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C Kurata

Publications and source records attributed to C Kurata.

At least 37 records · Page 2Linked to original sources
PubMed1997

[A case of Wilson-Mikity syndrome with marked and monoclonal elevation of IgM in blood].

Wilson-Mikity syndrome, a chronic respiratory insufficiency occurring in premature newborn infants, is known to show an elevation of serum IgM, but its etiology is obscure. We studied the immunological properties of IgM in a female infant of this syndrome, whose IgM in cord blood was very high level at 639.1 mg/dl with monoclonal elevation. The IgM bound to protein(s) in human umbilical venous endothelial cells and in human lung tissue. However, IgMs from this patient after recovery, from patient's mother and from another normal newborn did not bind to the proteins. Tissue-binding activity of the patient's IgM may be associated with tissue damages in this syndrome.

Female↗
PubMed1997

Influence of blood substrate levels on myocardial kinetics of iodine-123-BMIPP.

UNLABELLED: To evaluate the influence of blood substrate levels on myocardial uptake of 123I-labeled beta-methyl-iodophenyl-pentadecanoic acid (BMIPP), we examined the correlation between myocardial BMIPP uptake and blood levels of free fatty acid (FFA), glucose, insulin, triglyceride and total cholesterol. METHODS: In 180 patients, venous blood samples were obtained, and the early and late myocardial uptakes (MU15 and MU150) were determined on planar images at 15 and 150 min after injection at rest, respectively, and the clearance rate of BMIPP from the myocardium was calculated. Dynamic SPECT with BMIPP, PET with [18F]fluoro-deoxyglucose and determination of myocardial carnitine contents were performed in 15, 1 and 3 patients, respectively. RESULTS: In the 180 patients, MU15 correlated with blood insulin (r = 0.22, p = 0.005) and FFA (r = -0.19, p = 0.02) levels, whereas MU150 did not correlate with blood levels of any variables that were measured (p > 0.05). The clearance rate correlated with blood insulin (r = 0.28, p < 0.001), glucose (r = 0.17, p = 0.03) and FFA (r = -0.40; p < 0.001) levels. The correlations were, however, weak, and five patients (2.8%) with no myocardial BMIPP uptake, all of whom had anterior myocardial infaction, had no characteristics regarding the blood substrate levels. Although dynamic SPECT demonstrated rapid myocardial extraction of BMIPP in 13 patients with myocardial BMIPP uptake, it demonstrated no myocardial BMIPP extraction in two patients with no myocardial BMIPP uptake. One of the five patients with no myocardial BMIPP uptake showed increased myocardial [18F]fluorodeoxyglucose uptake and decreased myocardial carnitine content. CONCLUSION: The influence of blood substrate levels on myocardial BMIPP uptake is not very significant, although high serum FFA levels may be associated with slow clearance of BMIPP from the myocardium. The complete absence of myocardial BMIPP uptake is not rare and may not be associated with changes in blood substrate levels or early back diffusion of BMIPP.

Adolescent↗
PubMed1997

Cardiac sympathetic neuropathy and effects of aldose reductase inhibitor in streptozotocin-induced diabetic rats.

UNLABELLED: Cardiac autonomic neuropathy can be a cause of sudden death in patients with diabetes mellitus. Clinical evaluation methods for diabetic cardiac sympathetic neuropathy have not been established. Using 125I-metaiodobenzylguanidine (MIBG) and streptozotocin (STZ)-induced diabetic rats, we evaluated cardiac sympathetic neuropathy and the effects of aldose reductase inhibitor (ARI). METHODS: Myocardial MIBG uptake was measured 4 hr after injection in the following groups: control rats, rats treated with insulin or ARI (epalrestat, 100 mg/kg/day) from immediately to 4 wk after STZ injection and rats treated with insulin or ARI from 4-8 wk. Myocardial MIBG distribution and norepinephrine content were evaluated in the control and diabetic rats with or without ARI therapy started immediately after STZ injection. RESULTS: Myocardial MIBG uptake was significantly lower in diabetic rats than in control rats; the reduction was marked in the subendocardial myocardium. Myocardial norepinephrine content was increased significantly in diabetic rats compared with control rats. Decreased MIBG uptake and increased norepinephrine content in diabetic myocardium were completely prevented by insulin therapy started immediately after STZ injection and partially, but significantly, by ARI administered from immediately after STZ injection. Heterogeneous MIBG distribution also disappeared with the ARI therapy. In contrast, diabetic rats treated with insulin or ARI therapy started 4 wk after STZ injection showed no improvement in MIBG uptake. CONCLUSION: These results suggest that MIBG abnormalities observed in diabetic rats may reflect diabetic cardiac sympathetic neuropathy independently of cardiomyopathy, nephropathy or coronary heart disease secondary to diabetes and that MIBG imaging may be useful for clinical assessment of cardiac sympathetic neuropathy.

