Muscle magnetic resonance imaging abnormality in neuroleptic malignant syndrome: a case report.

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a rare and occasionally fatal undesirable reaction to dopamine antagonists, and its phenotype is diverse owing to causative drugs. Classically, elevation of serum creatine kinase is described in NMS. Some reports have described muscular pathological findings; however, muscle magnetic resonance imaging (MRI) has not been reported previously. CASE PRESENTATION: A 63-year-old woman with a history of schizophrenia presented to our hospital with a high fever, excessive sweating, muscle weakness, and elevated serum creatine kinase levels. Muscle MRI revealed T2 high-intensity lesions in several muscles with gadolinium enhancement, and the pathology of the muscle biopsy showed a very mild presence of muscle fiber necrosis and regeneration with type 2c fibers without inflammation. Her symptoms resolved by treatment with levodopa/carbidopa, dantrolene. Finally, the patient was diagnosed with NMS. CONCLUSIONS: This is the first report of muscle MRI abnormalities in a patient with NMS. Muscle MRI abnormalities in NMS may be associated with non-inflammatory myopathic changes. The cause of creatine kinase elevation cannot be explained by abnormal strong muscle contraction nor inflammation.

NKX2-1 re-expression induces cell death through apoptosis and necrosis in dedifferentiated thyroid carcinoma cells.

NK2 homeobox 1 (NKX2-1) is a thyroid transcription factor essential for proper thyroid formation and maintaining its physiological function. In thyroid cancer, NKX2-1 expression decreases in parallel with declined differentiation. However, the molecular pathways and mechanisms connecting NKX2-1 to thyroid cancer phenotypes are largely unknown. This study aimed to examine the effects of NKX2-1 re-expression on dedifferentiated thyroid cancer cell death and explore the underlying mechanisms. A human papillary thyroid carcinoma cell line lacking NKX2-1 expression was infected with an adenoviral vector containing Nkx2-1. Cell viability decreased after Nkx2-1 transduction and apoptosis and necrosis were detected. Arginase 2 (ARG2), regulator of G protein signaling 4 (RGS4), and RGS5 mRNA expression was greatly increased in Nkx2-1-transducted cells. After suppressing these genes by siRNA, cell death, apoptosis, and necrosis decreased in RGS4 knockdown cells. These findings demonstrated that cell death was induced via apoptosis and necrosis by NKX2-1 re-expression and involves RGS4.

Case Report: Paraneoplastic Hashimoto's Encephalopathy Associated With Lymphomatosis Cerebri With Periodic Synchronous Discharges Resembling Creutzfeldt-Jakob Disease.

Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy that presents with various clinical symptoms, including cognitive deterioration, convulsive seizures, and personality changes. HE is associated with thyroid autoimmunity; however, few cases have been reported to develop as paraneoplastic syndrome. Herein, we report the case of a 73-year-old woman with onset of rapidly progressive dementia. Brain magnetic resonance imaging showed diffuse T2 hyperintensity areas involving the bilateral cerebral white matter, right midbrain tegmental area, left cerebral peduncle, and right middle cerebellar peduncle without clear diffusion hyperintensities and gadolinium enhancement. Her neurological symptoms worsened rapidly, and she presented with the apallic syndrome. Electroencephalogram showed periodic synchronous discharge, suggestive of Creutzfeldt-Jakob disease. However, a brain biopsy revealed infiltration of atypical lymphoid cells expressing CD20, and the anti-NH2 terminal of the α-enolase antibody was detected, diagnosing the complication with lymphomatosis cerebri and HE. High-dose intravenous methylprednisolone therapy and oral prednisolone with whole cranial irradiation enabled her to have simple conversations and consume food orally; however, severe cognitive impairment persisted. Although HE is a rare complication of malignant lymphoma, clinicians should be aware that it could be strongly suspected if the clinical symptoms worsen in the absence of imaging changes.

