MRIにおける葉状腫瘍と線維腺腫の鑑別

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Features of Phyllodes Tumours and Fibroadenomas Differ on MR Images

This retrospective study aimed to determine how the magnetic resonance imaging (MRI) and histopathological findings of phyllodes tumours (PT) and fibroadenomas (FA) correlate and verify whether they are useful for preoperative diagnosis. We retrospectively reviewed 12 PT and 43 FA that were surgically resected after MRI assessment between 2009 and 2015. The shape and signal intensity (SI) of the tumours on T2-weighted images (T2WI), the apparent diffusion coefficient, and SI were dynamically assessed. High SI areas suggestive of haemorrhage were significantly more frequent on pre-contrast T1WI of PT than that of FA (66.7% vs. 16.2%, p = 0.00034). The results of the SI analysis showed a higher intratumoural SI for PT than FA on T2WI (7.07 vs. 4.37, p = 0.0022). Overall enhancement was more intense among PT than FA, while SI was significantly higher at 100 seconds (2.03 vs. 1.60, p = 0.043) when enhanced effects on pre-enhanced tumours were quantified based on SI ratios. Not only can MRI morphologically differentiate PT from FA, it can also provide information about tissue composition and vascularization, the quantitation of which seems useful for differentiation

Wortmannin, an inhibitor of phosphatidylinositol kinases, blocks the MgATP-dependent recovery of Kir6.2/SUR2A channels

In order to investigate the mechanism underlying MgATP-dependent recovery of ATP-sensitive potassium (KATP) channels, we expressed Kir6.2/SUR2A (inwardly rectifying K+ channel subunit/sulfonylurea receptor) or C-terminal-truncated Kir6.2 (Kir6.2ΔC26) in COS7 cells (Green monkey kidney cells), and carried out inside-out patch clamp experiments.After patch excision in ATP-free internal solution, the activity of Kir6.2/SUR2A channels could be maximally recovered by the application of 5 mM MgATP. Subsequent application of 100 μM Ca2+ induced a rapid decay of Kir6.2/SUR2A activity to 11·6 ± 1·1 % (mean ± s.e.m.) of the control level (Ca2+-induced run-down; n = 64).MgATP (5 mM) recovered 99·4 ± 4·2 % (n = 13) of the Ca2+-induced run-down. Protein kinase inhibitors such as W-7, H-7, H-8 and genistein did not inhibit this reaction. However, wortmannin, an inhibitor of phosphatidylinositol 3- and 4-kinases, blocked the MgATP-dependent recovery in a concentration-dependent manner; the magnitudes of recovery were 35·7 ± 7·2 % (10 μM) and 4·3 ± 2·5 % (100 μM) of the Ca2+-induced run-down.MgUDP (10 mM) reversed the Ca2+-induced run-down of Kir6.2/SUR2A channels by 60·4 ± 7·6 % (n = 5). Wortmannin failed to modify this reaction.Kir6.2ΔC26 channels, which opened in the absence of SUR2A, were less sensitive to Ca2+; Kir6.2ΔC26 channels were inactivated to 44·8 ± 4·4 % (n = 14) by 100 μM Ca2+. MgATP recovered the Ca2+-induced run-down of Kir6.2ΔC26 by 89·8 ± 7·7 % (n = 9), and 100 μM wortmannin inhibited this reaction (1·8 ± 2 %, n = 7).Application of 10 μM phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) recovered the activity of Kir6.2/SUR2A channels after Ca2+-induced run-down (104·3 ± 6·4 %, n = 10). Even after the MgATP-dependent recovery was blocked by 100 μM wortmannin, PI-4,5-P2 reactivated the channels (102·3 ± 8·6 %, n = 5). Similar results were obtained with Kir6.2ΔC26.These results suggest that the entity of MgATP-dependent recovery may be membrane lipid phosphorylation rather than protein phosphorylation, and that synthesis of PI-4,5-P2 or phosphatidylinositol-3,4,5-trisphosphate may upregulate Kir6·2 channels

On the mechanism of ADP-induced alteration of sulphonylurea sensitivity in cardiac ATP-sensitive K(+) channels

1. To study the mechanism of regulation of sulphonylurea sensitivity in ATP-sensitive K(+) (K(ATP)) channels, we used the inside-out patch clamp technique in guinea-pig ventricular myocytes. 2. In the absence of nucleotides, the half maximal concentration of tolbutamide inhibition of K(ATP) channels (IC(50)) was 0.4 mM, and it decreased to 0.1 mM when 0.1 mM ATP was added. 3. Increasing the ADP concentration from 0 to 0.1 and 0.3 mM in the absence of ATP shifted the IC(50) from 0.4 to 5.3 and 11.4 mM, respectively. Increasing the ADP concentration further to 1 and 3 mM conversely reduced the IC(50) to 9.5 and 4.4 mM, respectively. 4. In the absence of Mg(2+) and ADP, the IC(50) was calculated to 16.6 mM which was found to be less, 12.3, 5.1 and 2.5 mM, respectively, when the ADP concentration was increased to 0.1, 0.3 and 1 mM. 5. The IC(50)s for tolbutamide obtained at various concentrations of ADP in the presence of Mg(2+) were best fitted by equations reflecting a model that assumed two binding sites for ADP; one is a high affinity site that reduces the sensitivity to the sulphonylurea, while the other is a low affinity site that increases such sensitivity. Dissociation constants calculated for ADP to sites 1 and 2 were 2.6 μM and 46.7 mM, respectively. In the absence of Mg(2+), data were fitted by equations corresponding to a single site model (site 2); the dissociation constant for ADP was 25.0 mM. 6. It is concluded that ADP modifies tolbutamide sensitivity by binding to two sites. The high affinity site is strongly Mg(2+)-dependent, whereas the low affinity site is Mg(2+)-independent

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Introduction Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methods We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.Results Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.Conclusions Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting