Parathyroid imaging: the myth and the reality.
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Adenoma↗
Biomedical subjects
R Udelsman
Publications and source records attributed to R Udelsman.
Activation of heat shock transcription factor 1 in rat aorta in response to high blood pressure.
We have previously demonstrated that acute hypertension induces heat shock protein gene expression in rat arterial wall. Here we provide evidence that this induction is mediated through the activation of heat shock transcription factor 1 in response to high blood pressure. Rats subjected to restraint or immobilization stress displayed an acute elevation in systolic pressure accompanied by an increase in heat shock protein 70 mRNA expression. Consistent with the rapid time course of mRNA induction, an increase in binding activity to an oligonucleotide encompassing a consensus heat shock element sequence was seen in protein extracts from aorta of restrained rats as assessed with gel mobility shift assays. A similar increase in DNA binding activity was also observed in aortic extracts from rats treated with various hypertensive agents, including phenylephrine, angiotensin II, and vasopressin. That the DNA binding activity was attributed to heat shock factor 1 was shown through use of antibodies to the transcription factor that retarded the DNA-protein complexes in gel mobility supershift assays. Western blot analysis of heat shock factor 1 protein expression in aortic extracts showed a slower mobility form of the protein in hypertensive rats, indicative of an activated, presumably phosphorylated, form of the transcription factor. These findings support the view that heat shock factor 1 is responsible for induction of heat shock protein 70 in the arterial wall during acute hypertension, a response that is likely to play an important role in protecting arteries during hemodynamic stress.
Acute Disease↗
Acute hypertension induces heat-shock protein 70 gene expression in rat aorta.
BACKGROUND: Many factors cause acute systemic hypertension, which in turn can result in damage to the vessel wall and lead to vascular disease. In previous studies, we demonstrated that restraint, or immobilization stress, results in the induction of heat-shock protein 70 (hsp70) gene expression in the aorta of adult rat and showed that this response was markedly attenuated with age. METHODS AND RESULTS: Here we provide evidence that restraint-induced hsp70 expression occurs secondary to a rise in systemic blood pressure. Old rats were unable to mount a significant stress-induced hypertensive response, providing an explanation for the reduced hsp70 response in the old rats. A variety of vasoactive agents that induce acute hypertension through distinct signal transduction pathways, including phenylephrine, dopamine, vasopressin, angiotensin II, and endothelin-1, were found to result in hsp70 mRNA induction in the aorta. The magnitude of hsp70 expression achieved with these hypertensive agents was directly correlated with their relative effects on blood pressure. Rats were treated with the vasodilator sodium nitroprusside, which prevented an acute rise in blood pressure from the hypertensive agents tested and abolished induction of hsp70 expression. CONCLUSIONS: These findings support the conclusion that hsp70 induction occurs as a physiological response to acute hypertension and suggest the possibility that hsp70 plays a role in the protecting the vasculature from damage during hemodynamic stress.
Aging↗
Adrenocorticotropic hormone-secreting pheochromocytomas: the exception to the rule.
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.
17-Hydroxycorticosteroids↗
Aortic crosstransplantation between young and old rats: effect upon the heat shock protein 70 stress response.
In previous studies we demonstrated that restraint, or immobilization stress, resulted in the induction of HSP70 mRNA in the vasculature of rats. This response was confined to the vascular smooth muscle, was associated with alpha 1-adrenergic receptor stimulation, and was attenuated with age. In the present study, we examined the influence of transplanting aged vessels into young animals and young vessels into aged animals to determine if this age-related diminution was due to changes intrinsic to the aorta or the result of alterations in the environment in which the aorta resides. We demonstrate that restraint-induced HSP70 expression in transplanted vessels is influenced to a greater degree by the age of the recipient than by the age of the transplanted vessel. Transplantation of aged vessels into young animals leads to preservation of the response, whereas transplantation of young vessels into aged animals leads to attenuation. These findings indicate that the environment in which the vessel resides is a major factor in determining this molecular response to stress.
Aging↗
Follicular lesions of the thyroid. Does frozen section evaluation alter operative management?