3-Iodobenzylguanidine↗
PubMed1997

Effects of cilazapril and verapamil on myocardial iodine-125-metaiodobenzylguanidine accumulation in cardiomyopathic BIO 53.58 hamsters.

UNLABELLED: Sympathetic nervous system activation is important in the pathophysiology of congestive heart failure. However, little about how the treatment for heart failure may influence myocardial sympathetic nervous activity has been established. In this study, we evaluated effects of cilazapril (CLZ) and verapamil (VER) on myocardial sympathetic nervous activity in cardiomyopathic BIO 53.58 hamsters using [125I]metaiodobenzylguanidine ([125I]MIBG). METHODS: We used BIO 53.58 hamsters aged 3, 6 and 10 mo and age-matched normal F1b hamsters. We divided BIO 53.58 hamsters into untreated, CLZ- and VER-treated groups. We measured myocardial [125I]MIBG uptakes and norepinephrine concentrations and evaluated the extent of fibrosis and the distribution of [125I]MIBG. RESULTS: The myocardial [125I]MIBG uptake was significantly lower in BIO 53.58 hamsters aged 6 and 10 mo than in age-matched F1b hamsters. Myocardial [125I]MIBG uptake was significantly correlated to myocardial norepinephrine concentration in BIO 53.58 hamsters. Myocardial [125I]MIBG uptake was significantly higher in both of the treated groups than in the untreated group. The extent of myocardial fibrosis was significantly lower in both of the treated groups than in the untreated group. The myocardial [125I]MIBG uptake showed a significant inverse correlation with the extent of fibrosis. Myocardial [125I]MIBG distribution was highly heterogeneous in the untreated BIO 53.58 hamsters, whereas it was homogeneous in the F1b hamsters aged 6 mo and the treated BIO 53.58 hamsters. CONCLUSION: In BIO 53.58 hamsters, myocardial [125I]MIBG uptake decreased with the progression of cardiomyopathy, and the decreased uptake was improved by treatment with CLZ and VER. Thus, myocardial [125I]MIBG uptake can reflect the effects of treatment on cardiomyopathy, as well as the progression of cardiomyopathy.

3-Iodobenzylguanidine↗
PubMed1996

Quantification of left ventricular size on exercise thallium-201 single-photon emission tomography.

The purposes of this study were to determine whether quantification of the left ventricular size on exercise thallium-201 single-photon emission tomography (SPET) correlates with echocardiographic measurements, whether the quantification reflects the severity of coronary artery disease, and whether it can provide supplementary information regarding the severity of coronary artery disease. In 42 control subjects and 110 patients who underwent coronary angiography, we performed exercise 201Tl SPET and quantified six non-regional markers: lung 201Tl uptake on an initial planar image (Lung/Heart), left ventricular width on a tomogram (Width), change in the Width from the initial to delayed tomograms (DeltaWidth), count ratio of the left ventricular cavity to the myocardium (C/M), count ratio of the lung to the myocardium (L/M), and count ratio of the lung to the left ventricular cavity (L/C). In 76 patients, furthermore, the Width was compared with echocardiographic measurements. The Width correlated with echocardiographic measurements (P<0.001). The Width and DeltaWidth were significantly different among zero-, one-, two- and three-vessel disease (P<0.001). However, the Width and DeltaWidth could not improve the power of discrimination for multi-vessel disease derived from the Lung/Heart. The six non-regional markers correlated with each other (P<0.001). Among the six markers, the Lung/Heart was only the independent discriminator for multi-vessel disease. In conclusion, quantification of the left ventricular size on exercise 201Tl SPET correlated with echocardiographic measurements and reflected the severity of coronary artery disease, but may be replaced with quantitation of the lung 201Tl uptake.

