HbA1c levels Measured by Enzymatic Assay and Immunoassay during Off-Site Health Checkups Are Both Lower than Those Measured by On-Site HPLC Assay.

It has already been reported that HbA1c levels measured by immunoassay (IA) (IA-HbA1c) during off-site health checkups present falsely lower results. We also reported that HbA1c levels measured by enzymatic assay (EA) (EA-HbA1c) during off-site health checkups are lower. In the present study, we compared IA-HbA1c levels or EA-HbA1c levels during off-site health checkups with on-site high-performance liquid chromatography (HPLC)-HbA1c levels using the same samples. Subjects were 88 non-diabetic individuals who had health checkups in Nishinomiya Municipal Central Hospital. Subjects with a history of diabetes mellitus and those with HPLC-HbA1c ≥ 6.5% were excluded. IA-HbA1c levels (Study 1) or EA-HbA1c levels (Study 2) in the health checkups were compared with on-site HPLC-HbA1c levels using the same samples. Both IA-HbA1c levels and EA-HbA1c levels had positive correlations with HPLC-HbA1c levels (p <0.0001 for both), although both were significantly lower than HPLC-HbA1c levels (p <0.0001 for both). The degrees of reductions in the IA-HbA1c levels and EA-HbA1c levels compared with HPLC-HbA1c levels were almost same to each other. Similarly to IA-HbA1c levels, EA-HbA1c levels during the health checkups were lower than HPLC-HbA1c levels. It was demonstrated that HbA1c levels decrease similarly if measured by either EA or IA during off-site health checkups.

Aesthetic utility of addition of nipple-areola recentralization to rotation flap according to nipple tumor distance for patients with lower-outer or upper-inner located breast cancers.

We aimed to validate the cosmetic utility of addition of nipple-areola recentralization (NAR) to rotation flap according to nipple tumor distance (NTD) as a volume displacement technique after breast conserving surgery (BCS) for lower-outer and upper-inner breast cancers. Twenty breast cancer patients who had been treated with rotation flap with (Group 1; n = 6) or without (Group 2; n = 14) NAR after BCS for lower-outer or upper-inner located tumors, and those who had undergone BCS without oncoplastic surgical technique for tumors in the same area (Control group; n = 43), were retrospectively investigated. Cosmetic outcome was evaluated using Harvard scale and/or BCCT.core. As a result, the ratio of patients categorized as excellent/good was 83% in Group 1 and 93% in Group 2, respectively, and there was no significant difference between them (P = 0.521). In addition, Group 1 + 2 showed a significantly higher ratio of patients classified as excellent/good than the control group (90% vs. 56%; P = 0.009). After adjustment of clinical background parameters using propensity score matching analysis between Group 1 + 2 and the control group, 12 pairs with similar background factors were matched. Among them, Group 1 + 2 showed a higher ratio of patients categorized as excellent/good than the control group (92% vs. 42%; P = 0.034). In conclusion, addition of NAR to rotation technique according to NTD may enable us to perform a volume displacement after BCS for lower-outer or upper-inner located tumors irrespective of NTD without sacrificing postoperative breast appearance.

Thermodynamically stable structure of hydroxy alkane sulfonate surfactant monomers in water achieving high water solubility and a low CMC.

Although sodium internal olefin sulfonates (IOSs) derived from petrochemicals are known to act as anionic surfactants, these compounds have few practical applications and their interfacial properties have not been examined in detail because they have complex compositions and are challenging to prepare. However, IOSs obtained from vegetable oils have recently been applied to detergents. The present work represents the first study of the IOS sodium 5-hydroxyhexadecane-4-sulfonate (C16-4S-5OH) as a pure substance. The properties of C16-4S-5OH in aqueous solution were assessed by differential scanning calorimetry, equilibrium surface tension measurements, Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. This compound was found to have a low Krafft point and a low CMC, both of which are necessary for a modern sustainable surfactant. Although these two characteristics are normally difficult to achieve simultaneously, this work demonstrated that C16-4S-5OH in aqueous solution has a highly fixed stereostructure that enables both properties to be achieved. The C16 main carbon chain of this compound acts as a C12 and a C4 chain both oriented in the same direction, while the hydrophilic sulfo and hydroxy head groups form a rigid cyclic moiety including two carbons of the C16 alkyl chain based on hydrogen bonding. This highly fixed molecular structure of the C16-4S-5OH in water is maintained in the monomer and micellar states below and above the CMC, respectively.

