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Background: Patients with primary hyperparathyroidism and baseline intraoperative parathyroid hormone levels in the normal range are challenging. This study compares the predictive value of a commonly used intraoperative parathyroid hormone algorithm, a software model for cure prediction, and surgeon judgment in this population., Methods: This was a retrospective review of consecutive patients who underwent parathyroidectomy for primary hyperparathyroidism at a single institution from March 2013 to October 2014., Results: Of 541 operative patients, 114 (21.1%) had a mean normal baseline intraoperative parathyroid hormone of ≤69 pg/mL (median 59.0 ± 10.3; range 26-69). Of the 114 patients, 93 (81.6%) were women, median age was 61 years (range 18-88). Overall, 107/108 (99.1%) patients were cured; 47 (41.2%) patients had single adenomas, 16 (14%) had double adenomas, and 51 (44.7%) had multigland hyperplasia. Using the 50% decline algorithm, a correct prediction was made in 86 (75.4%) patients. Using the computer software, a correct prediction was made in 88 (77.2%) patients. Surgeon judgment, however, was 99.1% accurate., Conclusion: Patients with normal baseline intraoperative parathyroid hormone have a high incidence of multigland disease (58.8%), greater than reported previously. Current software modeling and the 50% decline algorithm are insufficient to predict cure in this population; intraoperative parathyroid hormone interpretation combined with operative findings and surgical judgment yield optimal outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: There is a paucity of data regarding prognosis of primary thyroid lymphoma (PTL), with only case reports and institutional series reported. This is the first population-based study of PTL in the United States., Methods: PTL patients were identified in the SEER database. Bivariate (chi(2), Kaplan-Meier, and log rank) and multivariate (Cox proportional hazards) analyses were used to assess the associations between patient characteristics and survival., Results: A total of 1,408 patients were identified over 32 years of follow-up (median, 3.75 years). Mean age was 66 years; 75% were female and 93% white. Overall, 98% had non-Hodgkin's lymphoma; 68% had diffuse large B-cell, 10% follicular, 10% marginal zone, and 3% small lymphocytic. A total of 88% had stage I-II disease. Median survival was 9.3 years. On bivariate analysis, older age, single marital status, stage II-IV disease, histology (large B-cell, follicular, or other non-Hodgkin's), earlier year of diagnosis, lack of prior malignancies, and no radiation/surgery predicted worse survival. Age >or=80 years, advanced stage, no radiation/surgery, and large B-cell or follicular histology predicted worse prognosis in multivariate analysis., Conclusion: Older age, advanced stage, histologic subtype, and lack of radiation/surgical treatment are associated with worse survival. Thyroid resection offers benefit only for patients with stage I disease. Management of PTL requires multidisciplinary collaboration.

Background: High surgeon volume is associated with improved outcomes in adult endocrine surgery. This is the first population-based outcomes study for thyroidectomy/parathyroidectomy in children., Methods: Cross-sectional analyses were performed using 1999 to 2005 Healthcare Cost and Utilization Project Nationwide Inpatient Sample data. Outcomes included complications, length of stay (LOS), and costs. High-volume surgeons performed >30 cervical endocrine procedures per year in adults and children; pediatric surgeons restricted >90% of their practices to patients

Background: There has been an increase in the incidence of endocrine diseases and the number of endocrine procedures in the United States. Higher surgeon volume is associated with improved patient outcomes. Fellowship programs will lead to more specialty-trained endocrine surgeons. We make projections for the supply of endocrine surgeons and demand for endocrine procedures over the next 15 years., Methods: Supply projections are based on data from the Accreditation Council for Graduate Medical Education, a survey of American Association of Endocrine Surgery fellowship program graduates, and Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS). Demand is estimated using HCUP-NIS, U.S. Census Bureau projections, and a literature review., Results: There were 64,275 endocrine procedures performed in 2000 and 80,505 in 2004. Using age-adjusted population projections and increasing incidence of endocrine diseases, 103,704 endocrine procedures are anticipated in 2020. High-volume endocrine surgeons are few in number, but perform 24% of endocrine procedures. Surgeon supply is projected to increase to 938 by 2020; this is based on fellowship graduation rates, retirement trends, and increasing annual endocrine case volume among high-volume surgeons. Alternative projections of supply and demand are generated to test the sensitivity of our analyses to different assumptions., Conclusion: Labor force planning in endocrine surgery is essential if the demand for more high-volume endocrine specialists is to be met.