OBJECTIVE: The authors determined the usefulness of frozen section (FS) evaluation in the operative management of follicular lesions of the thyroid. SUMMARY BACKGROUND DATA: Fine-needle aspiration (FNA) cannot reliably discriminate between benign and malignant follicular lesions of the thyroid. Accordingly, FS evaluation is used routinely to guide intraoperative management. METHODS: One hundred twenty-five consecutive patients with follicular thyroid lesions who underwent surgical exploration at the Johns Hopkins Hospital were reviewed. RESULTS: Frozen sections were categorized in 104 of 120 patients (87%) as "follicular lesion, defer to permanent section," rendering no useful clinical information. In only 4 of 120 patients (3.3%) did FS evaluation correctly modify the operative procedure. Notably, in six cases (5.0%), an incorrect FS evaluation misled the surgeon, resulting in four misguided operations. CONCLUSION: Frozen section evaluation is of minimal diagnostic value for follicular thyroid lesions, rendering no additional information 87% of the time; it prolongs the operation, increases costs, and leads to misguided interventions. Until a more definitive diagnostic tool exists for follicular thyroid lesions, FS evaluation could be omitted, resection of the lobe with the nodule could be performed, and the definitive operative management could be based on the final permanent histology.
Adolescent↗
A clinical moment with endocrinology and metabolism. Laparoscopic adrenalectomy.
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Adrenal Gland Neoplasms↗
Induction of heat-shock gene expression in postischemic pig liver depends on superoxide generation.
BACKGROUND/AIMS: Both hemorrhagic and cardiogenic shock are associated with hepatic shock gene expression at resuscitation. This study investigated the potential role of intravascular superoxide anion as a proximal trigger of heat shock protein gene expression. METHODS: Preanesthetized pigs were subjected to 120 m of total warm hepatic ischemia. The survival model consisted of warm, total hepatic ischemia and reperfusion (with active portal-systemic bypass) followed by reperfusion and survival for 3 days. Serial hepatic biopsy samples were evaluated for the expression of heat shock protein 72 (HSP-72) messenger RNA (mRNA) by Northern and Western analysis and by in situ RNA hybridization. The possible role of intravascular O2- as a mediator of heat shock response was evaluated by its specific inhibition by the intravenous infusion of recombinant human superoxide dismutase (SOD). RESULTS: Ischemia for 120 minutes followed by 60 minutes of reperfusion caused accumulation of HSP-72 mRNA. Transcripts were localized to hepatocytes. HSP-72 mRNA was detected neither following ischemia alone nor when SOD was infused for 15 minutes at reperfusion. Three days later, transcripts were not detectable, but HSP-72 protein accumulated irrespective of SOD administration. CONCLUSIONS: Warm hepatic ischemia induces the hepatocyte expression of HSP-72 at reperfusion by a mechanism that is dependent upon the superoxide anion, probably generated intravascularly. However, the transient dismutation of superoxide is insufficient to suppress subsequent accumulation of HSP-72.
Animals↗
Impaired wound healing in Cushing's syndrome: the role of heat shock proteins.
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.
Adrenal Glands↗
Endocrine and molecular responses to surgical stress.
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)
Acute-Phase Reaction↗
Adrenergic regulation of adrenal and aortic heat shock protein.
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.
Adrenal Glands↗
Endocrine control of stress-induced heat shock protein 70 expression in vivo.
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.
Adrenal Glands↗
Vascular heat shock protein expression in response to stress. Endocrine and autonomic regulation of this age-dependent response.
Adaptation to stress requires coordinated interactions between the vascular and endocrine systems. Previously we demonstrated that restraint stress induces the expression of the major heat shock protein, HSP70, in the adrenal cortex of the rat. Here we demonstrate that restraint also induces expression of HSP70 in the vasculature. We further demonstrate that the adrenal and vascular responses are differentially regulated: the adrenal response is adrenocorticotropin dependent, whereas the vascular response is under adrenergic control. In addition, the adrenal response is restricted to members of the HSP70 gene family, whereas in vascular tissue the low molecular weight HSP, HSP27, is also induced by restraint. Further characterization of the vascular response revealed that HSP70 induction occurred in both the thoracic and abdominal aortas as well as in the vena cava. However, no HSP70 induction was apparent in the heart or in a wide variety of other tissues examined. In situ hybridization showed that the vascular expression was localized to the aortic smooth muscle cells with minimal expression in the endothelium. Induction of HSP70 mRNA in both the adrenal cortex and aorta was followed by an elevation in HSP70 protein. Maximum HSP70 protein levels were seen within 3-12 h after restraint, but declined thereafter. Stress induced HSP70 expression was dramatically reduced with age, which may explain, in part, the diminished tolerance to stress seen in elderly individuals.
