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A 65-year-old Japanese woman with an intrapericardial tumor and neck tumor was admitted to our hospital. Intrapericardial tumor had not been resected because of massive bleeding from the hypervascular tumor and its invasion into the pericardium, ascending aorta, and pulmonary artery. The neck tumor had been successfully resected, and paraganglioma was pathologically diagnosed. Abnormal accumulation in the intrapericardial tumor was seen with (123)I-metaiodobenzylguanidine scintigraphy. Moreover, gene mutation of succinate dehydrogenase type D was found. Finally, paraganglioma of the carotid body and intrapericardium was diagnosed.

Objective: Hypothyroidism is not commonly considered a cause of hyperkalemia. We previously reported that hyperkalemia was observed mainly in elderly patients treated with renin-angiotensin-aldosterone system (RAS) inhibitors when levothyroxine treatment was withdrawn for the thyroidectomized patients with thyroid carcinoma to undergo radioactive iodine treatment. Here, we investigated whether acute hypothyroidism causes hyperkalemia in patients who were not treated with RAS inhibitors. We also investigated factors influencing potassium metabolism in hypothyroid patients. Methods: We conducted a single-center, prospective cohort study of 46 Japanese patients with thyroid carcinoma undergoing levothyroxine withdrawal prior to radioiodine therapy. All patients were normokalemic before levothyroxine withdrawal. Blood samples were analyzed 3 times: before, and at 3 and 4 weeks after levothyroxine withdrawal. We investigated factors that may be associated with the elevation of serum potassium levels from a euthyroid state to a hypothyroid state. Results: None of the patients developed symptomatic hyperkalemia. The mean serum potassium level was significantly higher at 4 weeks after levothyroxine withdrawal compared to baseline. The serum sodium levels, the estimated glomerular filtration rate (eGFR), and the plasma renin activity (PRA) decreased significantly as hypothyroidism advanced. In contrast, the plasma levels of adrenocorticotropic hormone, cortisol, aldosterone, and antidiuretic hormone were not changed, while serum thyroid hormone decreased. At 4 weeks after their levothyroxine withdrawal, the patients' serum potassium values were significantly correlated with the eGFR and the PRA. Conclusion: Acute hypothyroidism can cause a significant increase in the serum potassium level, which may be associated with a decreased eGFR and decreased circulating RAS. Abbreviations: ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; ATPase = adenosine triphosphatase; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; K+ = potassium; Na+ = sodium; PRA = plasma renin activity; RAS = renin-angiotensin-aldosterone system; T4 = thyroxine; TSH = thyroid-stimulating hormone

Aims: To evaluate the glycaemic control of combination therapy with basal insulin and liraglutide, and to explore the factors predictive of efficacy in patients with type 2 diabetes when switched from longstanding basal-bolus insulin therapy. Methods: We studied 41 patients who switched from basal-bolus insulin therapy of more than 3 years to basal insulin/liraglutide combination therapy. Glycaemic control was evaluated at 6 months after switching therapy and used to subdivide the patients into good-responders (HbA1c, Diabetes Research and Clinical Practice, 144, pp.161-170; 2018

Objective: Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare, chronic, relapsing inflammatory osteoarticular disorder with dermatologic manifestations. SAPHO syndrome can be a rare cause of atypical symptoms including neurologic defects. We report a case with SAPHO syndrome with the endocrinologic defects most likely associated with SAPHO syndrome.Methods: Case report and review of the literature.Results: A 61-year-old Japanese female with SAPHO syndrome presented with polyuria and polydipsia. Pituitary magnetic resonance imaging (MRI) with gadolinium enhancement showed an enlarged infundibulum and pituitary with ring-enhancing masses located at the posterior pituitary and upper infundibulum. Extensive diagnostic workup excluded local and systemic infection, brain metastasis, and various secondary hypophysitis as the cause of the infundibular and pituitary lesions. There were spontaneous improvements in the MRI findings taken 4 months after her initial presentation. The patient underwent a biopsy of the anterior pituitary, which showed a sterile lymphocytic infiltration.Conclusion: There are rare cases of SAPHO syndrome patients in which transient neurologic symptoms associated with the self-limiting ring-enhancing lesions consisting of a sterile and nonspecific inflammation are described. Since cystic formation in the infundibulum caused by idiopathic lymphocytic hypophysitis has not been reported, to the best of our knowledge, we concluded that the endocrinologic defects in our patient were most likely associated with SAPHO syndrome. Thus, SAPHO syndrome should be considered as one of the causes not only for ring-enhancing lesions in the brain but also for secondary hypophysitis, especially in patients with dermatologic and osteoarticular manifestations.

Aquaporin-5 (AQP5) is a water-selective channel protein that is expressed in submucosal glands and alveolar epithelial cells in the lungs. Recent studies have revealed that AQPs regulate not only water metabolism, but also some cellular functions such as cell growth and migration. Here, we report the role of AQP5 in inflammatory responses. In MLE-12 cells, knockdown of AQP5 using siRNA (10-50 nM) attenuated TNF-α-induced expression of keratinocyte chemoattractant (KC) mRNA and protein. Conversely, in NIH-3T3 cells, overexpression of AQP5 increased KC expression, NF-κB activation, and ERK phosphorylation. The AQP5-induced increase of KC expression was diminished by treatment with ERK inhibitors. Taken together, we propose a new function of AQP5 as an inflammatory signal potentiator, which may be mediated by increased activation of ERK and NF-κB.