Background: Clinical guidelines for the treatment of primary hyperparathyroidism (pHPT) often suggest parathyroidectomy, but generally fail to consider neurocognitive and psychiatric symptoms because of the relative paucity of evidence., Methods: In this prospective study, patients with pHPT (PTX) and benign euthyroid thyroid disease (THY) referred for operation were evaluated pre- and postoperatively with validated psychometric and neurocognitive instruments to determine whether learning, memory, or concentration improved with after parathyroidectomy. Statistical comparisons between groups were performed with univariate analysis and repeated measures of analysis of variance., Results: Fifty-five subjects, mean age of 54 years, were evaluated preoperatively; 41 returned postoperatively. There were no significant differences between groups by age and gender. PTXs reported more depression symptoms preoperatively (P = .04) that improved postoperatively. There were no differences between the 2 groups on verbal memory and trait anxiety. For PTXs, average preoperative serum calcium concentration (11.3 mg/dL) and serum PTH level (100 pg/mL) normalized postoperatively. Preoperatively PTXs showed greater delays in their spatial learning (P = .03). All subjects learned across the 5 trials, but PTXs were more delayed (P = .03). After operation, PTXs improved and functioned at a level equivalent to the THYs. There was an interaction between trial (neurocognitive testing), visit (pre- vs postoperative), status (PTX vs THY), and change in PTH level (P = .06), suggesting that individuals with greater change in PTH were more likely to improve in their learning efficiency postparathyroidectomy., Conclusions: PHPT may be associated with a spatial learning deficit and processing that improves after parathyroidectomy. While longer-term follow-up is necessary, neurocognitive symptoms perhaps should be considered as criteria for parathyroidectomy.

Background: Delayed technetium-99m sestamibi single photon emission computed tomography (SPECT) scans were prospectively analyzed in a large series of patients with primary hyperparathyroidism., Methods: Three hundred thirty-eight patients underwent sestamibi-SPECT and were explored. Prospective data included preoperative demographics, clinical, sestamibi, and operative findings, laboratory values, and pathologic and follow-up laboratory results from all patients., Results: Between 1994 and 2000, 287 unexplored patients (85%) and 51 re-explored patients (15%) participated. The abnormal parathyroid glands excised from 336 of 338 patients included 299 single adenomas (88%) and 23 double adenomas (7%), and 14 patients had multigland hyperplasia (4%). Sestamibi SPECT correctly lateralized 349 of 400 abnormal parathyroid glands, with an overall sensitivity of 87%, an accuracy of 94%, and a positive predictive value of 86%. Precise localization occurred in 82% of the abnormal parathyroid glands. Sestamibi sensitivity was similar in unexplored (87%) and reoperative (92%) cases; two hundred eighty-six of 299 (96%) solitary adenomas, 38 of 46 (83%) double adenomas, but only 25 of 55 (45%) hyperplastic glands were identified. The mean weight of the true-positive glands (1252 +/- 1980 mg) was greater than that of the false-negative glands (297 +/- 286 mg) (P <.005). Three patients had persistent primary hyperparathyroidism, in spite of the excision of sestamibi-identified lesions in 2 cases. Follow-up indicated curative resection in 99% of the unexplored cases and 94% of the remedial cases., Conclusions: Sestamibi SPECT is highly accurate for the localization of parathyroid adenomas in unexplored and re-explored cases, where it is often the only imaging required. Its sensitivity is limited in multiglandular disease.

