The Potential of Computed Tomography Volumetry for the Surgical Treatment in Bilateral Macronodular Adrenal Hyperplasia: A Case Report.

Although adrenal resection is a major option to control hypercortisolemia in patients with bilateral macronodular adrenal hyperplasia, a predictive method for postoperative cortisol production has not been established. A 53-year-old man with ulcerative colitis was referred to our hospital for bilateral multiple adrenal nodules and hypertension. Physical and endocrinological examination revealed inappropriate cortisol production and suppressed secretion of adrenocorticotropic hormone with no typical signs of Cushing's syndrome. Imaging analysis revealed bilateral adrenal nodular enlargement, the nodules of which had the radiological features of adrenocortical adenomas without inter-nodular heterogeneity. In addition, computed tomography volumetry demonstrated that the left adrenal gland (70 mL) accounts for three quarters of the total adrenal volume (93 mL). The patient was diagnosed as subclinical Cushing's syndrome due to bilateral macronodular adrenal hyperplasia, and subsequently underwent a left laparoscopic adrenalectomy with the estimation of 75% decrease in the cortisol level based on the adrenal volume. The surgical treatment ultimately resulted in control of the cortisol level within the normal range, which was compatible to our preoperative prediction. However, regardless of the sufficient cortisol level, ulcerative colitis was exacerbated after the surgery, which needed a systemic therapy for remission. This case indicates successful surgical control of hypercortisolemia based on computed tomography volumetry in bilateral macronodular adrenal hyperplasia, as well as the perioperative exacerbation risk for inflammatory diseases in Cushing's syndrome. We report the potential utility of computed tomography volumetry as a quantitative method with retrospective evaluation of our historical cases.

Entire FGF12 duplication by complex chromosomal rearrangements associated with West syndrome.

Complex rearrangements of chromosomes 3 and 9 were found in a patient presenting with severe epilepsy, developmental delay, dysmorphic facial features, and skeletal abnormalities. Molecular cytogenetic analysis revealed 46,XX.ish der(9)(3qter→3q28::9p21.1→9p22.3::9p22.3→9qter)(RP11-368G14+,RP11-299O8-,RP11-905L2++,RP11-775E6++). Her dysmorphic features are consistent with 3q29 microduplication syndrome and inv dup del(9p). Trio-based WES of the patient revealed no pathogenic single nucleotide variants causing epilepsy, but confirmed a 3q28q29 duplication involving FGF12, which encodes fibroblast growth factor 12. FGF12 positively regulates the activity of voltage-gated sodium channels. Recently, only one recurrent gain-of-function variant [NM_021032.4:c.341G>A:p.(Arg114His)] in FGF12 was found in a total of 10 patients with severe early-onset epilepsy. We propose that the patient's entire FGF12 duplication may be analogous to the gain-of-function variant in FGF12 in the epileptic phenotype of this patient.

Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients. METHODS: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters. RESULTS: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035). CONCLUSION: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.

Effects of changes in polycyclic aromatic hydrocarbons (PAHs) emissions and degradation on their concentrations in Tokyo from 2007 and 2016.

The concentrations of polycyclic aromatic hydrocarbons (PAHs) in aerosol were measured in Shinjuku, which is central Tokyo, Japan, for 10 years from 2007 to 2016. The effects of changes in emission sources and their degradation by reaction with ozone were assessed in this study. There was no significant increasing or decreasing trend of the PAH concentrations during 10 years (P > 0.05). The average selected seven the PAH concentrations (0.88 ng m-3) during 10 years was lower than those in New York and Paris. However, the trend of ozone concentrations is increasing in central Tokyo. This inconsistency raises a question. Did the fact that the ozone concentration was higher than the PAH concentrations promote PAH degradation? To apportion the PAH sources, we used PAH concentration profiles and positive matrix factorization analysis. The contribution of vehicle emissions to the PAHs ranged from 40 to 80%. Ozone concentrations increased by 3.70%/year during 10 years. The theoretical degradation rates of PAHs by ozone, which were calculated using a pseudo-first-order rate equation, suggested that the lifetimes of benzo[a]pyrene (BaP) decreased by 1 min from 2007 to 2016. We investigated the aging of BaP using the profile of the isomer ratios. We found that the aging of BaP at the urban and roadside sites were nearly identical indicating aging regardless of the season. Although the decomposition of BaP is promoted by the photochemical oxidation reaction, this result suggests that a certain threshold value exists as the degree of the decomposition. This degradation of PAH can improve chemical loss processes in air quality model.

Cellular Senescence in Human Aldosterone-Producing Adrenocortical Cells and Related Disorders.

In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on in situ senescence. We analyzed 30 surgical cases of aldosterone-producing adenoma (APA), 10 idiopathic hyperaldosteronism (IHA) and 19 normal adrenals (NA). CYP11B2 and senescence markers p16 and p21 were immunolocalized in all those cases above and results were correlated with histological/endocrinological findings. In the three cohorts examined, the zona glomerulosa (ZG) was significantly more senescent than other corticosteroid-producing cells. In addition, the ZG of adjacent non-pathological adrenal glands of APA and IHA had significantly higher p16 expression than adjacent non-pathological zona fasciculata (ZF), reticularis (ZR) and ZG of NA. In addition, laboratory findings of primary aldosteronism (PA) were significantly correlated with p21 status in KCNJ5-mutated tumors. Results of our present study firstly demonstrated that non-aldosterone-producing cells in the ZG were the most senescent compared to other cortical zones and aldosterone-producing cells in PA. Therefore, aldosterone production, whether physiological or pathological, could be maintained by suppression of cell senescence in human adrenal cortex.