Synthesis and evaluation of the inhibitory activity of the four stereoisomers of the potent and selective human γ-glutamyl transpeptidase inhibitor GGsTop.

2-Amino-4-{[3-(carboxymethyl)phenoxy](methoxy)phosphoryl}butanoic acid (GGsTop) is a potent, highly selective, nontoxic, and irreversible inhibitor of γ-glutamyl transpeptidase (GGT). GGsTop has been widely used in academic and medicinal research, and also as an active ingredient (Nahlsgen) in commercial anti-aging cosmetics. GGsTop consists of four stereoisomers due to the presence of two stereogenic centers, i.e., the α-carbon atom of the glutamate mimic (l/d) and the phosphorus atom (RP/SP). In this study, each stereoisomer of GGsTop was synthesized stereoselectively and their inhibitory activity against human GGT was evaluated. The l- and d-configurations of each stereoisomer were determined by a combination of a chiral pool synthesis and chiral HPLC analysis. The synthesis of the four stereoisomers of GGsTop used chiral synthetic precursors that were separated by chiral HPLC on a preparative scale. With respect to the configuration of the α-carbon atom of the glutamate mimic, the l-isomer (kon=174M-1s-1) was ca. 8-fold more potent than the d-isomer (kon=21.5M-1s-1). In contrast, the configuration of the phosphorus atom is critical for GGT inhibitory activity. Based on a molecular modeling approach, the absolute configuration of the phosphorus atom of the active GGsTop isomers was postulated to be SP. The SP-isomers inhibited human GGT (kon=21.5-174M-1s-1), while the RP-isomers were inactive even at concentrations of 0.1mM.

Phosphonate-based irreversible inhibitors of human γ-glutamyl transpeptidase (GGT). GGsTop is a non-toxic and highly selective inhibitor with critical electrostatic interaction with an active-site residue Lys562 for enhanced inhibitory activity.

γ-Glutamyl transpeptidase (GGT, EC 2.3.2.2) that catalyzes the hydrolysis and transpeptidation of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive pharmaceutical target. We report here the evaluation of a phosphonate-based irreversible inhibitor, 2-amino-4-{[3-(carboxymethyl)phenoxy](methoyl)phosphoryl}butanoic acid (GGsTop) and its analogues as a mechanism-based inhibitor of human GGT. GGsTop is a stable compound, but inactivated the human enzyme significantly faster than the other phosphonates, and importantly did not inhibit a glutamine amidotransferase. The structure-activity relationships, X-ray crystallography with Escherichia coli GGT, sequence alignment and site-directed mutagenesis of human GGT revealed a critical electrostatic interaction between the terminal carboxylate of GGsTop and the active-site residue Lys562 of human GGT for potent inhibition. GGsTop showed no cytotoxicity toward human fibroblasts and hepatic stellate cells up to 1mM. GGsTop serves as a non-toxic, selective and highly potent irreversible GGT inhibitor that could be used for various in vivo as well as in vitro biochemical studies.

Incompatibility between fasting and postprandial plasma glucose in patients with Cushing's syndrome.

It is shown that glucocorticoids have discordant effects on plasma glucose concentration through their effects on hepatic glycogen deposition, gluconeogenesis and peripheral insulin resistance. Cushing's syndrome caused by cortisol overproduction is frequently accompanied with diabetes mellitus, but fasting plasma glucose (FPG) and post-glucose load plasma glucose levels are not examined in patients with Cushing's syndrome. The aim of this study was to investigate FPG, HbA1c and oral glucose tolerance test (OGTT) 2-h PG and their relationship in patients with Cushing's syndrome, in comparison with control subjects. Sixteen patients with Cushing's syndrome (ACTH-dependent 31%, ACTH-independent 69% and diabetes mellitus 50%) and 64 controls (32 patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI) were enrolled in this study. HbA1c and FPG in the patients with Cushing's syndrome were not different from the controls, whereas the FPG/HbA1c ratio was significantly lower in the patients with Cushing's syndrome than the controls. OGTT 2-h PG was significantly higher in the non-diabetic patients with Cushing's syndrome than the non-diabetic controls, while HbA1c was not different between both groups and FPG was significantly lower in the patients with Cushing's syndrome than the controls. HOMA-ß but not HOMA-R was significantly higher in the patients with Cushing's syndrome than the controls. In conclusion, FPG was rather lower in the patients with Cushing's syndrome than the controls. Postprandial PG or post-glucose loaded PG, but not FPG, is useful to evaluate the abnormality of glucose metabolism in patients with Cushing's syndrome.

Protective effect of naturally occurring anti-HER2 autoantibodies on breast cancer.

Anti-HER2-autoantibodies (HER2-AAbs) are found in breast cancer patients as well as healthy individuals. However, the clinical relevance of the antibodies is unknown. We established an enzyme-linked immunosorbent assay with high sensitivity and quantified serum HER2-AAbs in 100 healthy women, 100 untreated patients with ductal carcinoma in situ (DCIS), and 500 untreated patients with invasive breast carcinoma (IBC). The associations between the levels of HER2-AAbs and breast cancer risk, and recurrence-free survival, were examined. High levels of HER2-AAbs were significantly associated with a reduced risk of DCIS (odds ratio [OR] 0.19, P = 4.6 × 10(-7)) or IBC (OR 0.31, P = 3.7 × 10(-7)). Subgroup analysis of IBC revealed a stronger association of HER2-AAbs with a reduced risk of the hormone receptor (HR)(-)/HER2(+) subtype (OR 0.12) than the other subtypes (HR(+)/HER2(-) [OR = 0.32], HR(+)/HER2(+) [OR 0.38], and HR(-)/HER2(-) [OR 0.29]). When we set the cutoff of HER2-AAbs at 20 ng/mL, recurrence-free survival of HER2-AAb-positive patients (N = 74) was significantly better than that of HER2-AAb-negative patients (N = 426) (P = 0.015). Univariate and multivariate analyses demonstrated that HER2-AAbs, as well as histological grade, were independently and significantly (P = 0.0065 and 0.049, respectively) associated with recurrence-free survival. Our exploratory study suggests a protective effect of naturally occurring HER2-AAbs on the development of primary and recurrent breast cancer. Further studies on HER2-AAbs are warranted.

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing's disease and subclinical Cushing's disease.

Cushing's disease (CD) and subclinical Cushing's disease (subCD) are both diseases caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. However, ACTH autonomy in subCD is weaker than in CD and there are no Cushingoid features in subCD. The differences of molecular mechanisms in ACTH autonomy between CD and subCD have not yet been reported. Therefore, we aimed to investigate the differences in molecular mechanisms of ACTH-secretion autonomy between CD and subCD. The study included 23 patients [7 CD, 6 subCD, and 10 non-functioning pituitary tumors (NFTs)] who underwent transsphenoidal surgery at the Osaka University Hospital between December 2009 and October 2013. Using quantitative real-time PCR, various ACTH-related gene expressions in tumor tissues from CD, subCD, and NFT were measured such as pro-opiomelanocortin (POMC), POMC transcription factor (Tpit, Pitx1, NeuroD1, and Nur77), POMC peptide processing enzymes (prohormone convertase: PC1/3 and PC2), and ACTH secretion-related factors (corticotropin-releasing hormone receptor 1: CRHR1 and glucocorticoid receptor α: GRα). Only Nur77 mRNA levels were significantly higher in CD than in subCD. Furthermore, we stained 6 CD and 6 subCD with anti-Nur77 antibody. All tumor samples from CD had Nur77 protein positive cells. On the other hand, Nur77 protein was expressed in only one tumor sample from subCD. This sample showed high expression of Nur77 mRNA. Nur77 is an important to regulate POMC transcription and negative-feedback by glucocorticoids. Nur77 gene expression levels might involve different autonomy of ACTH production between CD and subCD.

