ABSTRACT
BACKGROUND: Complete surgical resection of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the gold standard of treatment of Cushing disease. Ectopic location of these adenomas is an extremely rare condition that may compromise the diagnosis and surgical success. We present the first case of an ectopic intracavernous ACTH-secreting macroadenoma totally resected with endoscopic endonasal surgery (EES). CASE DESCRIPTION: A 36-year-old woman presented with Cushing syndrome. Increased ACTH, serum cortisol, and free urine cortisol levels were identified; however, pituitary magnetic resonance imaging failed to show a pituitary tumor; instead, a parasellar lesion in the left cavernous sinus (CS) was noticed. Inferior petrosal sinus sampling showed a significant central to peripheral and lateralized left-sided ACTH gradient. The patient underwent EES. No tumor was found in the sella; however, the left CS was widely explored and a tumor was found lateral to the paraclival segment of the carotid artery. There were no complications after EES. Pathology confirmed the diagnosis of an ACTH-secreting adenoma. During the immediate postoperative course, serum cortisol levels decreased lower than 5 µg/dL. Postoperative magnetic resonance imaging showed complete tumor resection. At 20 months follow-up, the patient remained in clinical and biochemical remission of Cushing disease. CONCLUSIONS: Only 12 cases of ectopic intracavernous ACTH-secreting adenomas have been reported and all were microadenomas. The presence of an ectopic ACTH-secreting macroadenoma in the CS represents a surgical challenge. EES is the ideal approach for complete resection of ectopic intracavernous adenomas, allowing for a wide exploration of the CS with no surgical complications.
Subject(s)
ACTH-Secreting Pituitary Adenoma/complications , Adenoma/complications , Cushing Syndrome/surgery , Natural Orifice Endoscopic Surgery/methods , Neurosurgical Procedures/methods , ACTH-Secreting Pituitary Adenoma/surgery , Adenoma/surgery , Adult , Cushing Syndrome/etiology , Humans , Magnetic Resonance Imaging , Male , Remission InductionABSTRACT
Low levels of brain-derived neurotrophic factor (BDNF) peptide are linked to the pathophysiology of mood disorders. Several single-nucleotide polymorphisms (SNPs) across the BDNF gene (BDNF) have been associated with bipolar illness. Since both elevated intracellular sodium and apoptosis are believed to contribute to cellular dysfunction in bipolar disorder, it is important to determine the effect of exogenous BDNF on apoptosis induced by the high levels of intracellular sodium seen in ill bipolar patients. Human olfactory neuroepithelial progenitor cells were treated with monensin, a sodium ionophore that increases intracellular sodium and leads to apoptosis. Apoptosis was quantified with enzyme-linked immunosorbent assay (ELISA) for mono- and oligonucleosomes. Elevation of intracellular sodium concentration by monensin induced apoptosis. BDNF 100ng/mL pretreatment or co-treatment attenuated the monensin-induced apoptosis. Pretreatment with BDNF for 24h reduced monensin-induced apoptosis by 93%. Co-treatment of BDNF and monensin increased intracellular sodium concentration and reduced apoptosis by 66%. Monensin for 24h models a process that is believed to occur during ill phases of bipolar illness. Treatment with BDNF greatly attenuates or prevents monensin-induced apoptosis. The functional consequences of BDNF SNPs, known to be associated with bipolar illness, need to be examined.
Subject(s)
Apoptosis/drug effects , Brain-Derived Neurotrophic Factor/pharmacology , Neuroepithelial Cells/drug effects , Olfactory Bulb/cytology , Stem Cells/drug effects , Analysis of Variance , Cells, Cultured , Dose-Response Relationship, Drug , Drug Interactions , Enzyme-Linked Immunosorbent Assay/methods , Humans , Ionophores/pharmacology , Monensin/pharmacology , Time FactorsABSTRACT
Neurosphere forming cells (NSFCs) have been established from cultures of adult olfactory neuroepithelium obtained from patients and cadavers as described previously. They remained undifferentiated in serum or defined media with or without neurotrophic factors. Many factors affect the differentiation of stem cells along a neuronal pathway. Retinoic acid (RA), forskolin (FN), and sonic hedgehog (Shh) have been reported to act as growth promoters during neurogenesis of embryonic CNS in vivo. The effect of RA, FN, and Shh on NSFCs' neuronal lineage restriction has not been described. The application of RA, FN, and Shh to NSFCs induced the expression of motoneuronal transcription factors, tyrosine hydroxylase, an indicator of dopamine production, and neurite formation. These studies further heighten the potential for using olfactory neuroepithelial progenitors for future autologous cell replacement strategies in neurodegenerative conditions and trauma as well as for use in diagnostic evaluation.
Subject(s)
Cell Differentiation/physiology , Neurons/physiology , Olfactory Mucosa/cytology , Stem Cells/physiology , Adult , Aged, 80 and over , Analysis of Variance , Animals , Cell Differentiation/drug effects , Cells, Cultured , Chick Embryo , Choline O-Acetyltransferase/metabolism , Coculture Techniques/methods , Colforsin/pharmacology , Drug Interactions , Female , Gene Expression Regulation, Developmental/drug effects , Hedgehog Proteins , Humans , Indoles , Male , Muscle Cells/physiology , Neurites/drug effects , Neurites/physiology , Neurites/ultrastructure , Neurons/drug effects , Neurons/ultrastructure , Phosphopyruvate Hydratase/metabolism , Stem Cells/drug effects , Synapsins/metabolism , Tetrazolium Salts , Thiazoles , Trans-Activators/pharmacology , Transcription Factors/metabolism , Tretinoin/pharmacology , Tyrosine 3-Monooxygenase/metabolism , Vesicular Acetylcholine Transport Proteins/metabolismABSTRACT
Neurosphereforming cell (NSFC) lines have been established from cultures of human adult olfactory neuroepithelium. Few of these cells ever express mature neuronal or glial markers in minimal essential medium supplemented with 10% fetal bovine serum or defined medium. However, these neural progenitors have the potential to differentiate along glial or neuronal lineages. To evaluate the potential of NSFCs to form motoneurons, transcription factors Olig2, Ngn2, and HB9 were introduced into NSFCs to determine if their expression is sufficient for motoneuron specification and differentiation, as has been shown in the early development of the avian and murine central nervous systems in vivo. NSFCs transfected with Olig2, Ngn2, and HB9 alone exhibited no phenotypic lineage restriction. In contrast, simultaneous transfection of Ngn2 and HB9 cDNA increased the expression of Isl1/2, a motoneuron marker, when the cells were maintained in medium supplemented with retinoic acid, forskolin, and sonic hedgehog. Furthermore, a population of Olig2-expressing NSFCs also expressed Ngn2. Cotransfection of NSFCs with Olig2 and HB9, but not Olig2 and Ngn2, increased Isl1/2 expression. Coculture of NSFCs trans-fected with Ngn2-HB92 or Olig2 and HB9 with purified chicken skeletal muscle demonstrated frequent contacts that resembled neuromuscular junctions. These studies demonstrate that transcription factors governing the early development of chick and mouse motoneuron formation are able to drive human adult olfactory neuroepithelial progenitors to differentiate into motoneurons in vitro. Our long-term goal is to develop cell populations for future studies of the therapeutic utility of these olfactory-derived NSFCs for autologous cell replacement strategies for central nervous system trauma and neurodegenerative diseases.