The Na+/Ca2+ exchanger (NCX), an ion-transporter located in the plasma membrane of neuronal cells, contributes to intracellular Ca2+ homeostasis. Within the brain, three isoforms (NCX1, NCX2, and NCX3) are widely distributed. However, it is not clear to what extent these isoforms are involved in ischemic brain damage in mammals. We therefore used genetically altered mice and isoform-selective NCX inhibitors in a model of transient focal ischemia to investigate the role of each NCX isoform in ischemic brain damage. NCX isoform-mutant mice (NCX1+/−, NCX2+/−, and NCX3+/−) and wild-type mice were subjected to 90 min of middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. One of three NCX inhibitors [SN-6, KB-R7943, or SEA0400 (3 or 10 mg kg−1, i.p.)] was administered to ddY mice at 30 min before more prolonged (4-h) MCAO followed by 24 h of reperfusion. After transient MCAO reperfusion, the cerebral infarcts in NCX1+/− mice, but not those in NCX2+/− or NCX3+/− mice, were significantly smaller than those in wild-type mice. SN-6 and SEA0400, which are more selective for the NCX1 isoform, significantly reduced the infarct volume at 10 mg/kg. In contrast, KB-R7943, which is more selective for NCX3, did not. These results suggest that the NCX1 isoform may act preferentially (vs. the NCX2 and NCX3 isoforms) to exacerbate the cerebral damage caused by ischemic insult in mice, and that NCX1-selective inhibitors warrant investigation as a potential therapeutic agents for stroke.

MUC1 is a type I transmembrane glycoprotein aberrantly overexpressed in various cancer cells. High expression of MUC1 is closely associated with cancer progression and metastasis, leading to poor prognosis. We previously reported that MUC1 is internalized by the binding of the anti-MUC1 antibody, from the cell surface to the intracellular region via the macropinocytotic pathway. Since MUC1 is closely associated with ErbBs, such as EGF receptor (EGFR) in cancer cells, we examined the effect of the anti-MUC1 antibody on EGFR trafficking. Our results show that: (1) anti-MUC1 antibody GP1.4, but not another anti-MUC1 antibody C595, triggered the internalization of EGFR in pancreatic cancer cells; (2) internalization of EGFR by GP1.4 resulted in the inhibition of ERK phosphorylation by EGF stimulation, in a MUC1 dependent manner; (3) inhibition of ERK phosphorylation by GP1.4 resulted in the suppression of proliferation and migration of pancreatic cancer cells. We conclude that the internalization of EGFR by anti-MUC1 antibody GP1.4 inhibits the progression of cancer cells via the inhibition of EGFR signaling.

NOD-H2(h4) mice, which express I-A(k) on the NOD background, spontaneously develop autoimmune thyroiditis, a model of Hashimoto thyroiditis in humans, by adding iodide in the drinking water. Parental NOD mice have previously been shown to have intrinsic numerical abnormalities in peripheral lymphocytes and lymphocyte subpopulations such as CD4(+)CD25(+) naturally occurring regulatory T cells (Treg). Therefore we first investigated whether the similar abnormalities exist in NOD-H2(h4) mice. We observed that, compared with other non-autoimmune disease prone BALB/c and C57BL/6 mice, NOD-H2(h4) mice have lower numbers of splenocytes, CD3(+)T, CD4(+)T and CD8(+)T cells but the ratios of Treg to CD4(+)T cells were comparable. Increasing the numbers of peripheral lymphocytes by Complete Freund's Adjuvant immunization or splenocyte transfer did not affect development of thyroiditis, indicating that lymphopenia does not play a critical role in the pathogenesis of thyroiditis. We next examined the significance of Treg by depleting this lymphocyte subset with anti-CD25 antibody. Treg depletion, performed 4days before the administration of NaI water for 8 weeks, significantly exacerbated thyroiditis (p

Aquaporin-5 (AQP5) is a water-selective channel protein that is expressed in lacrimal glands, salivary glands, and distal lung. Several studies using AQP5 knockout mice have revealed that AQP5 plays an important role in maintaining water homeostasis in the lung. We report here that all-trans retinoic acid (atRA) increases plasma membrane water permeability, AQP5 mRNA and protein expression, and AQP5 promoter activity in MLE-12 cells. The promoter activation induced by atRA was diminished by mutation at the Sp1/Sp3 binding element (SBE), suggesting that the SBE mediates the effects of atRA. In addition, atRA increased the binding of Sp1 to the SBE without changing the levels of Sp1 in the nucleus. Taken together, our data indicate that atRA increases AQP5 expression through transactivation of Sp1, leading to an increase in plasma membrane water permeability.

Aquaporin-3 (AQP3), which is expressed in the basal layer of keratinocytes and airway epithelial cells, regulates not only water and glycerol permeability at plasma membrane, but also cell migration. We have previously shown that the expression of AQP3 is decreased by inflammatory cytokines, such as TNF-α and IL-1β. However, underlining mechanism for this decrease in AQP3 remains to be clear. In the present study, therefore, we examined the effect of IL-1β on AQP3 mRNA expression and promoter activity in A549 lung epithelial cells. IL-1β decreased both AQP3 protein and mRNA expression, in a concentration- (0.5-50 ng/ml) dependent manner. IL-1β also decreased promoter (−990/+88) activity, suggesting that IL-1β repressed AQP3 gene transcription. The IL-1β-induced decrease in AQP3 was relieved with PD98059, a MEK/ERK inhibitor. We then prepared a series of 5’-deletion constructs of AQP3 promoter. Among these, IL-1β did not decrease the activity of mutant promoters without −374/-272 region. The promoter, which has point mutation at CCAAT enhancer binding protein (C/EBP) binding element located at −276/-262, was also insensitive to IL-1β. Taken together, it was suggested that IL-1β decreases AQP3 expression via MEK/ERK- and C/EBP-dependent signaling.