-dalton proSS-NTP-containing species. No 4000-dalton species was observed. The absence of 4000-dalton proSS-NTP species in 24-h culture medium, the lack of degradation of 4000-dalton proSS-NTP (recovered from CA77 cell extracts) added to tissue culture medium, and the selective secretion of the 8000-dalton proSS-NTP species under both basal and stimulated conditions coordinate with the secretion of SS indicate that the 4000-dalton proSS-NTP-containing species is not secreted.

Secretion of insulin-like growth factor-I and binding proteins by rat liver fat-storing cells: regulatory role of platelet-derived growth factor.

Insulin-like growth factor (IGF-I) is synthesized in multiple organs, including the liver, and may play a role in tissue growth and repair. We report that liver fat-storing cells (FSC) secrete IGF-I immunoreactivity in the culture medium. Secretion of IGF-I immunoreactivity was blocked in the presence of cycloheximide, suggesting de novo synthesis. Culture medium conditioned by FSC was concentrated and applied to a Sephadex G100 column equilibrated in a denaturing buffer. Two major species with apparent mol wts of 7.5 and greater than 25 k were identified by IGF-I RIA. Reverse phase HPLC of the 7.5 kilodalton species (the size of IGF-I) showed that it eluted in a single peak. To determine whether the higher mol wt species possessed IGF-I binding activity, appropriate fractions were desalted, incubated with [125I]IGF-I for 2 h at 30 C and applied to a Sephadex G100 column equilibrated in a nondissociating buffer. The major peak of radioactivity was confined to a high mol wt region. Western blot ligand analysis revealed the presence of two insulin-like growth factor binding proteins of approximately 28 and 31 kilodaltons. Platelet-derived growth factor, a potent mitogen for FSC, resulted in a 230% increase in release of IGF-I immunoreactivity that could be accounted for by an increase in IGF-I binding activity. In addition IGF-I increased DNA synthesis in FSC and this effect was additive to that of platelet-derived growth factor. IGF-I treatment also resulted in an increase in cell number. IGF-I and insulin-like growth factor binding proteins secreted by FSC may play a role in the hepatic tissue response to injury via autocrine and/or paracrine mechanisms.

Elaboration of nonsomatostatin peptides containing the amino-terminal portion of prosomatostatin in a somatostatin-secreting human medullary thyroid carcinoma cell line.

We identified a system, the TT human medullary thyroid carcinoma cell line which contained 74.5 +/- 26.0 ng (mean +/- SD) immunoreactive SRIH/mg protein, for studying the products of SRIH gene expression. The close homology between man and rat for the entire proSRIH and complete homology for a portion of the amino terminus (proSRIH-NTP) permitted the application of a RIA directed toward the amino terminus of rat proSRIH. Immunohistochemical studies of the human TT cell line showed that SRIH and proSRIH-NTP immunoreactivities were present in the same cells. RIA of gel filtration fractions showed that the major cellular proSRIH-NTP-containing species lack SRIH and had an apparent mol wt of 8000. A 10,000-dalton SRIH-containing species coeluting with proSRIH-NTP immunoreactivity, putative proSRIH, also was found. Similar species were found in culture medium. The major cellular and secreted form of SRIH immunoreactivity had a mol wt of 1600 (SRIH). High pressure liquid chromatography revealed that both cellular and secreted 8000-dalton proSRIH-NTP-containing material consisted of a major and several minor species. None of the species contained SRIH. The precise structure of these proSRIH-NTP-containing species and their physiological roles are not known. The fact that proSRIH-NTP-containing species are secreted suggests that they may be functional. Since the processing of proSRIH and consequently the final products appear to be tissue specific, alterations in the relative presence of different forms might reflect specific pathological processes.

Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

High dose dexamethasone suppression testing has been widely employed in the differentiation between pituitary ACTH-dependent hypercortisolism [Cushing's disease (CD)] and the ectopic ACTH syndrome. We hypothesized that the high dose dexamethasone suppression test as it is performed in practice does not improve the ability to differentiate between these two types of ACTH-dependent Cushing's syndrome. Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing's syndrome, who were then classified based upon results of inferior petrosal sinus sampling for ACTH levels. Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients for whom results are available. Statistical modeling was performed using the 68 cases with complete data on all assessed variables. Logistic regression models were used to predict the probability of pituitary-dependent Cushing's syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates. Of the 112 patients with ACTH-dependent Cushing's syndrome, 15.2% had the ectopic ACTH syndrome, and the remainder had pituitary-dependent Cushing's syndrome (CD). Patients with the ectopic ACTH syndrome were significantly older (mean, 51.9 vs. 40.2), were more likely to be male (58.8% vs. 27.4%), had shorter duration of clinical findings (mean, 11.6 vs. 39.9 months), were more likely to have hypokalemia (50% vs. 8.6%), had higher baseline 24-h urinary free cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs. 422 microg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L (210 vs. 78 pg/mL)] and were less likely to suppress urinary free cortisol or plasma cortisol with high dose dexamethasone using the standard criterion of 50% or more suppression compared with patients with pituitary-dependent Cushing's syndrome. Based upon the standard criterion, the sensitivity and specificity of the high dose dexamethasone suppression test for the diagnosis of pituitary-dependent Cushing's syndrome were 81.0% and 66.7%, respectively. Although the mean percent suppression was significantly greater for patients with CD than for those with the ectopic ACTH syndrome (72.2% vs. 41.3%), the range of suppression was 0-99% for each diagnosis. The area under the receiver operating characteristic curve was 0.710 (95% confidence interval, 0.541-0.879). Logistic regression models were used to evaluate the probability of CD given the responsiveness to high dose dexamethasone suppression testing before and after adjustment for the potential contributions of other factors. A model including all of the variables (age, sex, duration, presence of hypokalemia, urinary free cortisol, and plasma ACTH) had a diagnostic accuracy of 92.7%. A model including all of these variables plus a binary variable indicating whether the patient met the criterion of suppression by 50% or more resulted in 95.6% accuracy, whereas substitution of this binary variable by percent suppression resulted in a model with 94.1% accuracy. There were no statistically significant differences among these models; their values for the c statistic, which is equivalent to the area under the curve in a receiver operating characteristic analysis, were all greater than 0.9. Logistic regression models indicate that the results of the dexamethasone suppression test add little to the differential diagnosis of ACTH-dependent Cushing's syndrome, especially after taking other clinical information into account. In our patient population, the sensitivity and specificity of the dexamethasone suppression test were less than those reported by others. However, because 20-33% of cases of ectopic ACTH syndrome are misdiagnosed with these logistic regression models, other techniques are necessary to achieve greater diagnostic accuracy.

Feminizing adrenocortical tumor: steroid hormone response to ketoconazole.

A 58-yr-old man presented with gynecomastia and elevated serum estrogens. The diagnosis of an estrogen-secreting adrenal tumor was made based upon the finding of a 4-cm left adrenal mass, elevated levels of estradiol in peripheral and left adrenal venous blood, and increased urinary 17-ketosteroids. In addition to marked elevations in estradiol and 17-ketosteroids there was an increased baseline level of 11-deoxycorticosterone and a slightly decreased level of 18-hydroxycorticosterone, suggesting the possibility of impaired P450c11 activity. The effect of ketoconazole administration (600 mg/day) for 4 weeks was studied. Urinary free cortisol and 17-ketosteroid excretion and serum testosterone levels fell acutely (1 week). Serum estradiol levels decreased gradually over the 4-week course. Plasma aldosterone levels were essentially unaltered and 18-hydroxcorticosterone levels fell gradually, but there were marked increases in 11-deoxycorticosterone and corticosterone. Coincident with the increase in 11-deoxycorticosterone there was an increase in blood pressure and a transient fall in serum potassium. We conclude that ketoconazole administration may result in a hypermineralocorticoid state. Therefore, the usefulness of ketoconazole therapy for steroid hormone-producing neoplasms will depend upon the individual tumor's steroidogenic profile.

Synthesis and binding of insulin-like growth factor I by human glomerular mesangial cells.