Familial hypocalciuric hypercalcemia with a de novo heterozygous mutation of calcium-sensing receptor.

UNLABELLED: A de novo heterozygous inactivating mutation of calcium-sensing receptor (CASR) gene typically causes neonatal hyperparathyroidism (NHPT) with moderate hypercalcemia and hyperparathyroid bone disease. We present a case of asymptomatic hypocalciuric hypercalcemia with a de novo heterozygous mutation in CASR, S591C, which is primarily reported to be responsible for NHPT. A 54-year-old female was referred for investigation of asymptomatic hypercalcemia that was initially found in the 1980s but without a history of bone disease during the perinatal period. She had moderate hypercalcemia (12.4 mg/dl) and relative hypocalciuria (fractional extraction of calcium 1.07%) but normal intact parathyroid hormone and serum 1,25-dihydroxyvitamin D3. Pedigree analysis revealed that she carried a de novo heterozygous mutation of S591C, which she transmitted to an affected child with moderate hypercalcemia but not to other children, who had normal serum calcium levels. A de novo heterozygous CASR mutation that is responsible for NHPT may also present in individuals with asymptomatic hypocalciuric hypercalcemia. Caution is required when predicting course and outcome in a pedigree with CASR mutation, as well as incidental hypercalcemia, because of its variable phenotypes. LEARNING POINTS: The phenotype and severity of CASR mutations are thought to be dependent on genotypes.We report an asymptomatic case of the de novo heterozygous S591C mutation in CASR, which has previously been reported as a responsible mutation of NHPT with bone diseases.Variable phenotypes of CASR raise a cautionary note about predicting outcome by genotyping in a pedigree with CASR mutation.

Lithium toxicity precipitated by thyrotoxicosis due to silent thyroiditis: cardiac arrest, quadriplegia, and coma.

BACKGROUND: Lithium is widely used to treat bipolar disorders. Lithium toxicity is generally caused by inappropriately high doses of lithium or impaired lithium excretion. Most lithium is eliminated via the kidneys and, since thyroid hormone increases tubular reabsorption of lithium, thyrotoxicosis could contribute to the development of lithium toxicity. We report a case of severe lithium toxicity that was apparently precipitated by the onset of thyrotoxicosis resulting from silent thyroiditis and dehydration. PATIENT FINDINGS: The patient was a 64-year-old woman who was admitted for muscle weakness in the lower extremities, diarrhea, and palpitations. She had bipolar disorder and was being treated with lithium carbonate, which she discontinued one week before admission. Her circulating lithium levels had been monitored yearly. Early in her admission she was dehydrated and had febrile episodes, paroxysmal atrial fibrillation, and muscle weakness. Initially, fluid therapy was started, but she lost consciousness and had a cardiac arrest for 2 minutes due to prolonged sinus arrest. Chest compression and manual artificial ventilation were performed, and body surface pacing was started. Serum lithium was markedly elevated to 3.81 mEq/L (therapeutic range, 0.4-1.0 mEq/L), and thyroid hormone levels were increased (free triiodothyronine, 8.12 pg/mL; free thyroxine, 4.45 ng/dL), while thyrotropin (TSH) was suppressed (<0.01 µIU/mL). Hemodialysis was performed, and a temporary pacemaker was inserted for severe sinus bradycardia. The serum thyroglobulin was 4680 ng/mL (reference range, <32.7 ng/mL). A TSH receptor antibody test was negative. Glucocorticoid therapy and inorganic iodine (100 mg) were administered and continued until day 11. However, her neurological symptoms deteriorated with floppy quadriplegia and deep coma. She gradually recovered. On day 36, she was discharged without any neurological symptoms or thyrotoxicosis. SUMMARY: A 64-year-old woman taking lithium for bipolar disorder developed lithium toxicity in the setting of what seemed likely to be a recent onset of thyrotoxicosis due to silent thyroiditis. CONCLUSIONS: Thyrotoxicosis may be a contributing cause of lithium toxicity, particularly if it is abrupt in onset and even with cessation of lithium therapy if renal function is compromised. Thyroid function should be assessed immediately in patients with suspected lithium toxicity.

