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Research by Dr. F


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Horm Metab Res. 2007 Jun ;39 (6):451-6 17578763

Dynamic Pituitary MRI has High Sensitivity and Specificity for the Diagnosis of Mild Cushing's Syndrome and should be Part of the Initial Workup*.

[My paper] T C F. , E Zuckerbraun , M L Lee , M S Kabil , H S.

AIM: The diagnosis of mild or episodic Cushing's syndrome is difficult. The standard tests include 24-hour urinary free cortisol (UFC), night-time blood, or salivary cortisol measurements, and dexamethasone suppression tests. Imaging studies of the pituitary have not been recommended as part of the initial workup (only to help distinguish pituitary Cushing's disease from the ectopic ACTH syndrome) because of poor sensitivity and specificity. With the development of dynamic pituitary MRI which uses multiple coronal dynamic sequences following gadolinium intravenous contrast, we hypothesized that the sensitivity and specificity would be increased and MRI would provide useful information for the initial diagnosis of Cushing's syndrome. METHODS: This was a retrospective chart review examining charts from 87 consecutive patients who were evaluated for Cushing's syndrome in a tertiary Endocrinology clinic over a one-year period. Most patients had mild and/or episodic hypercortisolism. Of these patients, 24 eventually were diagnosed with pituitary Cushing's syndrome by biochemical testing (24-h UFC and urinary 17-hydroxycorticosteroids, 11 PM salivary cortisol measurements, evening plasma cortisol), and 22 had the diagnosis of Cushing's syndrome excluded. Dynamic pituitary MRI (1.5 Tesla) was performed on all patients. The reader of the MRI was blind to the diagnosis. RESULTS: Twenty-three of 24 patients had a MRI consistent with a pituitary lesion (21 with a microadenoma, two with pituitary asymmetry). In contrast, only 3 of 20 patients (2 patient did not have MRIs) in the Cushing's excluded group had a pituitary lesion on dynamic MRI. Dynamic pituitary MRI had the highest sensitivity and negative predictive value of any testing modalities and its specificity and positive predictive value were similar to that of other tests. CONCLUSION: We conclude that almost all patients in this series with Cushing's syndrome have a lesion on dynamic pituitary MRI, a rate much higher than the 50-60% rate reported for non-dynamic MRIs. The false positive rate of 16% in our group of Cushing's excluded patients is similar to the literature value of 10% seen in normal volunteers and is acceptable since MRI is not used solely as a determinant for the diagnosis. While a negative MRI will miss those patients with adrenal or ectopic Cushing's syndrome, those patients can usually be diagnosed by other testing. Thus this preliminary study implies that dynamic pituitary MRI adds valuable information to assist in the diagnosis of Cushing's syndrome and should be ordered as part of the initial workup.

J Neurochem. 2006 Oct 25; : 17064351

Repeated stress alters the ability of nicotine to activate the hypothalamic-pituitary-adrenal axis.

[My paper] Kabirullah Lutfy , Maria C Brown , Namiko Nerio , Otaren Aimiuwu , Benjamin Tran , Adrian Anghel , Theodore C F.

Acute nicotine administration has been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis and stimulate secretion of adrenocorticotrophic hormone (ACTH), corticosterone/cortisol and beta-endorphin (beta-END) in both rodents and humans, raising the possibility that activation of the HPA axis by nicotine may mediate some of the effects of nicotine. Since stress can increase the risk of drug use and abuse, we hypothesized that repeated stress would increase the ability of nicotine to stimulate the secretion of HPA hormones. To test our hypothesis, mice were exposed to repeated stress (swimming in 15 degrees C water for 3 min/day for 5 days) and killed 15 min after injection of saline or nicotine (0.1 mg/kg, s.c.). Repeated exposure to stress increased the ability of nicotine to stimulate plasma ACTH (p < 0.05) and beta-END (p < 0.05), but not corticosterone secretion. In contrast, repeated exposure to stress increased the post-saline injection levels of corticosterone (p < 0.05), but not ACTH and beta-END. The present results suggest that chronic stress leads to an enhanced sensitivity of some components of the HPA axis to a subsequent nicotine challenge.

Am J Physiol Endocrinol Metab. 2006 Aug 22; : 16926379

Cellular co-localization and co-regulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism.

[My paper] Veronica Paez Espinosa , Monica Ferrini , Xiaoxiong Shen , Kabirullah Lutfy , Eduardo A Nillni , Theodore C F.