Insulin-like growth factor I (IGF-I) has been found in the kidney, but its precise cellular localization is not known. Since there is evidence that IGF-I is an autocrine factor in many tissues and since murine mesangial cells have IGF-I receptors, we examined whether human mesangial cells produce IGF-I. Culture medium conditioned by mesangial cells was concentrated by reverse phase chromatography and applied to a Sephadex G-100 column equilibrated in a denaturing buffer. Two major species with apparent mol wt (MW) of 7,500 and 25,000 daltons were identified by IGF-I RIA. To determine whether the high MW species possessed IGF-I binding activity, appropriate fractions were desalted, incubated with [125I]Thr59-IGF-I for 2 h at 30 C, and applied to a Sephadex G-100 column equilibrated in a nondissociating buffer. The major peak of radioactivity was confined to a high MW region; there was no radioactivity in the fractions corresponding to 7,500 daltons. Further characterization of 7,500 dalton IGF-I immunoreactive species by reverse phase high performance liquid chromatography showed that it coeluted with synthetic human IGF-I. Isoelectric focusing revealed it to have a pI between 8.1 and 8.5, corresponding to the pI of human IGF-I of 8.25. Northern blot analyses of poly(A)+ RNA from human mesangial cells and human liver using a cDNA probe for human IGF-I showed that a 2.0-kilobase transcript predominated in the mesangial cells, whereas the liver contained 1.1- and 2.0-kilobase species. Specific binding of IGF-I to mesangial cells was demonstrated, and competition curves indicated a rank order of potency (IGF-I greater than IGF-II greater than insulin) consistent with type I IGF receptors. We conclude that human mesangial cells 1) express IGF-I mRNA transcripts, 2) secrete IGF-I and IGF-I-binding activity, and 3) possess specific IGF-I receptors. These data suggest that IGF-I may act as an autocrine or paracrine factor that regulates glomerular cell functions.

Management of incidental pituitary microadenomas: a cost-effectiveness analysis.

The objective of this study was to compare the cost-effectiveness of four management strategies for a patient with an incidentally discovered asymptomatic pituitary microadenoma. A decision analytic Markov model was used to determine the incremental cost-effectiveness of four clinical management strategies: 1) expectant management, 2) PRL screening, 3) an endocrine screening panel (PRL, insulin-like growth factor I, and 1-mg dexamethasone suppression test), and 4) magnetic resonance imaging (MRI) follow-up. The model incorporated the natural history of incidental microadenomas, test characteristics, pharmacological and surgical treatment outcomes, patient's quality of life, discounting, and the costs of hormone testing, bromocriptine, MRIs, hospitalization for surgery, and physician services. PRL screening, endocrine screening panel, and MRI follow-up all provided slightly greater quality-adjusted survival than expectant management, but the costs increased disproportionately more than the benefits. The incremental cost per quality-adjusted life year for PRL screening is $1,428, and that for the endocrine screening panel is $69,495. These results are most sensitive to patient anxiety about the microadenoma; increased anxiety shifts the recommended strategy to the endocrine screening panel. We conclude that in patients with an incidental asymptomatic pituitary microadenoma, a single PRL test may be the most cost-effective management strategy.

Familial adrenocorticotropin-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia.

Familial Cushing's syndrome is rare, and when it occurs, it is usually associated with primary micronodular dysplasia. We report two cases, a mother and daughter, who each presented with clinical features of Cushing's syndrome at age 38 yr and were found to have ACTH-independent macronodular adrenal hyperplasia. In each case, bilateral adrenalectomy revealed the massively thickened adrenal cortex with nodules up to 1.3 cm in diameter and hyperplasia between nodules. Dynamic testing showed no suppression of free cortisol with high dose dexamethasone and no stimulation of 17-hydroxycorticosteroids with metyrapone. Two samples of serum obtained preoperatively from one patient that showed ACTH immunoreactivity of 4.6 and less than 2.2 pmol/L, respectively, each showed less than 2.2 pmol/L ACTH bioactivity. The lack of suppression with high dose dexamethasone, lack of stimulation with metyrapone, and low levels of ACTH immunoreactivity and bioactivity suggest that the bilateral hyperplasia was not dependent upon ACTH. These patients represent the first cases of ACTH-independent macronodular adrenal hyperplasia occurring in two generations of one family and illustrate the expanding clinical spectrum of Cushing's syndrome.