Cardiac Catheterization↗
PubMed1996

Prognosis of hypertrophic cardiomyopathy: assessment by 123I-BMIPP (beta-methyl-p-(123I)iodophenyl pentadecanoic acid) myocardial single photon emission computed tomography.

123I-BMIPP (beta-methyl-iodophenyl pentadecanoic acid) has shown unique properties for potential use in assessing myocardial metabolism. Previous basic and clinical studies demonstrated that the disturbances of myocardial metabolism precede the occurrence of myocardial perfusion abnormalities by using 201Tl in hypertrophic myocardium. The present study was therefore undertaken to determine whether or not 123I-BMIPP myocardial SPECT is useful in predicting the prognosis of hypertrophic cardiomyopathy (HCM) in 65 patients in 6 facilities. There were 33 patients with non-obstructive HCM, 12 with obstructive HCM, 12 with apical HCM and 8 with dilated-phase HCM. Fasted patients at rest received an intravenous injection of 111 MBq of 123I-BMIPP. Twenty to thirty minutes later, myocardial SPECT was carried out. The BMIPP severity score (BMIPP SS) was evaluated semiquantitatively by using representative short axial SPECT images. We followed up the incidence of cardiac events for a mean period of 3.0 +/- 0.6 years. Cardiac events occurred in 13 patients. Of these, 11 developed heart failure and 6 died (4 from heart failure and 2 from sudden death). The BMIPP SS in the dilated-phase HCM was significantly lower than that for the nonsurvivors. The BMIPP SS was particularly high in patients with fatal heart failure. Furthermore, there was a close negative correlation between the BMIPP SS and percent fractional shortening measured by echocardiography (r = -0.49). Finally, the mortality over the three years increased according to the extent of the BMIPP SS. In conclusion, these results indicate that BMIPP SS is useful in evaluating the severity of HCM. We conclude that 123I-BMIPP is a valuable metabolic tracer in predicting the outcome of HCM.

Adult↗
PubMed1996

Sympathetic nerve activity in the spasm-induced coronary artery region is associated with disease activity of vasospastic angina.

OBJECTIVES: We assessed the relation between sympathetic nerve activity and disease activity of vasospastic angina. BACKGROUND: The autonomic nervous system has been proposed to play a key role in attacks of vasospastic angina. A unique feature of vasospastic angina attacks is periodic fluctuation, which complicates the assessment of disease activity. METHODS: Twenty-five patients with left anterior descending coronary artery (LAD) spasm were studied: 12 with recent onset of chest pain (group 1) and 13 free of angina for more than 3 months after discontinuing medication (group 2). Group 1 underwent iodine-123 metaiodobenzylguanidine (MIBG) imaging (in the active phase) and atropine-stress MIBG imaging early after diagnostic angiography, and repeat MIBG imaging when they were free of angina for more than 3 months with medication (in the stable phase). Group 2 also underwent MIBG imaging (in remission). On a bull's-eye map, quantitative analysis of percent uptake and washout rate of MIBG was performed regionally. RESULTS: In group 1 in the active phase, the washout rate of the LAD territory was significantly lower than the rates in the stable phase, in remission and during atropine-stress MIBG imaging. The regional washout rate of the territories of the right coronary artery and the circumflex artery in the active phase was also significantly lower than that during atropine-stress MIBG imaging. The washout rate of the LAD territory in the active phase was significantly lower than the rates of the other two regions. In contrast, there were no significant differences in the distribution of regional percent uptake in every image. A similar distribution of washout rate was observed among group 1 patients in the stable phase, in group 1 patients during atropine-stress MIBG imaging and in group 2 patients. CONCLUSIONS: The MIBG washout rate of the spasm-induced coronary artery territory changed according to the degree of disease activity. Thus, sympathetic nerve activity could reflect disease activity of vasospastic angina.

3-Iodobenzylguanidine↗
PubMed1995

Localization of [125I]endothelin-1 in injured aorta of rabbits.