The prohormone convertases (PCs), PC1/3 and PC2, are involved in the tissue-specific endoproteolytic post-translational processing of many hormonal precursors within the secretory pathway. One important prohormone, pro-TRH, is expressed in both hypophysiotropic (where it regulates the secretion of thyroid-stimulating hormone) and non-hypophysiotropic regions of the brain. Pro-TRH is processed at specific sites in the secretory pathway primarily by PC1/3 followed by PC2. We hypothesized that thyroid hormone status in specific nuclei of the brain would alter pro-TRH processing by inducing changes in PC1/3 and PC2 expression. Therefore, we examined pro-TRH, PC1/3 and PC2 co-expression and co-regulation in the paraventricular nucleus (PVN), lateral hypothalamus (LH) and ventromedial nucleus (VMN) of hypothyroid and euthyroid rats. Our results show that 6-n-propyl-2-thiouracil (PTU treatment producing hypothyroidism induced a significant increase in the expression of PC1/3, PC2 and pro-TRH in the PVN and LH, but not VMN. When confocal studies were performed, an increase in co-localization of PC1/3 or PC2 in pro-TRH was observed only in PVN sites, a response that was especially prominent in the ventral and medial areas of the PVN. PTU did not regulate co-localization in the VMH or LH. Regulation of co-localization of processing enzyme and prohormone expression is a novel mechanism to alter hormonal biosynthesis. Key words: Post-translational processing, prohormone convertase, hypothalamus, pro-TRH, peptide.

Exp Clin Endocrinol Diabetes. 2006 Jul ;114 (7):356-360 16915537

An Update on the Overnight Dexamethasone Suppression Test for the Diagnosis of Cushing's Syndrome: Limitations in Patients with Mild and/or Episodic Hypercortisolism.

[My paper] T F.

The overnight one-mg dexamethasone suppression test has been used for many years to screen for Cushing's syndrome. This test has usually been evaluated in controls versus patients with severe hypercortisolism. Under these conditions, the overnight dexamethasone suppression test has been reported to have high sensitivity and specificity. The objective of this study was to determine the sensitivity of the one mg overnight dexamethasone suppression test in patients with mild and/or periodic Cushing's syndrome. Therefore, an overnight dexamethasone suppression test was performed in 17 consecutive patients presenting to an endocrinology clinic with signs and symptoms of hypercortisolemia who were later proven to have Cushing's syndrome. The majority of patients were found to have both mild and periodic hypercortisolism. One mg of dexamethasone was given at midnight and a plasma cortisol was measured by radioimmunoassay at 08:00 the following morning. Using a cut-off for a morning cortisol following overnight dexamethasone of > 5 microg/dL, only three of 17 patients failed to suppress to a value less than this cut-off (sensitivity 18 %). A cut-off of > 2 microg/dL gave similar sensitivity. Even with a stringent cut-off point of > 1.8 microg/dL, only seven of 17 patients failed to suppress to a value less than this cut-off point (sensitivity of 41 %). These results demonstrate that the great majority of patients with mild and/or periodic Cushing's syndrome suppress to overnight dexamethasone. Since patients with mild and/or periodic Cushing's syndrome are the patients in whom the identification of hypercortisolism is difficult, our results from this relatively small study suggest that this test should no longer be used to exclude these patients from further workup for Cushing's syndrome.

Endocrinology. 2006 Jul 27; : 16873540

Liver X Receptor Agonist T0901317 Inhibition of Glucocorticoid Receptor Expression in Hepatocytes May Contribute to the Amelioration of Diabetic Syndrome in db/db Mice.

[My paper] Yanjun Liu , Chaoying Yan , Ying Wang , Yuichi Nakagawa , Namiko Nerio , Adrian Anghel , Kabirullah Lutfy , Theodore C F.

The glucocorticoid receptor (GR) is a crucial target gene for glucocorticoid-induced insulin resistance and hepatic gluconeogenesis linked to the development of type 2 diabetes. The liver X receptors (LXRs) are nuclear receptors that play an important role in the regulation of metabolic gene linked to carbohydrate homeostasis. To assess the tissue-specific interaction of LXR with GR in the development of type 2 diabetes, we examined the possible effect of LXR agonist T0901317 on GR gene expression in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). Chronic ligand activation of LXR by a synthetic LXR T0901317 markedly decreased the expression of both GR mRNA and its protein in liver and improved the phenotype of type 2 diabetes in obese db/db mice. Suppression of hepatic GR expression was correlated with reduced levels of glucose and corresponded to the inhibition of phosphoenolpyruvate carboxykinase (PEPCK) mRNA and 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1)-mediated synthesis of active corticosterone from inactive 11-dehydrocorticosterone in liver. Treatment of db/db mouse primary hepatocytes with T0901317 resulted in dramatic suppression of GR mRNA and required ongoing protein synthesis. Addition of T0901317 to primary hepatocytes also suppressed the expression of both 11beta-HSD1 and PEPCK. These findings suggest that some of antidiabetic actions of LXR agonist T0901317 may be mediated, at least in part, through the suppression of hepatic GR gene expression.

Behav Neurosci. 2006 Feb ;120 (1):10-5 16492112

Differential involvement of enkephalins in analgesic tolerance, locomotor sensitization, and conditioned place preference induced by morphine.