Silent pituitary apoplexy: subclinical infarction of an adrenocorticotropin-producing pituitary adenoma.

A young woman developed intermittent headaches and progressive hyperpigmentation after bilateral adrenalectomy for Cushing's disease. Results of sellar polytomography were abnormal. Her plasma ACTH levels increased to 4750-7340 pg/ml and did not rise with insulin-induced hypoglycemia. Although she experienced no clinical features associated with spontaneous infarction of a pituitary tumor, plasma ACTH levels fell to 474-575 pg/ml, and hemorrhagic necrosis was found in a 5-mm chromophobe adenoma at transsphenoidal surgery. Postoperatively, ACTH levels returned to normal (51-88 pg/ml), with the rest of her anterior pituitary function remaining intact 4 yr later. Spontaneous infarction of pituitary microadenomas may be subclinical, resulting in improvement of pituitary hormone hypersecretion without impairment of other anterior pituitary hormone secretion.

Cushing's syndrome: problems in diagnosis.

Cushing's syndrome, an unusual group of disorders characterized by hypercortisolism, must be considered in the differential diagnosis of such common clinical problems as hirsutism, menstrual irregularity, hypertension, diabetes mellitus, and obesity. Its distinct forms--pituitary-dependent Cushing's syndrome (Cushing's disease), adrenal tumor and ectopic ACTH syndrome--must be identified correctly so that specific therapy can be administered. In the majority of cases, use of a relatively simple diagnostic sequence will provide accurate and rapid diagnosis. However, in our experience with more than 60 patients, diagnostic difficulties may arise from a variety of conditions (e.g., drug interference, alcohol ingestion, and depression). In addition, unusual circumstances, such as unexpected responses to dexamethasone, may complicate the diagnosis. Our approach to these problems is illustrated through a report of seven cases, and we emphasize that the proper management of Cushing's syndrome mandates a thorough marshalling of all the available data.

Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome. Report of two cases and review of the literature.

Cushing's syndrome due to nodular adrenal hyperplasia comprises a clinically and biochemically heterogeneous group of disorders whose pathogenesis is unclear. We describe two patients with atypical steroid dynamics and large unilateral adrenal nodules who had pituitary ACTH-dependent disease. In the differential diagnosis of Cushing's syndrome, we recommend repeated ACTH measurement and selective venous sampling-particularly in those patients with impaired dexamethasone suppressibility and abnormal findings on computerized tomography.

Ectopic ACTH syndrome and CRH-mediated Cushing's syndrome.

The ectopic ACTH syndrome accounts for a substantial number of patients with naturally occurring Cushing's syndrome. Despite the progress achieved in elucidating the pathophysiology of Cushing's syndrome, clinicians continue to experience diagnostic and therapeutic challenges. This is especially true in those patients presenting with disease mediated by ectopically produced ACTH and CRH. Patients with these disorders may be indistinguishable based on clinical grounds or simple biochemical and radiologic testing from those with Cushing's disease. However, this differentiation is critical because their therapies differ. While clinical researchers continue to develop more effective diagnostic techniques and therapies, further advances in the molecular and cell biology of ACTH and CRH-producing tumors will undoubtedly shed light on the pathogenesis of this perplexing, fascinating and still controversial entity.

Cushing's syndrome and hypertension.

Cushing's syndrome refers to the signs and symptoms that result from excessive glucocorticoid action, usually from endogenous production or exogenous administration. This article reviews the pathophysiology of hypertension in Cushing's syndrome and current concepts in the diagnosis and treatment of this disorder.

Health services research and the endocrinologist.

This article highlights the importance of health services research to endocrinologists. The content and goals of health services research are defined, and, with examples related to endocrinology, the field's focus and key themes are described and its methods and sources of data delineated. Considerations that informed readers should keep in mind when reading this literature are illustrated, with a recent example that has important implications for the role of endocrinologists in the management of diabetic patients.