Background: Technetium-99m-sestamibi (sestamibi) is the imaging agent of choice for preoperative parathyroid localization. The subcellular localization of sestamibi uptake in enlarged parathyroid glands in patients with hyperparathyroidism has not been determined. This study investigated the mechanism of retention of sestamibi by human parathyroid tissue., Methods: Twenty-three freshly harvested and 15 cryopreserved parathyroid glands excised from patients with primary or secondary hyperparathyroidism were analyzed for subcellular localization of Tc-99m-sestamibi. Tissues were incubated with 100 microCi of sestamibi and isolated for mitochondria by differential centrifugation, and the integrity of subcellular fractions was quantified with the mitochondrial enzyme marker, succinate dehydrogenase., Results: Ninety-two percent of sestamibi activity was associated with mitochondria. Furthermore, after adding the mitochondrial uncoupler, carbonylcyanide m-chlorophenylhydrazone (CCCP), to fresh parathyroid tissues, 84.96% and 73.86% of sestamibi was released from the mitochondrial and tissue fragment components, respectively. In addition, sestamibi activity in the mitochondrial component of cryopreserved human parathyroid tissue decreased to the same amount as the CCCP-treated group., Conclusions: These data confirm that mitochondrial activity is the major component of sestamibi uptake by human parathyroid tissue in patients with hyperparathyroidism.

Background: Despite the high cure rate and low morbidity of bilateral neck exploration for primary hyperparathyroidism, there is a movement toward minimizing the process in terms of incision, cost, extent of exploration, and length of hospital stay, while maintaining excellent outcomes., Methods: Between March and November 1998, 33 patients with primary hyperparathyroidism underwent minimally invasive parathyroidectomy. All had preoperative sestamibi-SPECT scans suggesting a single adenoma, underwent anterior cervical block anesthesia by the surgeon, and were explored through a 1- to 4-cm incision. Intraoperative parathyroid hormone assays were performed before and 5 to 10 minutes after parathyroid resection. Outcomes were compared with those of 184 consecutive patients who underwent bilateral parathyroid exploration under general anesthesia by the same surgeon between August 1990 and May 1996., Results: The mean age of the patients undergoing minimally invasive parathyroidectomy was 61 +/- 2 years, and 24 of the 33 patients were women. Thirty (91%) had resection of a single adenoma under regional anesthesia; 26 of these were done as outpatient procedures. Three patients underwent conversion to general anesthesia for bilateral exploration and were found to have multigland disease (two double adenomas, one hyperplasia). All 33 patients were normocalcemic postoperatively. There was no morbidity. When the minimally invasive parathyroidectomy and bilateral parathyroid exploration groups were compared, they were found to be similar with respect to age, preoperative calcium and parathyroid hormone levels, cause of primary hyperparathyroidism, weight of resected glands, cure rates, and morbidity. However, the minimally invasive parathyroidectomy group had a significantly shorter length of hospital stay (0.3 +/- 0.2 vs 1.8 +/- 0.1 days, P < .001) and lower costs ($3174 +/- $386 vs $6328 +/- $292, P < .001)., Conclusions: Minimally invasive parathyroidectomy is a safe, cost-effective alternative to bilateral exploration and may be the procedure of choice for select patients with primary hyperparathyroidism.

Background: Although fine-needle aspiration (FNA) is the most sensitive method for the detection of thyroid carcinoma, it cannot provide a definitive diagnosis of malignancy in 60% of the patients operated on for suspicious lesions. Recently, human telomerase reverse transcriptase (hTERT) has been found to be a diagnostic marker of malignancy. We therefore sought to determine whether hTERT gene expression could serve as an adjunct to FNA in the differential diagnosis of thyroid nodules., Methods: Twenty-four FNA samples from thyroid nodules that were suspected of malignancy were collected. RNA was extracted, and hTERT gene expression was examined by RT-PCR. Cytologic and histologic examinations were also performed., Results: Two of three follicular, three of three Hürthle cell, and eight of eight papillary thyroid carcinomas had corresponding FNA samples that were positive for hTERT. One of two Hürthle cell adenomas was hTERT positive. FNA samples from three follicular adenomas and five hyperplastic nodules were negative for hTERT. Positive and negative predictive values were 93% and 90%, respectively., Conclusions: The detection of hTERT gene expression in thyroid FNA samples holds promise as a diagnostic marker in the distinction of benign from malignant thyroid lesions. Its application could alter the surgical management of these patients.

