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Biomedical subjects

M Nagata

Publications and source records attributed to M Nagata.

At least 91 records · Page 5Linked to original sources

Lens Epithelial Cell Damage and Apoptosis in Atopic Cataract. Histopathological and Immunohistochemical Studies.

Purpose: To elucidate the relationship between damage of lens epithelial cells and apoptotic cell death in patients with atopic cataract.Methods: Histopathological and immunohistochemical studies were carried out using anterior lens capsules obtained at surgery from 13 patients with atopic cataract and from 25 patients with senile cataract.Results: No specific histopathological findings were found in the lens epithelial cells in atopic cases. However, the frequency and severity of histopathological findings such as flattening, nuclear pyknosis, and loss of cells were more frequent and more severe in atopic cases than in senile cases. The terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP-biotin nick end labelling (TUNEL) method revealed that the mean ratio of cells containing fragmented DNA to whole epithelial cells was almost the same in both atopic and senile cases. However, the mean ratio of Bax-positive cells was significantly higher in atopic cases (mean +/- standard deviation, 29.1 +/- 35.0%) than in senile cases (2.7+/-7.0%) (P<.05). The mean ratio of Bcl-2-positive cells was significantly lower in atopic cases (1.4+/-3.4%) than in senile cases (44.3+/-35.7%) (P<.05).Conclusion: These results suggest that apoptotic cell death may play an important role in the development of lens epithelial cell damage in atopic cataract.

Journal Article↗

Factor VIII C2 domain contains the thrombin-binding site responsible for thrombin-catalyzed cleavage at Arg1689.

Thrombin-catalyzed factor VIII activation is an essential positive feedback mechanism regulating intrinsic blood coagulation. A factor VIII human antibody, A-FF, with C2 epitope, exclusively inhibited factor VIII activation and cleavage at Arg(1689) by thrombin. The results suggested that A-FF prevented the interaction of thrombin with factor VIII and that the C2 domain was involved in the interaction with thrombin. We performed direct binding assays using anhydro-thrombin, a catalytically inactive derivative of thrombin in which the active-site serine is converted to dehydroalanine. Intact factor VIII, 80-kDa light chain, 72-kDa light chain, and heavy chain fragments bound dose-dependently to anhydro-thrombin, and the K(d) values were 48, 150, 106, and 180 nm, respectively. The C2 and A2 domains also dose-dependently bound to anhydro-thrombin, and the K(d) values were 440 and 488 nm, respectively. The A1 domain did not bind to anhydro-thrombin. A-FF completely inhibited C2 domain binding to anhydro-thrombin (IC(50), 18 nm), whereas it did not inhibit A2 domain binding. Furthermore, C2-specific affinity purified F(ab)'(2) of A-FF, and the recombinant C2 domain inhibited thrombin cleavage at Arg(1689). Our results indicate that the C2 domain contains the thrombin-binding site responsible for the cleavage at Arg(1689).

Antibodies, Monoclonal↗

Intracerebral hemodynamics probed by near infrared spectroscopy in the transition between wakefulness and sleep.

Previous imaging studies have shown that cerebral metabolism is gradually reduced at the beginning of sleep. Few studies have examined the sleep state transition periods from wakefulness to sleep and sleep to wakefulness. The current study used the Near Infrared Spectroscopy (NIRS) technique to describe the intracerebral hemodynamics at the frontal pole in the circumscribed period between wakefulness and sleep. Nine healthy young adults were studied during afternoon naps. Optical probes were placed on the forehead and EEG electrodes on the scalp. At sleep onset oxygenated hemoglobin (oxy-Hb) was reduced (P<0.01) and deoxygenated hemoglobin (deoxy-Hb) showed a near significant reduction (P<0.063). At sleep offset there were increases in oxy-Hb (P<0.005) and deoxy-Hb (P<0.05). In 18 of 26 transitions to sleep there was a coordinated fall in both NIRS parameters, we call the Switch Point, that lasted a mean of 3.6 s. In 32 of 36 transitions to wakefulness there was an analogous Switch Point that lasted a mean of 3.4 s. Before and after the Switch Point, changes were small and the relationship between oxy-Hb and deoxy-Hb was a combination of parallel and reciprocal fluctuations. A synchronized, parallel and short-lived change in oxy-Hb and deoxy-Hb is a discrete event in the transition period between wakefulness and sleep. The concentration of these light absorbing molecules is abruptly set to a new level at sleep-wake transitions and probably reflects the different perfusion demands of these states.