[My paper] Paul Marquez , Ramkumarie Baliram , Nagaraju Gajawada , Theodore C F. , Kabirullah Lutfy

In this study, the authors investigated the role of enkephalins in morphine-induced conditioned place preference, locomotor sensitization, and analgesic tolerance. Both preproenkephalin wild type (ppENK [+/+]) and knockout (ppENK [-/-]) mice showed similar preference for the morphine-paired chamber over the vehicle-paired chamber, indicating morphine induced comparable conditioned place preference in ppENK (+/+) and ppENK (-/-) mice. Sensitization developed to the motor stimulatory action of morphine after its repeated administration, but the magnitude of this response was not altered in ppENK (-/-) mice. However, as shown previously, ppENK (-/-) mice displayed blunted morphine analgesic tolerance. Taken together, the results suggest that enkephalins may be important for the development of analgesic tolerance but not for conditioned place preference or behavioral sensitization induced by morphine. (© 2006 APA, all rights reserved).

Pituitary. 2005 ;7 (3):193-4 16328569

Bilateral cerebral aneurysms impinging on the pituitary.

[My paper] Theodore C F. , Hrayr S.

 

Endocrinology. 2005 Oct ;146 (10):4514-23 15994347

Glucose dependence of the regulated secretory pathway in alphaTC1-6 cells.

[My paper] Rebecca McGirr , Christina E Ejbick , David E Carter , Joseph D Andrews , Ying Nie , Theodore C F. , Savita Dhanvantari

We have investigated the effects of chronically elevated glucose concentrations on the pancreatic alpha-cell line alphaTC1-6. We show that basal glucagon secretion and proglucagon gene expression were increased in response to high glucose levels. The extent of acute stimulated secretion of glucagon was also increased in response to high glucose, as was the transcription of the prohormone processing enzymes PC1/3 and PC2. The secretion of GLP-1, a proglucagon-derived peptide produced by cleavage of proglucagon by PC1/3, was also increased in response to high glucose. Gene expression profiling experiments showed that a number of components of the regulated secretory pathway were up-regulated at high glucose concentrations, including processing enzymes and exocytotic proteins. Immunoblot analysis showed that the expression of the exocytotic SNARE proteins, as well as that of PC1/3, chromogranin A, and 7B2, were all increased after chronic exposure to high glucose levels. Immunocytochemistry showed no changes in the expression of the mature alpha-cell markers glucagon and brn-4 and no induction of the immature alpha-cell marker pdx-1. We conclude that chronically elevated glucose concentrations up-regulate the regulated secretory response of the alpha-cell.

Mesh-terms: Animals; Cell Division, drug effects; Cell Line; Glucagon Precursors; Glucagon, metabolism; Glucagon, secretion; Glucagon-Like Peptide 1; Glucose, pharmacology; Islets of Langerhans, drug effects; Islets of Langerhans, secretion; Kinetics; Peptide Fragments, metabolism; Protein Precursors, metabolism; Protein Precursors, secretion; Rats; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Reverse Transcriptase Polymerase Chain Reaction;

 

J Mol Endocrinol. 2005 Jun ;34 (3):739-51 15956344

Endocrinomic profile of neurointermediate lobe pituitary prohormone processing in PC1/3- and PC2-Null mice using SELDI-TOF mass spectrometry.

[My paper] Atira Hardiman , Theodore C F. , William C Grunwald Jr , Machi Furuta , Ziaorong Zhu , Donald F Steiner , David R Cool

Pro-vasopressin and pro-oxytocin are prohormones processed in the neurointermediate lobe pituitary to form the biologically active peptide hormones, arginine vasopressin (AVP) and oxytocin. Neurointermediate lobe pituitaries from normal (+/+), heterozygous (+/-), PC2-Null (-/-), PC1/3-Null and oxytocin-Null mice were analyzed by SELDI-TOF mass spectroscopy for the peptide hormone products, AVP, oxytocin and neurophysin I and II. Molecular ion species with masses characteristic of oxytocin, AVP, neurophysin I and II, i.e. 1009.41, 1084.5, 9677 and 9679 daltons respectively, were identified in all but the oxytocin-Null mice by comparison with synthetic standards or by C-terminal sequence analysis. Other ion species were found specifically in PC2-Null, heterozygote or normal mice. The results indicate that, in mice, both PC1/3 or PC2 enzyme activity are capable, but not required to correctly process pro-vasopressin or pro-oxytocin to their constituent active peptide hormones.

Mesh-terms: Amino Acid Sequence; Animals; Argipressin, metabolism; Humans; Mice; Mice, Knockout; Molecular Sequence Data; Neurophysins, chemistry; Neurophysins, metabolism; Oxytocin, analogs & derivatives; Oxytocin, metabolism; Pituitary Gland, metabolism; Proprotein Convertase 1, genetics; Proprotein Convertase 1, metabolism; Proprotein Convertase 2, genetics; Proprotein Convertase 2, metabolism; Protein Precursors, metabolism; Proteome; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.; Spectrum Analysis, Mass, methods;

 

Pituitary. 2005 Apr 28; : 15868092

Bilateral Cerebral Aneurysms Impinging on the Pituitary.

[My paper] Theodore F. , Hrayr S.

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