Background: Controversy exists about optimal management of patients with primary hyperparathyroidism. To date, no studies have explored the cost implications of variation in practice., Methods: Results from a national survey of endocrine surgeons were combined with results from a survey of endocrinologists and financial data from Medicare. Patterns of use of resources were identified, annual costs for the surgical management of primary hyperparathyroidism in the United States were calculated, and the financial impact of variation in practice was estimated., Results: Survey respondents (n = 109) were experienced endocrine surgeons, performing an average of 33 parathyroidectomies annually. Seventy-five percent of patients undergo localization before initial exploration for primary hyperparathyroidism. In order of preference, these studies were sestamibi (43%), ultrasonography (28%), and sestamibi with single-photon emission computed tomography (26%). Although there is variation in preoperative and postoperative practice, in-hospital costs have the greatest influence on total cost. An estimated $282 million is spent annually in the United States on operations for primary hyperparathyroidism. National health expenditures could range by more than $70 million, depending on whether management strategies involving low or high use of resources are employed., Conclusions: Substantial variation among endocrine surgeons in the management of primary hyperparathyroidism has important cost implications. Implementation of evidence-based guidelines to optimize clinical and economic performance should be considered.

Background: Parathyroidectomy for primary hyperparathyroidism (PHPT) can cause secondary hyperparathyroidism, with increased serum parathyroid hormone (PTH) and normal or low serum calcium concentrations., Methods: A prospective study investigated 78 consecutive patients who underwent exploration for PHPT. Serum intact PTH and total calcium concentrations were measured the evening after operation and ionized Ca++ the following morning. These levels were reassayed 1 week later., Results: Before operation, the mean PTH level was 138 +/- 15 pg/mL, total calcium concentration was 11.6 +/- 0.1 mg/dL, and ionized Ca++ concentration was 1.44 +/- 0.02 mmol/L. On the night of the operation, the PTH level was 11 +/- 2 pg/mL, and the total calcium concentration was 8.9 +/- 0.1 mg/dL. Fifty-five patients had hypoparathyroidism, with a PTH level less than 10 pg/mL. The day after the operation, the ionized Ca++ level was 1.14 +/- 0.01 mmol/L. One week later, PTH, ionized Ca++, and total serum calcium concentrations returned to normal levels. In 9 patients (12%), PTH levels were increased (98 +/- 16 pg/mL), although ionized Ca++ concentrations were normal (1.18 +/- 0.02 mmol/L), demonstrating secondary hyperparathyroidism. Risk factors for postoperative secondary hyperparathyroidism included older age, symptomatic hyperparathyroidism, higher preoperative PTH and alakaline phosphatase levels, and lower serum phosphorous levels. In 70% of these patients, PTH levels returned to normal in 3 to 12 months., Conclusions: Secondary hyperparathyroidism occurs in 12% of patients after surgical treatment of PHPT. It is transient, possibly compensating for relative hypocalcemia.