Adult↗

Production of IL-10 and IL-12 in CD40 and interleukin 4-activated mononuclear cells from patients with Graves' disease.

We investigated the effect of T cell-dependent B cell activation on the production of IL-10 and IL-12 by peripheral blood mononuclear cells (PBMCs) obtained from patients with Graves' disease vs Hashimoto's thyroiditis, type 1 diabetes or normal controls. Incubation of PBMCs, from each of the subject groups, with a combination of anti-CD40 monoclonal antibodies and interleukin 4 (IL-4)-activated B cells, as shown by an increased level of soluble CD23. There was also a notable increase in the number of CD23(+)cells in PBMCs from patients with Graves' disease as compared to the other subject groups. This combination of B cell stimulants increased production of IL-10 in PBMCs obtained from patients with Graves' disease relative to those patients with Hashimoto's thyroiditis, type 1 diabetes, or the control subjects. The production of IL-12 showed wide variation that depended on the basal IL-12 level. In subjects with a low basal IL-12 level there was a positive correlation between the production of IL-12 and that of IL-10 from PBMCs stimulated with anti-CD40 antibodies plus IL-4. On the contrary, in the patients with a high basal IL-12 level, no change or a decrease of IL-12 production was observed after the stimulation. Thus, T cell-dependent B cell activation via a CD40 pathway triggers the overproduction of IL-10 and overcome the effect of IL-12 to shift the Th(1)/Th(2)balance to Th(2)dominance in patients with Graves' disease but not in Hashimoto's thyroiditis or type 1 diabetes.

Adult↗

Heterotopic thyroid tissue at the porta hepatis in a fetus with trisomy 18.

Heterotopic thyroid tissue at the porta hepatis in a fetus with trisomy 18 is described. The fetus had an eutopic thyroid gland without any abnormalities. The heterotopic thyroid was found at the porta hepatis and showed histological features similar to the eutopic thyroid. Immunohistochemically, the heterotopic follicles were positive for thyroglobulin, but no calcitonin-positive cells were found. Intra-abdominal heterotopic thyroid is exceedingly rare in locations other than the ovary, and to our knowledge, this is the first report of a fetal case. The present case provides clear evidence that abdominal heterotopic thyroid can occur as a congenital anomaly. Migration abnormality of the median anlage of the thyroid is the most likely histogenesis of heterotopic thyroid at the porta hepatis.

Abnormalities, Multiple↗

Steroid-sensitive nephrotic syndrome associated with Kimura disease.

We report an 11-year-old Japanese boy with Kimura disease and associated nephrotic syndrome. Before the diagnosis of Kimura disease was established, the patient had three episodes of swelling on the left cheek with subsequent nephrotic syndrome. Steroids were effective for both conditions. However, both conditions recurred within months of discontinuation of steroids. For the fourth episode of swelling on the left cheek, cyclosporine (CsA) was used. The subcutaneous tumor responded to CsA and disappeared within a few days. There has been no subsequent relapse of the nephrotic syndrome to date.

Angiolymphoid Hyperplasia with Eosinophilia↗

Comparison of the validity of the criteria for gestational diabetes mellitus by WHO and by the Japan Society of Obstetrics and Gynecology by the outcomes of pregnancy.

Data for 416 Japanese pregnant women who received a 75g oral glucose tolerance test (OGTT) for determination of gestational diabetes mellitus (GDM) in 13 hospitals in Japan were analyzed retrospectively. Comparison of the diagnostic criteria of the World Health Organization (WHO) and the Japan Society of Obstetrics and Gynecology (JSOG) revealed pregnant women who met the latter criteria for GDM to have significantly higher incidences of low Apgar scores, respiratory problems, neonatal hypoglycemia, preterm delivery and requirements for insulin therapy and cesarean section. The women who met the WHO criteria but not the JSOG criteria had minor complications. These observations suggest that the GDM criteria of the JSOG are more appropriate than the WHO criteria from the standpoint of therapeutic intervention for pregnant women.

Adult↗

Event-related potential indices of semantic priming using masked and unmasked words: evidence that the N400 does not reflect a post-lexical process.