Endothelin-1 is a potent vasoconstrictor. This study was performed to determine whether arterial injury, induced by either hypercholesterolemia or mechanical disruption of the endothelium, is associated with increased localization of endothelin-1 in the artery. The blood clearance and tissue distribution of intravenously injected [125I]endothelin-1 was evaluated in 33 rabbits--control animals (n = 7), balloon de-endothelialized animals (n = 12), cholesterol-fed animals (n = 6) and animals that had both balloon de-endothelialization and high cholesterol diet (n = 8). The blood clearance half time was less than 10 min, with slightly slower clearance in the ballooned/cholesterol-fed animals. [125I]Endothelin-1 localized in the lung (approximately 12% injected dose (ID)/organ) and kidney (approximately 8%ID/organ). [125I]Endothelin-1 localization in the injured aorta increased from the baseline level of 0.06%kgID/g to its highest level within 5 min of balloon de-endothelialization (0.2%kgID/g) and decreased to 0.11%kgID/g within one week and remained essentially unchanged through 16 weeks. The area with increased binding of [125I]endothelin-1 corresponded to the zone of arterial injury stained with Evans blue. On the other hand, the binding in the aorta did not increase with the atherogenic diet. These findings suggest that endothelin-1 accumulates in injured vessels, attaining the highest levels immediately after mechanical injury.

Animals↗
PubMed1995

Diagnostic and prognostic value of myocardial scintigraphy with thallium-201 and gallium-67 in cardiac sarcoidosis.

STUDY OBJECTIVE: To examine the diagnostic and prognostic value of myocardial scintigraphy using thallium-201 and gallium-67 in cardiac sarcoidosis. PATIENTS: Twenty-five patients with sarcoidosis. METHODS: All patients underwent myocardial thallium-201 scintigraphy. Six patients with myocardial thallium-201 defects were classified into group A and another 19 without defects were classified into group B. Between group A and B, we compared the results of other noninvasive examinations, including standard 12-lead ECG, 24 h ambulatory ECG, chest radiography, measurements of serum angiotensin-converting enzyme (ACE) and lysozyme levels, and gallium-67 scintigraphy. RESULTS: Proportions of subjects who had varying degrees of heart block, severe ventricular arrhythmias (more than or equal to third grade of Lown's classification), and high levels of serum ACE and lysozyme levels were not different between these two groups (p > 0.05). Although an enlarged cardiothoracic ratio was more frequent in group A (p < 0.05), bilateral hilar lymphadenopathy was more frequent in group B (p < 0.01). Four patients of group A and 15 of group B underwent gallium-67 scintigraphy. Although no subjects of group B had myocardial uptake of gallium-67, two of four group A patients showed cardiac uptake. These four group A patients were treated with corticosteroids. The therapy provided clinical and scintigraphic improvement in two patients with myocardial gallium-67 uptake, although it did no improvement in the other two patients without gallium-67 uptake. CONCLUSIONS: When cardiac sarcoidosis was diagnosed according to myocardial thallium-201 defects, other noninvasive examinations were not useful to detect this disease. However, gallium-67 uptake may predict the efficacy of corticosteroids. Thus, the combination of thallium-201 and gallium-67 scintigraphy may be useful not only in diagnosis of cardiac sarcoidosis but also in prediction of effects of corticosteroids.

Adrenal Cortex Hormones↗
PubMed1995

Enhanced cardiac clearance of iodine-123-MIBG in chronic renal failure.

UNLABELLED: We studied myocardial accumulation and clearance of [123I]metaiodobenzylguanidine (MIBG) along with measurements of plasma norepinephrine concentrations. METHODS: Myocardial imaging with MIBG and plasma norepinephrine concentration measurements were performed in 21 patients with chronic renal failure on dialysis and 11 control subjects. Dynamic acquisitions, begun immediately after MIBG injection, and planar images 15 and 150 min after injection were used to measure early and late myocardial uptake and clearance rates of MIBG from the heart. RESULTS: Early and late MIBG uptake was not significantly different from that in controls but MIBG clearance was significantly more rapid in controls. Based on echocardiographic findings, the patients were divided into three subgroups: those without left ventricular hypertrophy and dysfunction (n = 10), with hypertrophy (n = 4) and with dysfunction (n = 7). Among controls and the three patient subgroups, MIBG clearance was significantly higher in all the subgroups and also was significantly higher in patients with dysfunction than in those without hypertrophy and dysfunction. Plasma norepinephrine levels were significantly higher in patients than in controls and correlated significantly with the clearance rate. CONCLUSION: MIBG clearance from the heart was rapid in patients with chronic renal failure on dialysis, particularly those with left ventricular dysfunction or hypertrophy, suggesting cardiac sympathetic overactivity in these patients.

