Effects of Olopatadine Hydrochloride, a Histamine H1 Receptor Antagonist, on Histamine-Induced Skin Responses

Effects of olopatadine hydrochloride, a histamine H1 receptor antagonist, on histamine-induced skin responses were evaluated in 10 healthy subjects in comparison with placebo, fexofenadine hydrochloride, and bepotastine besilate. Olopatadine significantly suppressed histamine-induced wheal, flare, and itch, starting 30 minutes after oral administration. Olopatadine was more effective than fexofenadine and bepotastine. None of the drugs studied impaired performance of word processing tasks. These results suggest that olopatadine can suppress skin symptoms caused by histamine soon after administration

Cancer Immunol Immunother

Purpose Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. Materials and Methods Nine patients having HLA-A*0201 or HLA-A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study. The patients received subcutaneous administration of the peptide as an emulsion form with Montanide ISA-51 VG once a week in a dose-escalation manner (doses of 0.5, 1.0, or 3.0 mg/body, 3 patients for each dose). The primary endpoint was safety, and the secondary endpoints were immunological and clinical responses. Results Vaccinations with HIG2-9-4 peptide could be well tolerated without any serious systemic adverse events. Peptide-specific cytotoxic T lymphocyte (CTL) responses were detected in eight of the nine patients. Doses of 1.0 or 3.0 mg/body seemed to induce a CTL response better than did a dose of 0.5 mg/body, although the number of patients was too small to draw a firm conclusion. The disease control rate (stable disease for ≥4 months) was 77.8 %, and the median progression-free survival time was 10.3 months. Conclusions HIG2-9-4 peptide vaccine treatment was tolerable and effectively induced peptide-specific CTLs in RCC patients. This novel peptide vaccine therapy for RCC is promising

Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism

The mineralocorticoid receptor (MR) is expressed in the kidneys and in adipose tissue, and primary aldosteronism (PA) is associated with metabolic syndrome. This study assessed the effects of MR blockade by eplerenone (EPL) and spironolactone (SPL) on blood pressure (BP) and metabolic factors in patients with PA. Fifty-four patients with PA were treated with one of two MRAs, EPL (25-100 mg daily, n=27) or SPL (12.5-100 mg daily, n=27) for 12 months. Visceral (VAT) and subcutaneous adipose tissue were quantified using CT and FatScan imaging analysis software. Body mass index, homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured before and after treatment. EPL and SPL decreased BP and increased serum potassium levels to similar degrees. PAC and PRA did not differ between the two groups. Although treatment with the MRAs did not change HOMA-IR or serum lipids, they significantly decreased UAE and VAT (P<0.05). These results suggest that EPL and SPL are effective and safe for the treatment of PA. The long-term metabolic and renal effects of these MRAs should be further investigated. © 2016 The Japanese Society of Hypertension. All rights reserved.Embargo Period 6 month

Overexpression of c-Met/hepatocyte growth factor receptors in human prostatic adenocarcinoma.

Hepatocyte growth factor (HGF) and c-met proto-oncogene product (c-Met) have varied biological functions in different tissues and have been implicated in mitogenic, motogenic and morphogenic responses in both organ regeneration and carcinogenesis. Some studies have suggested that the overexpression of c-Met and epidermal growth factor receptor (EGFR) are associated with growth advantage, while transforming growth factor-beta receptor II (TGF beta R II) is associated with growth disadvantage of human prostatic adenocarcinoma. However, it is unclear if the expression of c-Met correlates with the expression of EGFR and TGF beta R II, and with the proliferative status of human prostatic adenocarcinoma. Using immunohistochemical staining with anti-c-Met (C-12), anti-EGFR (NCL-EGFR) and anti-TGF beta R II (L-21) antibodies, we determined the frequency of expression of c-MET, EGFR, and TGF beta R II respectively in a series of 134 radical prostatectomy specimens. We evaluated the relationship between the expression of these receptors and clinicopathological characteristics. Overall, c-Met immunostaining was detected in 54 of 134 (40.3%) cases, EGFR in 45 (33.6%) and TGF beta R II in 64 (48.4%). The overexpression of c-Met was significantly more common in poorly differentiated (P &#60; 0.0001) and in the diffusely infiltrated specimens (P &#60; 0.0005). In contrast, TGF beta R II was significantly overexpressed in the well differentiated specimens (P &#60; 0.0001) and associated negatively with c-Met (P &#60; 0.0001). Overall, these data suggest that c-Met/HGF receptor and TGF beta R II overexpression may be involved in the differentiation of human prostatic adenocarcinoma, c-Met with de-differentiation and TGF beta R II with differentiation.</p