Clinical and endocrinological characteristics of adrenal incidentaloma in Osaka region, Japan.

The aim of this study was to investigate the clinical and endocrinological characteristics of adrenal incidentalomas in Osaka region, Japan. The study was a multicenter retrospective analysis of 150 patients with adrenal incidentalomas who underwent radiographic and endocrine evaluations between 2005 and 2013. Most adrenal incidentalomas were discovered by computed tomography (77.0%) and the rest were identified by abdominal ultrasonography (14.6%), magnetic resonance imaging (4.2%), or positron emission tomography (4.2%). Adrenal incidentalomas were more frequently localized on the left side than on the right. The average diameter of tumors was 21 ± 11 mm. On endocrinological evaluation, 14 patients were diagnosed with primary aldosteronism (9.3%), 10 with subclinical Cushing's syndrome (6.7%), 7 with pheochromocytoma (4.7%), 7 with Cushing's syndrome (4.7%), 2 with both subclinical Cushing's syndrome and primary aldosteronism (1.3%), and 110 with non-functioning tumors (73.3%). Patients with functioning tumors were significantly younger and had larger tumor diameters than those with non-functioning tumors. Except for hypertension, complications were comparable between patients with functioning and non-functioning tumors, including the presence of glucose intolerance, cardiovascular disease, and dyslipidemia. In conclusion, a higher prevalence of primary aldosteronism was observed compared with a previous report. Complications were comparable between patients with functioning and non-functioning tumors, including the frequencies of glucose intolerance, cardiovascular disease, and dyslipidemia. Long-term follow-up is required in patients with non-functioning tumors because the frequency of complications, such as glucose intolerance, cardiovascular disease, and dyslipidemia, was equal to that in patients with functioning tumors.

Serum albumin-adjusted glycated albumin is an adequate indicator of glycemic control in patients with Cushing's syndrome.

OBJECTIVES: We recently reported that glycated albumin (GA) in patients with Cushing's syndrome is low. In the present study, we examined whether serum albumin (SA)-adjusted GA (SAaGA) is an adequate indicator of glycemic control in patients with Cushing's syndrome. DESIGN AND METHODS: We studied 26 patients with Cushing's syndrome (13 patients without diabetes and 13 patients with diabetes). Twenty six non-diabetic subjects and 26 patients with type 2 diabetes mellitus matched for age, sex and BMI were used as the controls. SAaGA was calculated using the regression formula between SA and GA in non-diabetic patients with Cushing's syndrome and non-diabetic subjects. RESULTS: SA showed a significant correlation with GA in non-diabetic patients with Cushing's syndrome and non-diabetic subjects. GA, but not SAaGA, in non-diabetic patients with Cushing's syndrome was significantly lower than that in the non-diabetic controls. Furthermore, the GA/HbA1c ratio, but not the SAaGA/HbA1c ratio, in diabetic patients with Cushing's syndrome was significantly lower than that in the diabetic controls. The measured GA in the patients with Cushing's syndrome was significantly lower than the estimated GA, but there was no difference between SAaGA and the estimated GA. CONCLUSIONS: The present findings suggest that SAaGA is an adequate indicator of the glycemic control in patients with Cushing's syndrome.

