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K Pacak

Publications and source records attributed to K Pacak.

At least 19 recordsLinked to original sources
PubMed2001

Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma.

Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as(123) I-metaiodobenzylguanidine scintigraphy and 6-[(18) F]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.

Adrenal Gland Neoplasms↗
PubMed2001

Genetic aspects of pheochromocytoma.

We here review the literature on genetics related to pheochromocytoma. About 10 percent of these neuroendocrine tumors are hereditary and are most often associated with multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease, and neurofibromatosis type 1 (NF 1). Hereditary tumor syndromes such as the aforementioned ones, are ideal to study the molecular pathogenesis of tumorigenesis as opposed to sporadic tumors in which genetic alterations often merely represent epigenetic tumor progression phenomena. Recent advances in molecular genetics, especially of RET, VHL, NF1, and SDHD, helped better understand the pathogenesis of pheochromocytoma. In this paper, we not only summarize key points of genetic discoveries related to pheochromocytoma, but also report in table format all known RET germline mutations related to pheochromocytoma.

Drosophila Proteins↗
PubMed2000

Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas.

Inherited mutations of the RET proto-oncogene are tumorigenic in patients with multiple endocrine neoplasia type 2 (MEN 2). However, it is not understood why only few of the affected cells in the target organs develop into tumors. Genetic analysis of nine pheochromocytomas from five unrelated patients with MEN 2 showed either duplication of the mutant RET allele in trisomy 10 or loss of the wild-type RET allele. Our results suggest a "second hit" causing a dominant effect of the mutant RET allele, through either duplication of the mutant allele or loss of the wild-type allele, as a possible mechanism for pheochromocytoma tumorigenesis in patients with MEN 2.

Adrenal Gland Neoplasms↗
PubMed2000

Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism.

Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively.

Adrenergic beta-Agonists↗
PubMed2000

Plasma metanephrines: a novel and cost-effective test for pheochromocytoma.

Pheochromocytomas are rare chromaffin cell tumors that nevertheless must be excluded in large numbers of patients who develop sustained or episodic hypertension as well as in many others with suggestive symptoms or with a familial history of pheochromocytoma. Diagnosis of pheochromocytoma depends importantly on biochemical evidence of excess catecholamine production by a tumor. Imperfect sensitivity and specificity of commonly available biochemical tests and the low incidence of the tumor among the tested population mean that considerable time and effort can be expended in confirming or ruling out pheochromocytoma in patients where the tumor is suspected. Measurements of plasma free metanephrines provide a superior test compared to other available tests for diagnosis of pheochromocytoma. In particular, the high sensitivity of plasma free metanephrines means that a normal test result reliably excludes all but the smallest of pheochromocytomas so that no other tests are necessary. Measurements of plasma free metanephrines, when systematically combined with other diagnostic procedures outlined in this review, provide a more efficient, reliable and cost-effective approach for diagnosis of pheochromocytoma than offered by previously available approaches.

Adrenal Gland Neoplasms↗
PubMed1999

The role of ascending neuronal pathways in stress-induced release of noradrenaline in the hypothalamic paraventricular nucleus of rats.

Central catecholaminergic pathways carrying pain-related signals to the hypothalamic paraventricular nucleus (PVN) were investigated in laboratory rats. Four per cent formalin injected subcutaneously was employed as a stressful stimulus. Neuronal activity in brainstem catecholaminergic and paraventricular neurones was assessed by Fos immunohistochemistry. Stress-induced noradrenaline (NE) release from nerve terminals in the PVN was measured in extracellular fluid by in-vivo microdialysis. Within 30 min, formalin elicited a four- to sixfold increase in plasma ACTH and corticosterone concentrations and intense Fos-like activity was seen in the superficial zones of the lumbar spinal cord ipsilateral to the side of the formalin injection. In brainstem catecholaminergic neurones, the PVN, and midline thalamic nuclei, formalin-induced Fos-immunopositivity was equally present in the ipsi- and contralateral sides of the injection. An immediate elevation (4-5 times higher than baseline levels) of NE levels was measured in both the right and left PVN after a formalin injection into the right paw. Unilateral surgical transections at the medulla-spinal cord junction failed to affect formalin-induced elevations in NE levels in the PVN independently of the side of the formalin injection or the knife cut. Thus, this observation clearly shows that fibres carrying pain-evoked signals ascend bilaterally from the spinal cord to the brainstem and forebrain. Hemisections of the medulla oblongata between the level of A1-A2 NE cell groups and the locus coeruleus reduced but did not eliminate formalin-induced NE release from the PVN ipsilateral to the knife cut. This effect was independent of the side of the formalin injection. In the contralateral PVN, high and similar NE levels were measured in response to a formalin injection into the right or the left leg. The present study indicates that formalin-induced pain signals are carried by sensory fibres to the ipsilateral spinal cord. From there, axons of different dorsal horn neurones reach noradrenergic cells on both sides of the medulla oblongata. The majority of noradrenergic fibers ascend on the same side and innervate the ipsilateral PVN. Since formalin administration resulted in a moderate elevation of NE levels in the PVN on the operated side, the role of other ascending noradrenergic (from the locus coeruleus) or noncatecholaminergic fibres that could modulate NE release from the PVN should be considered.