A possible new syndrome with double endocrine tumors in association with an unprecedented type of familial heart-hand syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>The combination of a pituitary prolactinoma and an aldosterone-producing adrenal adenoma is extremely rare. To the best of our knowledge, double endocrine tumors in association with heart-hand syndrome have not previously been reported.</p> <p>Case presentation</p> <p>A 21-year-old Japanese woman presented with galactorrhea and decreased visual acuity. A large pituitary adenoma with an increased level of serum prolactin was apparent by computed tomography. She additionally showed mild hypertension (136/90 mmHg) accompanied by hypokalemia. The plasma aldosterone concentration was increased. Computed tomography showed a mass in the right adrenal gland. No other tumors were found despite extensive imaging studies. Physical and radiographic examinations showed skeletal malformations of the hands and feet, including hypoplasia of the first digit in all four limbs. An atrial septal defect was demonstrated by echocardiography. Similar digital and cardiac abnormalities were detected in our patient's father, and a clinical diagnosis of hereditary heart-hand syndrome was made.</p> <p>Conclusion</p> <p>No established heart-hand syndrome was wholly compatible with the family's phenotype. Her father had no obvious endocrine tumors, implying that the parent of transmission determined variable phenotypic expression of the disease: heart-hand syndrome with multiple endocrine tumors from the paternal transmission or no endocrine tumor from the maternal transmission. This suggests that the gene or genes responsible for the disease may be under tissue-specific imprinting control.</p

Associations between Sleep-Disordered Breathing and Metabolic Risk Factors beyond Obesity

金沢大学附属病院代謝内科Objective. Individuals with multiple metabolic risk factors often experience concomitant sleep-disordered breathing (SDB). We aimed to determine the associations of SDB with individual components of metabolic syndrome independent of obesity. Methods. A cross-sectional study was conducted in 1137 employees aged 30–64 years. Apnea-hypopnea index (AHI) was assessed using a portable monitor for obstructive sleep apnea by admission. Of these, 451 participants took an oral glucose tolerance test to assess homeostatic model assessment of insulin resistance (HOMA-IR) and Matsuda insulin sensitivity index (ISI). Results. The odds ratio (OR) of the highest category of the AHI (≥15 episodes per hour) compared to the lowest one (<5 episodes per hour) was significantly elevated for hypertension, for hypertriglyceridemia, and for low HDL-cholesterolemia when adjusted for age, sex, and alcohol and smoking status (). After further adjustment for body mass index (BMI) or waist circumference, the associations for hypertension still remained statistically significant () while those for hypertriglyceridemia and low HDL-cholesterolemia were no longer significant. The association between higher insulin resistance as assessed by HOMA-IR and Matsuda ISI and higher categories of the AHI was also lost after adjustment for BMI. Conclusion. Obesity was a strong confounding factor in the association between SDB and most metabolic risk factors including insulin resistance, except for hypertension. Further longitudinal study is needed to examine the temporal or causal relationships between SDB and metabolic risk factors. This trial is registered with UMIN-CTR UMIN000028067

Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues

金沢大学医薬保健研究域医学系Objective: Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. Methods: We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5′-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). Results: In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5′-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. Conclusion: NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia

金沢大学医薬保健研究域医学系Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter. © 2017 The Author(s)

Insulin Secretion and Risk for Future Diabetes in Subjects with a Nonpositive Insulinogenic Index

金沢大学附属病院代謝内科Aim. To characterize subjects with a nonpositive insulinogenic index and longitudinally observe changes in their glucose tolerance. Subjects and Methods. A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT) and the incidences of diabetes and impaired glucose tolerance (IGT) were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT). Results. Of the 1464 nondiabetic subjects at baseline, 72 (4.9%) subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (ΔGlu0–30 ≤ 0) and 30 had a nonpositive insulin response (ΔIns0–30 ≤ 0). Compared with subjects who had normal glucose tolerance (NGT) with insulinogenic index ≥ 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test (), whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes (). Conclusions. These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (ΔGlu0–30 ≤ 0) had a lower risk for future diabetes and that subjects with nonpositive insulin response (ΔIns0–30 ≤ 0) had a higher risk for future one