Renal Injuries in Primary Aldosteronism: Quantitative Histopathological Analysis of 19 Patients With Primary Adosteronism.

[Figure: see text].

The crosstalk between aldosterone and calcium metabolism in primary aldosteronism: A possible calcium metabolism-associated aberrant "neoplastic" steroidogenesis in adrenals.

Intracellular calcium (Ca) levels play pivotal roles in aldosterone biosynthesis. Several somatic mutations of ion channels associated with aldosterone over-production were reported to result in over-inflow of Ca ion. Recently, the main regulators of extracellular Ca including VDR, CaSR and PTH1R were also reported to regulate steroidogenesis including aldosterone production. Therefore, not only intracellular but also extracellular Ca levels could regulate aldosterone biosynthesis. In addition, primary aldosteronism (PA) is clinically associated with not only more frequent cardiovascular events but also secondary metabolic disorders including abnormal calcium metabolism, osteoporosis and others. However, the details of Ca metabolic abnormalities associated with, including the potential correlation between those abnormalities and aldosterone overproduction, have remained virtually unknown. Therefore, in this study, we first immunolocalized Ca metabolism-related receptors (CaSR, VDR and PTH1R) in normal adrenal glands (NAs), aldosterone-producing adenomas (APAs) and cortisol-producing adenoma (CPA). We then compared the findings with clinicopathological parameters of these patients and the patterns of KCNJ5 somatic mutation of the tumors among APA patients. In vitro study was also performed to further explore the potential effects of extracellular Ca, PTH, Vitamin D and ionophore on aldosterone production. Ca metabolism-related receptors were predominantly localized in aldosterone-producing cells (ZG and APA) in both immunohistochemistry and qRT-PCR analysis. CYP11B2 mRNA was significantly increased by CaCl2 treatment and further by adding ionophore. All the key enzymes related to aldosterone and cortisol biosynthesis including CYP11B2, CYP17A1 and CYP11B1 were upregulated by PTH treatment in this model and PTH could serve as a co-stimulator of ANG II to increase CYP11B2 expression. VDR mRNA levels were positively correlated with those of CYP11B2, CYP17A1 and CYP11B1 in APA tumor tissues and significantly higher in KCNJ5 mutated APAs than wild type. CYP11B1 levels were also significantly increased by VitD treatment. PTH1R mRNA levels were positively correlated with those of CYP17A1 and CYP11B1, both involved in cortisol production. In addition, the status of VDR was correlated with TRACP-5b levels, and that of PTH1R with serum Ca levels as well as urinary Ca excretion, respectively. Results of our present study did firstly demonstrate that aldosterone-producing cells were more sensitive to the fluctuations of extracellular Ca levels and Ca metabolism could directly influence steroidogenesis, especially "neoplastic" co-secretion of aldosterone and cortisol in APA patients.

SPE-GC/FTD determination of N-methyl-2-pyrrolidone and its metabolites in urine.

An analytical method using a combination of solid-phase extraction (SPE) and gas chromatography with a flame thermionic detector (GC/FTD) was developed for determination of N-methyl-2-pyrrolidone (NMP), N-methylsuccinimide (MSI), and 2-hydroxy-N-methylsuccinimide (2-HMSI) in human urine. The SPE cartridge of poly(divinylbenzene/hydroxymethacrylate) used was directly loaded with urine sample, followed by elution with methyl isobutyl ketone (MIBK) and subsequent centrifugation, and the supernatant was injected into the capillary GC using a DB1701. This method allowed efficient separation of NMP, MSI, and 2-HMSI, which were nearly free of interference by other GC peaks arising from urine. Recoveries of NMP, MSI, and 2-HMSI from the SPE cartridge were about 98, 101, and 67%, respectively, with limits of detection of 0.04, 0.02, and 0.06 mg/L, respectively, which met the regulatory requirements. The present method was used for assay in biological monitoring of workers exposed to NMP in their occupational environment.

Intraocular pressure lowering effect of brinzolamide 1.0% as adjunctive therapy to latanoprost 0.005% in patients with open angle glaucoma or ocular hypertension: an uncontrolled, open-label study.

PURPOSE: A prospective study was conducted to evaluate the intraocular pressure (IOP) lowering effect of brinzolamide 1.0% ophthalmic suspension as an adjunctive therapy with latanoprost 0.005% ophthalmic solution in patients with open angle glaucoma or ocular hypertension. PATIENTS AND METHODS: Fourteen patients with open angle glaucoma (OAG) or ocular hypertension (OH) who had been using latanoprost 0.005% for more than 6 months were initiated on adjunctive brinzolamide therapy. The IOP values at 1 month, 2 months, and 3 months were compared with those measured immediately before adding brinzolamide to the regimen (baseline). The incidence of adverse events such as conjunctival hyperemia and corneal epithelial defect were also examined. RESULTS: The baseline IOP was 21.1 +/- 4.8 mmHg (mean +/- standard deviation). After 1 month, 2 months, and 3 months of therapy IOP was 16.9 +/- 4.5 mmHg, 16.6 +/- 4.0 mmHg, and 15.9 +/- 3.1 mmHg, respectively, showing significant reductions in IOP at all the measuring time-points during the study compared with the baseline value (p < 0.01). Conjunctival hyperemia developed in one patient after 1 month and in another after 2 months; however, both were mild, and therapy was continued. Corneal epithelium defect was observed in 3 patients. One of them had mild defect before brinzolamide was added to the regimen. Increase of eye discharge was seen in one patient. No serious side effects were otherwise observed. CONCLUSION: The addition of brinzolamide to a latanoprost 0.005% regimen may further lower intraocular pressure in patients with open angle glaucoma or ocular hypertension.