Background: Implanted insulin pumps (IIPs) are an alternative treatment for diabetes mellitus. To maintain good glycemic control, patients with an IIP require frequent surgical interventions., Methods: Since November 1986, 21 patients with insulin-dependent diabetes mellitus at the Johns Hopkins Hospital have undergone implantation of pumps subcutaneously with a catheter delivering insulin into the peritoneal space. Patients were followed up with self-monitoring of blood glucose levels two to four times daily and percutaneous refills of the pump with U-400 insulin every 6 to 12 weeks., Results: In 153 patient-years, 77 pumps were placed. The mean pump life was 29 +/- 2 months. Morbidity was limited to pump site infections (3.9%) and one small bowel obstruction. Inadvertent insulin overdelivery has never occurred. Episodes of insulin underdelivery were caused by backflow anomalies (n = 67), which were cleared by percutaneous rinses, or catheter obstructions (n = 12), which required catheter replacements. Ninety-one operations were required to maintain pump function. All patients are alive and report improvements in quality of life. Significant reductions in hemoglobin A1C and plasma glucose levels were also seen., Conclusions: Long-term use of IIPs results in significant improvements in clinical parameters and quality of life for individuals with insulin-dependent diabetes mellitus. Relatively frequent operations are required for maintaining pump function, which are done with a local anesthetic with minimal morbidity.

Background: Although fine-needle aspiration (FNA) is 90% sensitive in the detection of papillary carcinoma (PC) of the thyroid, its specificity has been reported as low as 52%. Consequently, patients who have an FNA suspicious for PC may undergo operation for a benign process. The ribonucleoprotein telomerase has been noted to be activated in a wide variety of carcinomas. We examined 30 PCs for telomerase activity to determine whether this would be a useful adjunct to FNA in the diagnosis of lesions suspicious for PC., Methods: Standard telomere repeat amplification protocol assays were performed on fresh frozen tissue samples from 30 PCs, 3 benign nodules, and 10 normal thyroids., Results: Telomerase activity was documented in 20 of 30 (67%) of the PCs, 0 of 3 benign nodules, and 0 of 10 normal thyroids. In all, 11 of the 20 PCs had FNA cytology that was nondiagnostic of PC, and 2 of the benign nodules had FNA that was suspicious for PC., Conclusions: The telomerase assay appears useful in the distinction of benign from malignant thyroid lesions that have FNA suspicious for but not diagnostic of PC. On the basis of these findings, a prospective trial examining telomerase activity in FNAs suspicious for thyroid cancer has been initiated.

Background: Most resectable pancreatic or peripancreatic neuroendocrine tumors are treated by enucleation or distal pancreatectomy. A minority of tumors may require pancreaticoduodenectomy for complete tumor excision because of their large size, location, or lymph node involvement., Methods: This study reviews the management of 50 patients treated by pancreaticoduodenectomy for periampullary neuroendocrine tumors between 1962 and 1996 at a single institution., Results: There were 30 men and 20 women with a mean age of 52 +/- 2 years. Functional tumors were resected in 17 patients: insulinoma, seven tumors; gastrinoma, eight tumors; vipoma, one tumor; and glucagonoma, one tumor. Tumors were classified as malignant in 29 patients and benign in 21. The median intraoperative blood loss was 800 ml, and the median number of units of blood transfused was zero. The postoperative length of stay was 20 +/- 2 days. Postoperative morbidity included 11 patients (24%) with a pancreatic fistula and four patients (8%) with a biliary fistula. There was one in-hospital death (2%), in 1967. The actuarial survival rates at 2, 5, and 7 years are 81%, 73%, and 65%, respectively. Patients with benign tumors had a significantly improved 5-year survival rate (94%) compared with those with malignant tumors (61%; p = 0.03)., Conclusions: Selected patients with periampullary neuroendocrine tumors can be managed successfully by pancreaticoduodenectomy, with low mortality and acceptable morbidity rates.

