Author Correction: Gate Tuning of Synaptic Functions Based on Oxygen Vacancy Distribution Control in Four-Terminal TiO2-x Memristive Devices.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Gate Tuning of Synaptic Functions Based on Oxygen Vacancy Distribution Control in Four-Terminal TiO2-x Memristive Devices.

Recent developments in artificial intelligence technology has facilitated advances in neuromorphic computing. Electrical elements mimicking the role of synapses are crucial building blocks for neuromorphic computers. Although various types of two-terminal memristive devices have emerged in the mainstream of synaptic devices, a hetero-synaptic artificial synapse, i.e., one with modulatable plasticity induced by multiple connections of synapses, is intriguing. Here, a synaptic device with tunable synapse plasticity is presented that is based on a simple four-terminal rutile TiO2-x single-crystal memristor. In this device, the oxygen vacancy distribution in TiO2-x and the associated bulk carrier conduction can be used to control the resistance of the device. There are two diagonally arranged pairs of electrodes with distinct functions: one for the read/write operation, the other for the gating operation. This arrangement enables precise control of the oxygen vacancy distribution. Microscopic analysis of the Ti valence states in the device reveals the origin of resistance switching phenomena to be an electrically driven redistribution of oxygen vacancies with no changes in crystal structure. Tuning protocols for the write and the gate voltage applications enable high precision control of resistance, or synaptic plasticity, paving the way for the manipulation of learning efficiency through neuromorphic devices.

Demonstrative operation of four-terminal memristive devices fabricated on reduced TiO2 single crystals.

Resistive switching (RS) was demonstrated in four-terminal planar memristive devices fabricated on reduced TiO2 (TiO2-x) single crystal substrates. In the device, a pair of diagonally opposing electrode terminals is used to modify the distribution of oxygen vacancies in the region between another pair of diagonally opposing electrode terminals. This allowed microscopic visual observations of the oxygen vacancy distribution based on electrocoloring. The visual contrast observed in the TiO2-x reflects the oxygen vacancy concentration in the electrically active zone of the device, which can be modified by application of various external voltages to the electrodes. The current that flows in the device is significantly dependent on the modified oxygen vacancy distribution and the resultant resistance is switchable when the polarization of the applied external voltage is reversed. The crystallographic orientation of the TiO2-x substrate has a strong influence on the reversible RS phenomenon. Mechanisms behind the voltage-driven resistance change are elaborated with the aid of microscopic analysis for both crystalline and electronic structures in the electrically active zone of the device. Suppression of the formation of irreversible conductive structures comprised of accumulated oxygen vacancies is a key to establishing reversible RS in the device.

Effects of co-administration of candesartan with pioglitazone on inflammatory parameters in hypertensive patients with type 2 diabetes mellitus: a preliminary report.

BACKGROUND: Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects. METHODS: We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors. RESULTS: After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c. CONCLUSIONS: Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co-administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus. TRIAL REGISTRATION: UMIN-CTR: UMIN000010142.

Successful control of a case of severe insulin allergy with liraglutide.

A 72-year-old woman presented with repeated hypoglycemic and hyperglycemic episodes because of an insulin allergy. On admission, she was diagnosed with type B insulin resistance syndrome. She was also found to have anti-insulin antibodies. After steroid therapy, glycemic control improved dramatically accompanied by the disappearance of the insulin allergy. We then introduced liraglutide, which successfully stabilized her glycemic episodes without allergic reactions. Liraglutide might be useful to treat patients with severe insulin allergy.

Suppression of aldosterone synthesis and secretion by ca(2+) channel antagonists.

Aldosterone, a specific mineralocorticoid receptor (MR) agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II type 1 receptor antagonists (ARBs). However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called "aldosterone breakthrough" effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS) inhibitors) gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca(2+) channel blockers (CCBs) have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.

Effects of candesartan in hypertensive patients with type 2 diabetes mellitus on inflammatory parameters and their relationship to pulse pressure.

BACKGROUND: Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress in patients without arteriosclerosis. This study aimed to evaluate (1) whether an ARB (candesartan) decreases values for inflammatory parameters in hypertensive patients with type 2 diabetes mellitus of long duration accompanied by arteriosclerosis and (2) whether there any predictors of which patients would receive the benefits of organ protection by candesartan. METHODS: We administered candesartan therapy (12 mg daily) for 6 months and evaluated whether there was improvement in serum inflammatory parameters high molecular weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1) in serum and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of lowering of blood pressure and inflammatory factors and the relationship between pulse pressure and inflammatory factors. Finally, we analyzed predictive factors in patients who received the protective benefit of candesartan. RESULTS: After 6 months of treatment, significant improvements from baseline values were observed in all patients in HMW-ADN and PAI-1 but not in Hs-CRP, VCAM-1 and U-8-OHdG. Multilinear regression analysis was performed to determine which factors could best predict changes in HMW-ADN and PAI-1. Changes in blood pressure were not significant predictors of changes in metabolic factors in all patients. We found that the group with baseline pulse pressure <60 mmHg had improved HMW-ADN and PAI-1 values compared with the group with baseline pulse pressure ≥ 60 mmHg. These results suggest that pulse pressure at baseline could be predictive of changes in HMW-ADN and PAI-1. CONCLUSIONS: Candesartan improved inflammatory parameters (HMW-ADN and PAI-1) in hypertensive patients with type 2 diabetes mellitus of long duration independent of blood pressure changes. Patients with pulse pressure <60 mmHg might receive protective benefits by candesartan. TRIAL REGISTRATION: UMIN000007921.

Azelnidipine inhibits aldosterone synthesis and secretion in human adrenocortical cell line NCI-H295R.

Blockade of a mineralocorticoid receptor is a clinically useful approach to the prevention of cardiovascular disease. The present study was designed to evaluate the effect of azelnidipine, a unique dihydropyridine Ca(2+) channel blocker, on aldosterone production in the human adrenocortical cell line NCI-H295R. Azelnidipine inhibited angiotensin II- and KCl-induced expression of steroid 11beta-hydroxylase, steroid 18-hydroxylase, and the alpha1H subunit of the T-type Ca(2+) channel, and suppressed steroid biosynthesis in H295R cells by the same amount as efonidipine. On the basis of these findings, azelnidipine appears to suppress steroid biosynthesis in H295R cells beyond the blockade of L-type calcium channels.

Coexistence of aldosterone-producing adrenocortical adenoma and pheochromocytoma in an ipsilateral adrenal gland.

A 40-year-old female, diagnosed as essential hypertension, demonstrated a 2 cm mass in left adrenal gland by computed tomography without abnormal endocrinological findings. (131)I-adosterol and (123)I-metaiodobenzylguanidine (MIBG) scintigraphy at 39 years of age showed no abnormal accumulation. Follow up (131)I-adosterol scintigraphy performed one year later showed apparently abnormal uptake and slightly elevated uptake in left adrenal gland. Her physical examination was unremarkable except for mild hypertension. Routine blood chemistry was normal except for hypokalemia. Endocrinological date revealed suppressed plasma renin activity, and elevated plasma aldosterone concentration, and noradrenalin levels. Serial T2-weighted magnetic resonance imaging clearly demonstrated two distinct tumors. Furthermore, selective adrenal venous sampling with intravenous ACTH infusion indicated aldosterone-producing adrenocortical adenoma (APA) in left adrenal gland. During operation of adrenal tumor, blood pressure elevated markedly and complication of pheochromocytoma (PC) was suspected. Immunohistochemical findings after left adrenolectomy revealed that the adrenal mass was compatible with APA and PC. Risk of operation against undiagnosed PC is very high and, therefore, it must be diagnosed before surgery. Herein, we present an extremely rare case of the simultaneous occurrence of both APA and PC in an ipsilateral adrenal gland.