3-Iodobenzylguanidine↗
PubMed1994

Simultaneous dual myocardial imaging with iodine-123-beta-methyl iodophenyl-pentadecanoic acid (BMIPP) and thallium-201 in patients with coronary heart disease.

To assess the clinical value of simultaneous dual myocardial imaging with iodine-123-beta-methyl-iodophenyl-pentadecanoic acid (123I-BMIPP) and thallium-201 (201Tl), myocardial imaging was performed at rest and during exercise in seven patients with coronary heart disease. When 123I-BMIPP and 201Tl images were compared, the initial exercise and resting images agreed 87% and 64%, respectively. In the initial resting images, the regional uptake of 123I-BMIPP was frequently less than that of 201Tl. The incidence of exercise-induced reversible defects by 201Tl in the Tl > BMIPP regions was significantly higher than that in the Tl = BMIPP regions (57% vs 4%, p < 0.01) and the incidence of coronary narrowing of more than 90% in the Tl > BMIPP regions was also significantly higher than that in the Tl = BMIPP regions (91% vs 38%, p < 0.01). In addition, this disparity (Tl > BMIPP) was found more frequently in regions with abnormal wall motion than in regions with normal wall motion (hypokinetic regions; 68%, severe hypokinetic or akinetic regions; 50%, vs normokinetic region; 4%, p < 0.01). In contrast, the uptake of 123I-BMIPP correlated closely with that of 201T1 in normal myocardium and the uptake of both 123I-BMIPP and 201Tl was severely reduced in myocardium with severe ischemia during exercise and prior infarction. These results indicate that dual myocardial imaging with 123I-BMIPP and 201Tl may provide a unique means of identifying patients with metabolically disturbed myocardium, such as hibernating and stunned myocardium.

Aged↗
PubMed1993

Dual-tracer autoradiography with thallium-201 and iodine-125 MIBG in BIO 14.6 cardiomyopathic Syrian hamsters.

Dual-tracer imaging of the heart with 125I-metaiodobenzylguanicline (MIBG) and 201Tl can simultaneously demonstrate the distribution of sympathetic nerve endings and the underlying myocardial perfusion. A quantitative dual-tracer autoradiographic study with 201Tl and 125I-MIBG was performed to investigate changes in the distribution of cardiac sympathetic innervation with the progression of cardiomyopathy in BIO 14.6 hamsters. The distribution of 201Tl was uniform in control hamsters and BIO 14.6 hamsters at all stages of cardiomyopathy. In contrast, a reduction in MIBG accumulation occurred in the endocardial region of the left ventricular free wall and the left ventricular aspect of the interventricular septum in BIO 14.6 hamsters at 3 and 8 months of age. Thus, there was an uncoupling of the left ventricular distribution of 201Tl and 125I-MIBG in BIO 14.6 hamsters. In addition, interstitial fibrosis was increased in the interventricular septum, the subendocardial region of the left ventricular free wall, and the right ventricular wall, which were the sites of reduced MIBG accumulation. This study shows that dual myocardial imaging with MIBG and 201Tl may be useful for investigating patients with cardiomyopathy.

3-Iodobenzylguanidine↗
PubMed1993

Implications of delayed image on simultaneous thallium-201/technetium-99m pyrophosphate dual emission computed tomography early after acute myocardial infarction.

This study aimed investigate whether thallium-201 and technetium-99m pyrophosphate dual rest-redistribution emission computed tomography early after intracoronary thrombolysis may provide supplementary information for the management of patients with acute myocardial infarction. Fifty patients who received intracoronary thrombolysis underwent simultaneous dual emission computed tomography 3 days after first acute myocardial infarction. All patients who had a technetium-99m pyrophosphate accumulation were selected. Thallium-201/technetium-99m pyrophosphate overlap in the initial and delayed images early after intracoronary thrombolysis identified successful recanalization with sensitivities of 68% and 90% (p < 0.05), specificities of 47% 79% (p < 0.05), positive predictive accuracies of 68% and 88%, negative predictive accuracies of 47% and 80% (p < 0.05), and overall accuracy of 60% and 86% (p < 0.01), respectively. The patients were divided into 3 groups according to the change in thallium-201 uptake from the initial image to the delayed image on dual emission computed tomography: 20 patients had no change in thallium-201 uptake (fixed type), 16 had increases in thallium-201 uptake (redistribution type), and 14 had decreases in thallium-201 uptake (reverse redistribution type). The number of patients with successful recanalization was significantly higher in the redistribution type than in the other types (redistribution type vs reverse redistribution type or fixed type; p < 0.01, respectively). In the redistribution type a frequency of reinfarction in the same infarcted area during the hospital course was significantly higher than in the other types (redistribution type vs reverse redistribution type or fixed type; p < 0.05, respectively), which was mainly due to the patients having high grade residual stenosis. Thus, a thallium-201/technetium-99m pyrophosphate overlap in the delayed image early after acute myocardial infarction can be used as an index for predicting successful early recanalization and probably viable myocardium. In addition, the redistribution patterns on thallium-201 emission computed tomography early after intracoronary thrombolysis can be helpful in identifying patients with successful early recanalization and a high risk subset.