Background: Surgery for hyperparathyroidism is associated with high cure rates and low morbidity and mortality when performed by experienced surgeons. We wanted to determine whether referral of patients with hyperparathyroidism to an endocrine surgery center has an impact on patient outcomes and costs., Methods: Data from 901 patients who underwent parathyroidectomy recorded in the Maryland inpatient discharge database between 1990 and 1994 at 52 hospitals were compared with 169 consecutive patients who underwent surgical exploration by one surgeon (R.U.) at the Johns Hopkins Hospital., Results: Although in 47 of 52 hospitals fewer than 10 parathyroidectomies were performed each year, in these hospitals four of five related deaths occurred before patient discharge. The percentage of parathyroidectomies in Maryland performed by one endocrine surgeon has increased from 8% in 1990 to 21% in 1994 and is associated with a 97% cure rate and no mortality. Moreover, while hospital length of stay (LOS) in the state has decreased from 7 to 3.1 days, LOS for the high-volume provider has declined to a mean of 1.3 days., Conclusions: Patients with hyperparathyroidism are increasingly referred to an endocrine surgery center, which results in a high cure rate, low morbidity, no mortality, and a shorter LOS. Improved surgical outcomes and lower costs depend on an experienced surgeon and argue for the referral of these patients to endocrine surgery centers.

Background: Operative management of pheochromocytomas dictates resection of the involved adrenal and exploration-resection of the contralateral gland if enlarged. We describe an exception to this rule., Methods: We report the largest series of patients with adrenocorticotropic hormone (ACTH)-secreting pheochromocytomas and review the world literature., Results: Four patients presented with findings of adrenocorticoid and catecholamine excess, as well as elevated levels of plasma ACTH, urinary metanephrines, and urinary free cortisol. Abdominal computed tomography scans revealed bilateral adrenal hyperplasia, and magnetic resonance imaging scans showed a unilateral adrenal mass with a bright T2 signal suggesting a pheochromocytoma. Two patients underwent adrenal venous sampling localizing ACTH secretion to the pheochromocytoma. All underwent unilateral adrenalectomy for a benign tumor without morbidity or death, leaving the contralateral hyperplastic adrenal in situ. After operation all patients experienced normalization of their levels of plasma ACTH, urinary metanephrines, and urinary free cortisol with resolution of symptoms. Combining our series with previously reported cases of ACTH-secreting pheochromocytomas, almost all are benign (20 of 21), in contrast to most ACTH-secreting tumors., Conclusions: ACTH-secreting pheochromocytomas are the exception to the rule; unilateral adrenalectomy is curative and the contralateral hyperplastic adrenal can be preserved. This approach results in resolution of both syndromes of hormone excess and preserves long-term adrenal function.

Background: Glucocorticoids impair wound healing and cause surgical morbidity. Heat shock proteins are essential to cellular stress tolerance and are associated with glucocorticoids. The adrenal heat shock protein response is under hypothalmic-pituitary-adrenal-axis control, whereas the vascular response is associated with alpha-1 receptors. Because heat shock proteins affect cellular stress responses and are under hypothalmic-pituitary-adrenal-axis control in other tissues, we postulated an association between heat shock proteins and glucocorticoids in healing wounds., Methods: Modified Hunt-Schilling wound chambers were implanted subcutaneously in rats. They received subcutaneous time-release dexamethasone (25 mg) or placebo pellets. Wound chamber heat shock protein 25 and heat shock protein 72/73 were serially assayed for 21 days with western analysis and immunocytochemistry., Results: Dexamethasone caused Cushing's syndrome with approximately 10% weekly weight-loss and adrenal atrophy. Total wound tissue decreased 90% with profound differences in molecular wound responses manifested by decreased heat shock protein 25, 72, and 73 in animals treated with dexamethasone despite equal protein loads. Furthermore, dexamethasone caused heat shock protein 72 redistribution by immunocytochemistry., Conclusions: This study represents the first description of heat shock proteins in a wound healing model and demonstrates tissue-specific decrease of heat shock proteins with glucocorticoid therapy. Thus the heat shock protein response is intimately associated with normal wound healing and is profoundly altered in subjects with Cushing's syndrome. Manipulation of this response may have clinical importance in wound healing.

Background: Surgical stress results in catecholamine secretion and selective induction of the major heat shock protein (HSP70) in the adrenal gland and in the vasculature. The adrenal response is cortical-specific and corticotropin-dependent. The vascular response occurs in the smooth muscle and is corticotropin-independent. We previously suggested that the vascular response was associated with adrenergic receptor stimulation. Herein, we report a series of experiments designed to test the hypothesis that aortic HSP70 messenger RNA (mRNA) induction occurs as a direct and specific response to alpha 1-adrenergic receptor stimulation., Methods: Acute and chronic indwelling central venous catheter models were developed in the Wistar rat through which the following agents were infused: the alpha 1 agonist phenylephrine (0.14 mg/kg), the beta agonist isoproterenol (0.8 mg/kg), the alpha 1 antagonist prazosin (1 mg/kg), prazosin followed by phenylephrine, or saline solution alone. Hemodynamic responses were monitored; catecholamines were measured by high-performance liquid chromatography; 60 minutes after infusion, the animals were killed, and the adrenal glands and aortas were assayed for HSP70 mRNA expression on Northern blots., Results: Alpha 1 stimulation with phenylephrine resulted in marked hypertension, a reflexive bradycardia, and marked induction of aortic HSP70 mRNA. This effect could be completely abolished when the alpha 1 antagonist prazosin was administered before phenylephrine treatment. The beta agonist isoproterenol failed to induce aortic HSP70. A significant catecholamine response only occurred after prazosin administration., Conclusions: These studies show a functional interaction between alpha 1 receptor stimulation and vascular HSP mRNA induction.

Successful adaptation to stress is a prerequisite for the survival of all organisms living in an environment in which noxious stimuli are constantly present. Higher organisms, including human beings, have developed complex mechanisms to tolerate the myriad of insults that occur to cellular constituents and organ systems after trauma with its resultant blood loss and tissue injury. Surgical stress can be conceptualized in this context, and it is therefore not surprising that human beings have developed an array of integrated stress-response axes that work in concert to return the host to a sustainable homeostatic plateau. The most important aspects of these axes are depicted in Figure 24. Surgical stress activates the higher cortical center of the brain and the spinal and baroreceptor reflexes that stimulate the hypothalamus to secrete CRH. CRH stimulates the release of ACTH from the pituitary gland, which causes the release of glucocorticoids from the adrenal cortex. Simultaneously, in a parallel fashion, surgical stress activates the sympathetic system to release catecholamines. Glucocorticoids and catecholamines are the major effectors of stress adaptation and interact at multiple levels in a synergistic fashion. They bind to specific receptors that are present in virtually every organ, although the number and affinity of a given tissue's receptor vary dramatically for individual ligands. Receptor occupancy results in short-term and long-term effects that ultimately improve the host's prospects of tolerating the stressful event. The short-term effects result in rapid actions, such as cardiovascular and metabolic responses that benefit the host in a "fight or flight" reaction. The long-term effects generally occur through alterations in gene transcription that prepare the host for, or adapt the host to, repetitive or chronic stress. Changes in the phosphorylation state of intracellular proteins are a common mode of action for both the short-term and long-term responses. These stress-responsive proteins have an enormous functional capacity: they alter enzymatic pathways, modulate hormone levels, and act as transcription factors to modify the expression of stress-responsive genes. During the last decade considerable progress has been made in explaining the complex signal transduction pathways mediating these responses. The importance of the HSPs in the host response to acute stress and their intimate association with activation of the HPA axis and sympathetic nervous system have recently been appreciated. The HSPs are likely to be induced early during organ rejection or ischemia and thus serve as diagnostic indicators.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: Stress adaptation requires interactions between the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system, and a family of intracellular stress response proteins termed heat shock proteins (HSPs). These HSPs are present in every living organism and are selectively induced in the adrenal cortex and vascular smooth muscle after either surgical or restraint stress., Methods: We perturbed the hypothalamic-pituitary-adrenal axis by implanting in the rat subcutaneous pellets containing either placebo or dexamethasone (25 mg), ovine corticotropin releasing factor (CRF, 0.5 mg), or the glucocorticoid antagonist RU 486 (5 mg) for 2 weeks before randomization to either 90 minutes of restraint stress or immediate sacrifice. The adrenal glands were weighed, trunk blood was collected for adrenocorticotropic hormone (ACTH) and corticosterone measurements, and RNA isolated from the adrenal glands and aorta was assayed for HSP70 messenger RNA expression by Northern analysis., Results: Dexamethasone resulted in a twofold decrease in adrenal weight (p < 0.05). ACTH and corticosterone levels were markedly reduced in the dexamethasone treated group in the absence or presence of restraint stress. Restraint resulted in greater than 20-fold induction of HSP70 in both the adrenal gland and aorta of the placebo group compared with nonstressed controls (p < 0.01). Long-term dexamethasone treatment reduced adrenal HSP70 expression fourfold after restraint (p < 0.5), whereas neither CRF nor RU486 treatment significantly influenced the adrenal HSP70 response. Glucocorticoid manipulation with either dexamethasone or CRF did not significantly affect restraint-induced aortic HSP70 expression, whereas RU486 treatment resulted in a 50% diminution (p < 0.5) compared with placebo-treated controls., Conclusions: These data show dramatic induction of HSP70 messenger RNA expression in adrenal and aortic tissues after restraint stress. Differential organ specific HSP regulation is evidenced by the ability of the glucocorticoid dexamethasone to attenuate the adrenal but not the aortic response. The significant effect of RU486 on the aortic response suggests the possibility of vascular glucocorticoid-catecholamine interactions.