Adrenal Cortex↗
Pancreaticoduodenectomy for selected pancreatic endocrine tumors.
Endocrine tumors are distributed throughout the pancreas and can usually be removed by local excision or distal pancreatectomy. Those tumors arising in the pancreatic head and uncinate process may be difficult to enucleate because of size, location or malignant extension. In the past, surgeons have been reluctant to perform a pancreaticoduodenectomy (Whipple procedure) for these lesions because of the high morbidity and mortality rates. In recent years, we and others have reported a marked reduction in the morbidity and mortality rates after the Whipple procedure and, since 1981, have used pancreaticoduodenectomy to resect pancreatic endocrine neoplasms successfully in 12 patients. Tumors were resected from six men and six women who ranged in age from 28 to 61 years (median of 49 years). Six of the tumors were benign and included three insulinomas, one glucagonoma, one gastrinoma and one nonfunctioning islet cell tumor. The six malignant tumors included two insulinomas, one VIPoma and three nonfunctioning islet cell tumors. In all instances, enucleation could not be performed safely or would have resulted in an inadequate excision. Pylorus preservation was used in seven of the patients, including the last six. The average operative time was 6.8 hours, and six of the patients did not require perioperative blood transfusions. There was no hospital mortality. Hospital morbidity included three self-limited pancreatic fistulas, one gastrocutaneous fistula, one hepatic abscess and one postoperative myocardial infarction. One patient with a malignant VIPoma died three years postoperatively of metastatic tumor. The remaining 11 patients are alive and well with a median follow-up period of three and one-half years (range of zero to 9.7 years). These data indicate that pancreaticoduodenectomy is an appropriate procedure for properly selected patients with pancreatic endocrine neoplasms and can be performed with acceptable morbidity and mortality rates.
Adenoma, Islet Cell↗
Preoperative localization of occult medullary carcinoma of the thyroid gland with single-photon emission tomography dimercaptosuccinic acid.
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.
Adult↗
Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response.
The induction of heat shock proteins (HSP) by cellular stress and the activation of the hypothalamic-pituitary-adrenal axis by physiologic stress are biological responses that aid in the maintenance of cellular and organismal homeostasis, respectively. In this report, restraint stress, known to activate the hypothalamic-pituitary-adrenal axis, is shown to induce expression of HSP70 mRNA selectively in the adrenal cortex of the rat. Restraint-induced HSP70 expression in the adrenals is rapid and is preceded by the activation of a protein factor capable of binding to the heat shock transcriptional control element. The ability of restraint to induce HSP70 expression in the adrenal is virtually eliminated in hypophysectomized rats but can be restored by the exogenous administration of adrenocorticotropic hormone. The magnitude of this induction declines as a function of increasing age, which may contribute to a reduced stress tolerance by aged animals. These results support a role for HSP70 in the physiologic stress response mediated by the hypothalamic-pituitary-adrenal axis.
Adrenal Cortex↗
Pentavalent Tc-99m DMSA scintigraphy. Prospective evaluation of its role in the management of patients with medullary carcinoma of the thyroid.
Ten patients with suspected primary, recurrent or metastatic medullary carcinoma of the thyroid (MCT) were studied prospectively with Tc-99m(V) DMSA. Of these, two patients had primary disease, seven patients were asymptomatic but had persistent and serial elevations in serum calcitonin following previous thyroid resections for MCT, and one asymptomatic patient with normal serum calcitonin was studied because of suspected hilar nodes metastases. The serial calcitonin peak in the patients was 0.04-43ng/ml (normal less than 0.08ng/ml). Scintigraphy was considered positive in seven of the asymptomatic patients and equivocal in one. The two patients with primary disease had increased uptake before but not after thyroidectomy. Primary disease, localized recurrence and distant metastases in soft tissue (nine patients) and bone (one patient) were detected in these patients, and this resulted in early surgical resection (five patients) and radiotherapy (one patient). We conclude that Tc-99m(V) DMSA is a useful imaging agent in the evaluation of asymptomatic MCT patients with hypercalcitonemia.
Adult↗
Molecular response to surgical stress: specific and simultaneous heat shock protein induction in the adrenal cortex, aorta, and vena cava.
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.
Adrenal Cortex↗