New insulin sensitivity index from the oral glucose tolerance test.

A new insulin sensitivity index was devised on the basis of an autoregressive model and its validity was investigated. Using data from the 75-g oral glucose tolerance test (OGTT), 115 subjects were divided into 3 groups: 40 with normal glucose tolerance, 34 with impaired glucose tolerance, and 41 with type 2 diabetes mellitus. The new insulin sensitivity index: oral glucose insulin sensitivity index (GSI) was calculated from five sets of plasma glucose and insulin levels obtained at 0, 30, 60, 90 and 120 min during OGTT using a formula based on an autoregressive model. Forty-three of the 115 subjects were examined for insulin sensitivity index (ISI) by euglycemic hyperinsulinemic clamp. GSI decreased in the order of normal glucose tolerance group>impaired glucose tolerance group>diabetic group. There was a significant correlation between GSI and the ISI derived from euglycemic hyperinsulinemic clamp study data in all 43 subjects who underwent both tests (r=0.72; P<0.0001). The ISI calculated by previous methods poorly correlated with the ISIs obtained by euglycemic hyperinsulinemic clamp study. In conclusion, this new insulin sensitivity index based on the data obtained from OGTT using an autoregressive model is comparable to an insulin sensitivity index by euglycemic hyperinsulinemic clamp technique and may be superior to previous indexes that have been devised to determine insulin sensitivity from OGTT data.

Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells.

The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of beta-emitting radioiodide-131 ((131)I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance (131)I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) beta/gamma produced marked NIS induction; and selective stimulation of RARalpha, RARgamma, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR beta/gamma-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC(50) of tRA for NIS stimulation to approximately 7%, such that 10(-7) m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of (131)I greater than 10(-6) m tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of (131)I after combination treatment.

Adenovirus-mediated transfer of thyroid transcription factor-1 induces radioiodide organification and retention in thyroid cancer cells.

Loss of thyroid-specific gene expression and functions accompanied by loss of thyroid transcription factors render them unresponsive to radioiodide therapy in poorly differentiated and anaplastic thyroid cancer. In anticipation of reactivation of thyroid functions, we investigated the effect of thyroid transcription factor-1 (TTF-1) gene transfer on thyroid cancer cells. Reexpression of thyroperoxidase (TPO) and thyroglobulin (Tg) mRNA and protein was detected in poorly differentiated human thyroid cancer cells that were infected with an adenovirus vector containing TTF-1 (AdTTF-1). Although TTF-1 gene transfer faintly induced iodide uptake, the induction of sodium/iodide symporter (NIS) mRNA was not observed in AdTTF-1-infected cells. To analyze the effect of TTF-1 on iodide metabolism, we transfected an NIS expression vector into BHP18-21v cells and cloned a cell line (N-BHP18-21v) that stably expressed NIS. The treatment of N-BHP18-21v cells with AdTTF-1 significantly increased the amount of protein-bound radioiodide and prolonged the iodide efflux. AdTTF-1 injections significantly induced iodide retention and organification in tumors formed from N-BHP18-21v cells in nude mice. These results indicate that AdTTF-1 specifically induces iodide organification and retards iodide efflux in thyroid cancer cells in vitro and in vivo.

Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin.

Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate (125)I as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.

Systemic retinoic acid treatment induces sodium/iodide symporter expression and radioiodide uptake in mouse breast cancer models.