Background: Patients who undergo thyroidectomy for medullary carcinoma of the thyroid gland (MTC) often have elevations of postoperative serum calcitonin levels, which are indicative of metastatic or residual disease. It has been extremely difficult to localize tumor in these patients with standard diagnostic studies such as ultrasonography, computed tomography, or magnetic resonance imaging scans. Previous studies have suggested that planar technetium 99m (V) dimercaptosuccinic acid (DMSA) scintigraphic scans can localize MTC in these patients. We have recently increased the sensitivity of planar scintigraphic images by using single-photon emission tomography (SPECT). This study was performed to compare the sensitivity of planar DMSA scans with that of SPECT DMSA scans., Methods: Two normal volunteers and three patients with occult MTC after previous total thyroidectomy underwent planar and SPECT DMSA scans. Each patient subsequently underwent surgical exploration based on the DMSA scans., Results: Physiologic DMSA uptake was noted in the nasopharynx, axial skeleton, breast, liver, spleen, heart, kidneys, urinary bladder, great vessels, and skeletal muscles in both normal volunteers and patients with occult MTC. Planar DMSA scans and dynamic computed tomographic scans failed to localize MTC in any of these patients who had minimal disease. SPECT DMSA scans correctly localized cervical MTC in two of three patients, as proved by subsequent surgical resection. One patient who had a negative cervical exploration is presumed to have had a false-positive SPECT DMSA scan., Conclusions: SPECT DMSA scans appear to be a sensitive, safe, and noninvasive localization technique for patients with occult MTC who have undergone previous thyroidectomy.

The endocrine response to surgical stress results in activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The cellular response to a wide variety of stresses results in the synthesis of a family of stress response proteins termed heat shock proteins. Potential interactions between endocrine and cellular stress responses have not been investigated in vivo. A surgical model was developed to define the genetic response to surgical stress. Wistar rats underwent ether anesthesia, laparotomy, hemorrhage, and variable recovery periods. Tissues were subsequently harvested and the RNA was isolated and probed for HSP70 messenger RNA levels. These studies showed a strong induction of HSP70 but only in the adrenal gland, aorta, and vena cava. This specific induction was rapid, occurring 30 minutes after surgery, and dramatic (greater than twentyfold induction). The induction occurred in parallel with HPA axis activation and was adrenal cortical specific as determined by in situ hybridization. These observations suggest a functional interaction between the molecular stress response and HPA axis activation.