Adult↗
PubMed1992

Exercise testing and thallium-201 emission computed tomography in patients with intraventricular conduction disturbances.

The specificity of exercise thallium-201 emission computed tomography for coronary artery disease was assessed in patients with intraventricular conduction disturbances. Eighty-seven patients were studied: 33 with right bundle branch block (RBBB), 11 with RBBB and left-axis deviation, 11 with left (L)BBB, 12 on right ventricular pacing, and 20 with Wolff-Parkinson-White (WPW) syndrome. A control group of 349 consecutive patients with normal intraventricular conduction was also examined. The specificity of diagnosis of coronary artery disease in patients with LBBB (30%), right ventricular pacing (44%) or RBBB plus left-axis deviation (50%) was significantly lower than in patients with normal intraventricular conduction (94%; p less than 0.01). In contrast, there was no significant difference between specificity in patients with RBBB (86%) or WPW syndrome (90%) and patients with normal intraventricular conduction. Perfusion defects were found in the anterior, septal and inferior segments in patients with LBBB, and in the septal and inferior segments in patients with RBBB plus left-axis deviation despite the absence of coronary stenosis. Furthermore, diffuse slow washout was seen more often in patients with WPW syndrome (35%) than in controls who had normal intraventricular conduction (11%; p less than 0.05), despite a good exercise performance in the former group. This study suggests that there is an increased incidence of abnormal perfusion and clearance during exercise thallium-201 emission computed tomography in patients with intraventricular conduction disturbances.

Aged↗
PubMed1992

Physiologic capacity of well-developed collaterals in patients with isolated left anterior descending artery disease.

To assess the physiologic significance of well-developed collaterals, 34 patients, with isolated left anterior descending artery disease (LAD) and without overt prior myocardial infarction, underwent cardiac catheterization and exercise thallium-201 emission computed tomography. The patients were divided into 3 groups; 11 patients with 90% stenosis of the proximal LAD and without collaterals (group 1), 11 with 99% stenosis of the proximal LAD, and without collaterals (group 2) and 12 with a total occlusion of the proximal LAD which was completely filled by well-developed collaterals (group 3). On left ventriculography, shortening fractions of the anterior wall were significantly reduced in group 2 as compared to group 1 and 3 (group 1 vs group 2: p less than 0.01, group 2 vs group 3: p less than 0.05), which reflected the lower ejection fraction of group 2 (p less than 0.01 and p less than 0.05, respectively). The perfusion defects of the anterior wall on both the initial and the delayed images were severer in groups 2 and 3 than in group 1 (group 1 vs group 2 and group 1 vs group 3 on the initial image: p less than 0.01, for both, group 1 vs group 2 and group 1 vs group 3 on the delayed image: p less than 0.05, for both). However, recovery of the perfusion defects from the initial image to the delayed image was better in group 3 than in groups 1 and 2 (group 1 vs group 2 and group 1 vs group 3: p less than 0.05, for both). Therefore, coronary blood flow through well-developed collaterals was considered to be comparable to the flow through a diseased vessel with 90% stenosis at rest. During maximal exercise, blood flow through well-developed collaterals was considered to be comparable to the flow through a diseased vessel with 99% stenosis, although the blood flow through well-developed collaterals was considered to be better than that through 99% stenosis during the recovery period. These findings suggest that patients with well-developed collaterals must be treated like those with severe stenosis.

Aged↗