Lactating breast tissue and some breast cancers express the sodium/iodide symporter (NIS) and concentrate iodide. We recently demonstrated that all-trans retinoic acid (tRA) induces both NIS gene expression and iodide accumulation in vitro in well-differentiated human breast cancer cells (MCF-7). In the present study, we investigated the in vivo efficacy and specificity of tRA-stimulated iodide accumulation in mouse breast cancer models. Immunodeficient mice with MCF-7 xenograft tumors were treated with systemic tRA for 5 days. Iodide accumulation in the xenograft tumors was markedly increased, approximately 15-fold greater than levels without treatment, and the effects were tRA dose dependent. Iodide accumulation in other organs was not significantly influenced by tRA treatment. Significant induction of NIS mRNA and protein in the xenograft tumors was observed after tRA treatment. Iodide accumulation and NIS mRNA expression were also selectively induced in breast cancer tissues in transgenic mice expressing the oncogene, polyoma virus middle T antigen. These data demonstrate selective induction of functional NIS in breast cancer by tRA. Treatment with short-term systemic retinoic acid, followed by radioiodide administration, is a potential tool in the diagnosis and treatment of some differentiated breast cancer.

Enhanced expression of nicotinamide N-methyltransferase in human papillary thyroid carcinoma cells.

To gain an understanding of the molecular pathogenesis of thyroid cancer, we used DNA microarray to study the expression profiles of 10 different human thyroid carcinoma cell lines. These included papillary lines BHP 2-7, BHP 7-13, BHP 10-3, BHP 18-21, NPA 87, and TPC1; anaplastic lines ARO 81-1 and DRO 90-1; follicular line WRO 82-1; and medullary line HRO 85-1. Among the genes with increased expression in the cancer cell lines, a gene coding for nicotinamide N-methyltransferase (NNMT) was identified for being highly expressed only in the papillary cell lines. NNMT catalyzes N-methylation of nicotinamide and other structurally related compounds and is highly expressed in the human liver. The results were further confirmed by semiquantitative RT-PCR and Northern blot analysis. NNMT catalytic activities were determined in all of the cells described above and in additional cell lines. Significantly higher NNMT enzyme activities were detected in eight of 10 of the papillary lines and three of six of the follicular cell lines tested. Normal thyroid tissue, thyroid primary cultures, anaplastic cancer cells, and medullary cancer cells showed no or low enzyme activity. Immunohistochemical staining for NNMT of human thyroid specimens showed strong and abundant cytoplasmic reactions in the sections of papillary carcinomas, and weak or scanty reaction in the normal thyroid tissues. These results indicate that NNMT is a potential biomarker for papillary thyroid carcinoma.

A thyroid-specific far-upstream enhancer in the human sodium/iodide symporter gene requires Pax-8 binding and cyclic adenosine 3',5'-monophosphate response element-like sequence binding proteins for full activity and is differentially regulated in normal and thyroid cancer cells.

The sodium/iodide symporter (NIS) gene is highly expressed in the thyroid gland and is important for the diagnosis and radioiodide therapy of differentiated thyroid cancers. We investigated a human NIS (hNIS) gene 5'-far-upstream enhancer (hNUE) (-9847 to -8968). The hNUE is TSH responsive in both FRTL-5 cells and primary normal thyroid cells, but not in human papillary thyroid cancer cells (BHP cells). The hNUE enhanced expression of the basal hNIS promoter 15-fold and required both a Pax-8 binding site and a cAMP response element (CRE)-like sequence for full activity. The hNUE activated transcription in a thyroid-selective and cAMP-dependent manner, mediated by both protein kinase A (PKA)-dependent and PKA-independent pathways. Pax-8 and two CRE-like sequence binding proteins bind to the hNUE. Supershift binding assay indicated that one of the CRE-like sequence binding protein(s) was CRE-binding protein-1, activation transcription factor-1, and/or CRE modulator, and the other was an unknown factor(s) that is absent in BHP 2-7 cells. A far-upstream enhancer is important for hNIS regulation in the thyroid. Deficient CRE-like sequence binding protein(s) that bind to the hNUE in normal thyroid cells may be responsible for reduced NIS gene expression in some thyroid carcinomas.