Rapid decline in bone turnover markers but not bone mineral density in acromegalic patients after transsphenoidal surgery.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) play important roles in maintaining bone metabolism and bone mineral density (BMD) in adulthood, in addition to stimulating longitudinal bone growth in childhood. However, information on the effect of GH excess on bone metabolism and BMD is incomplete and requires further analysis. The aim of this study is to clarify the effect of rapid decline in GH levels after transsphenoidal surgery (TSS) on bone metabolism in acromegalic patients. In this prospective study, 22 patients (11 males and 11 females) with active acromegaly underwent TSS. Bone formation marker (serum bone alkaline phosphatase: BAP), bone resorption marker (urinary type I collagen cross-linked N-telopeptide: urinary NTx) and BMD were measured before and at 3 and 12 months after TSS. BAP was significantly decreased at 12 months after TSS, but not at 3 months. Urinary NTx was significantly decreased at 3 and 12 months after TSS. BMD did not change after TSS. In conclusion, the rapid fall in GH level after TSS had no effect on BMD for up to 12 months after TSS despite the decrease in markers of bone formation and resorption.

Glycated albumin is set lower in relation to plasma glucose levels in patients with Cushing's syndrome.

BACKGROUND: Glycated albumin (GA) is an indicator of glycemic control, which has some specific characters in comparison with HbA1c. Since glucocorticoids (GC) promote protein catabolism including serum albumin, GC excess state would influence GA levels. We therefore investigated GA levels in patients with Cushing's syndrome. METHODS: We studied 16 patients with Cushing's syndrome (8 patients had diabetes mellitus and the remaining 8 patients were non-diabetic). Thirty-two patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI were used as controls. RESULTS: In the patients with Cushing's syndrome, GA was significantly correlated with HbA1c, but the regression line shifted downwards as compared with the controls. The GA/HbA1c ratio in the patients with Cushing's syndrome was also significantly lower than the controls. HbA1c in the non-diabetic patients with Cushing's syndrome was not different from the non-diabetic controls, whereas GA was significantly lower. In 7 patients with Cushing's syndrome who performed self-monitoring of blood glucose, the measured HbA1c was matched with HbA1c estimated from mean blood glucose, whereas the measured GA was significantly lower than the estimated GA. CONCLUSIONS: We clarified that GA is set lower in relation to plasma glucose levels in patients with Cushing's syndrome.

Basal insulin requirements after progesterone treatment in a type 1 diabetic pregnant woman.

We herein report the case of a 37-year-old type 1 diabetic pregnant woman treated with an insulin pump. Although the patient's glycemic control deteriorated following progesterone treatment for the prevention of preterm delivery and miscarriage, it was improved by adjusting the basal insulin rate on the days of progesterone treatment. Excess progesterone is known to impair both insulin sensitivity and secretion. The present case is the first report to evaluate deterioration of glycemic control induced by progesterone treatment and to determine the dose of insulin required in a type 1 diabetic pregnant woman whose insulin secretion was completely depleted.

Large adrenal ganglioneuroma.

We herein report the case of a 41-year-old male patient with an incidentally identified large adrenal ganglioneuroma (GN). His endocrine examinations were normal except for one episode of elevated urinary dopamine and noradrenaline levels. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) showed a large solid tumor with calcifications and a slightly lobular edge in the right adrenal gland. We performed open tumor excision and diagnosed it as adrenal ganglioneuroma. Adrenal GN is a rare benign tumor, and its hormonal activity and imaging characteristics are occasionally very similar to those of other adrenal tumors. Therefore, it needs careful evaluation by endocrine examinations and multiple imaging procedures to rule out other types of tumors.

A case of hypogonadotropic hypogonadism caused by opioid treatment for nonmalignant chronic pain.

We report a case of 42-year-old male patient with hypogonadotropic hypogonadism. He suffered from general fatigue and erectile dysfunction after the treatment with transdermal fentanyl for chronic pain by traffic injury. Endocrine examinations and hormone stimulating tests showed that he had hypogonadotropic hypogonadism. Brain magnetic resonance imaging (MRI) showed no abnormal findings, and he had no past history of accounting for acquired hypogonadotropic hypogonadism. Therefore, his hypogonadism was diagnosed to be caused by opioid treatment. Although opioid-induced endocrine dysfunctions are not widely recognized, this case suggests that we should consider the possibility of endocrine dysfunctions in patients with opioid treatment.