Animals↗
PubMed1998

Solitary cerebellar metastasis from papillary thyroid carcinoma: a case report.

Papillary thyroid carcinoma is a common thyroid malignancy that generally has a good prognosis. However, this type of cancer may give rise to distant metastasis and may behave more aggressively in older patients. Here we report clinical, radiological, and pathological findings of a patient with papillary thyroid carcinoma who had a solitary cerebellar metastasis. The patient was known to have metastatic thyroid cancer to the lungs, but this had been stable and the cerebellar metastasis presented an unanticipated significant problem. The rapid detection of cerebellar metastatic disease is critical because neurosurgical removal of the solitary lesion should be considered as the treatment of choice. This case also serves to remind us of the importance of considering possible metastatic brain lesions and their acute life-threatening complications in contrast to the relatively prolonged course associated with metastases of thyroid carcinoma to other organs.

Aged↗
PubMed1998

Heterogeneous neurochemical responses to different stressors: a test of Selye's doctrine of nonspecificity.

Selye defined stress as the nonspecific response of the body to any demand. Stressors elicit both pituitary-adrenocortical and sympathoadrenomedullary responses. One can test Selye's concept by comparing magnitudes of responses at different stress intensities and assuming that the magnitudes vary with stress intensity, with the prediction that, at different stress intensities, ratios of increments neuroendocrine responses should be the same. We measured arterial plasma ACTH, norepinephrine, and epinephrine in conscious rats after hemorrhage, intravenous insulin, subctaneous formaldehyde solution, cold, or immobilization. Relative to ACTH increments, cold evoked large norepinephrine responses, insulin large epinephrine responses, and hemorrhage small norepinephrine and epinephrine responses, whereas immobilization elicited large increases in levels of all three compounds. The ACTH response to 25% hemorrhage exceeded five times that to 10%, and the epinephrine response to 25% hemorrhage was two times that to 10%. The ACTH response to 4% formaldehyde solution was two times that to 1%, and the epinephrine response to 4% formaldehyde solution exceeded four times that to 1%. These results are inconsistent with Selye's doctrine of nonspecificity and the existence of a unitary "stress syndrome," and they are more consistent with the concept that each stressor has its own central neurochemical and peripheral neuroendocrine "signature."

Adrenocorticotropic Hormone↗
PubMed1997

Stress-induced Fos-like Immunoreactivity in the Pons and the Medulla Oblongata of Rats.

Immunoreactivity of the immediate early gene c-fos was used to investigate changes in the activity of brainstem neurons in response to acute stressors like immobilization, formalin-induced pain, cold exposure, hemorrhage and insulin-induced hypoglycemia. Different stressors induced Fos-like immunoreactivity in different pontine and medullary neurons. A single, 3 hour immobilization was found to be a very strong stimulus that activated brainstem catecholaminergic (tyrosine hydroxylase-immunopositive) neurons and cells in the raphe and certain pontine tegmental nuclei, as well as in the reticular formation. Pain, induced by a subcutaneous injection of formalin was also effective on catecholamine-synthesizing neurons and on others cells in the nucleus of the solitary tract. Cold exposure activated cells mainly in the sensory spinal trigeminal and parabrachial nuclei and in the so-called "pontine thermoregulatory area". Moderate Fos-like immunoreactivity was induced by a hypotonic (25%) hemorrhage in medullary catecholaminergic neurons, the nucleus of the solitary tract and the Barrington nucleus. Among stressful stimuli used, insulin-induced hypoglycemia elicited the smallest Fos activation in the lower brainstem. The present observations indicate that different stressors may use different neuronal pathways in the central organization of the stress response.

Journal Article↗
PubMed1997

Regulation of Peripheral Catecholamine Responses to Acute Stress in Young Adult and Aged F-344 Rats.

Young adult (3-month-old) and aged (24-month-old) Fischer-344 male rats received i.v. infusions of 3H-labeled norepinephrine (NE) and epinephrine (EPI) to examine the effects of aging on the neuronal uptake of NE and sympathoadrenal release of NE and EPI. Spillovers of NE and EPI into plasma and their clearance from the circulation were estimated from plasma concentrations of endogenous and 3H-labeled NE and EPI. The efficiency of neuronal uptake was assessed from changes in plasma clearance of NE and concentrations of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG), during immobilization stress or neuronal uptake blockade with desipramine. Stress-induced increases in plasma NE and higher plasma NE concentrations in aged compared to young adult rats were due to both decreases in NE clearance and increases in NE spillover. EPI spillover and clearance were reduced in aged compared to young adult rats, so that plasma EPI levels did not differ between groups. Young adult and aged rats had similar desipramine-induced decreases in NE clearance, whereas desipramine-sensitive decreases and stress-induced increases in plasma DHPG were larger in aged rats. This indicates that neuronal uptake is intact and that increased NE spillover at rest and during stress in aged rats reflects increased NE release from sympathetic nerves. The results show that aging is associated with divergent decreases in EPI release from the adrenal medulla and increases in NE release from sympathetic nerves. Increased plasma concentrations of NE in aged compared to young adult rats also result from decreased circulatory clearance of NE, but this does not reflect any age-related impairment of NE reuptake.

Journal Article↗