Several authors have contended that the N400 is a reflection of a post-lexical event such as that proposed by Neely and Keefe [J.H. Neely, D.E. Keefe, Semantic context effects on visual word processing: a hybrid prospective/retrospective processing theory, in: G.H. Bower (Ed.), The Psychology of Learning and Motivation: Advances in Research and Theory, Vol. 23, Academic Press, New York, 1989, pp. 207-248.], whereby the subject compares the word on the current trial to the "context" provided by the word on the preceding trial [M. Besson, M. Kutas, The many facets of repetition: A cued-recall and event-related potential analysis of repeating words in same versus different sentence contexts, Journal of Experimental Psychology: Learning, Memory and Cognition, 19 (5) (1993), 1115-1133; C. Brown, P. Hagoort, The processing nature of the N400: Evidence from masked priming. Journal of Cognitive Neuroscience, 5(1) (1993), 34-44; P.J. Holcomb, Semantic priming and stimulus degradation: Implications for the role of the N400 in language processing, Psychophysiology 30 (1993), 47-61; M.D. Rugg, M.C. Doyle, Event-related potentials and stimulus repetition in indirect and direct tests of memory, in: H. Heinze, T. Munte, G.R. Mangun (Eds), Cognitive Electrophysiology, Birkhauser Boston, Cambridge, MA, 1994]. A study which used masked primes to directly test this possibility has been reported by Brown and Hagoort [C. Brown, P. Hagoort, The processing nature of the N400: evidence from masked priming. Journal of Cognitive Neuroscience, 5(1) (1993), 34-44]. When the primes were masked, no priming effect was observed on the N400. When behavioral data were collected in the same paradigm, from another group of subjects, the usual priming effect on RT was obtained. Considered together, the data from the two groups of subjects indicated that activation of semantic representations had occurred without conscious awareness. As no N400 priming effect was observed, it was suggested that N400 must reflect a post-lexical process. This interpretation, however, is at odds with the findings of other studies which have reported N400 priming effects under conditions where post-lexical processes would not be thought to operate[J. Anderson, P. Holcomb, Auditory and visual semantic priming using different stimulus onset asynchronies: an event-related brain potential study. Psychophysiology 32 (1995), 177-190; J. Boddy, Event-related potentials in chronometric analysis of primed word recognition with different stimulus onset asynchronies, Psychophysiology 23 (1986), 232-245; D. Deacon, T. Uhm, W. Ritter, S. Hewitt, The lifetime of automatic priming effects may exceed two seconds, Cognitive Brain Research 7 (1999), 465-472; P.J. Holcomb, Automatic and attentional process: an event-related brain potential analysis of semantic priming. Brain and Language 35 (1998) 66-85]. The present study replicated Brown and Hagoort using a repeated measures design, a shorter SOA (stimulus onset asynchrony), and a slightly different threshold setting procedure. Significant priming effects were obtained on the mean amplitude of the N400 regardless of whether the words were masked or unmasked. The findings imply that the processing subserving the N400 is not postlexical, since the N400 was manipulated without the subjects being aware of the identity of the words.

Adolescent↗

Surgical effects of combined trabeculotomy and sinusotomy compared to trabeculotomy alone.

PURPOSE: To elucidate long-term surgical results and problems of combined trabeculotomy and sinusotomy in comparison with trabeculotomy alone. METHODS: The study included 91 glaucomatous eyes in 57 patients with primary open angle glaucoma, who underwent either combined trabeculotomy and sinusotomy (40 eyes) or trabeculotomy alone (51 eyes). The mean follow-up period (+/-standard deviation) was 46.1+/-10.4 months (range: 30 to 60 months). RESULTS: At the final examination, in 37 (93%) of the 40 eyes after combined trabeculotomy and sinusotomy and in 40 (78%) of the 51 eyes after trabeculotomy alone, intraocular pressures were well controlled. The mean intraocular pressures at the end of the first postoperative year were 15.6+/-3.0 mmHg in the 40 eyes after the combined procedure, and 17.8+/-3.1 mmHg in the 51 eyes after trabeculotomy alone (p=0.0001, unpaired t-test). Complications included Descemet's membrane detachment in 1 eye (3%) and 4 eyes (8%), and transient elevation of intraocular pressure to higher than 30 mmHg (IOP spike) in 6 eyes (15%) and 11 eyes (22%), respectively, after the combined procedure and trabeculotomy alone. CONCLUSION: Combined trabeculotomy and sinusotomy is a useful surgical modality for the treatment of primary open angle glaucoma to obtain lower intraocular pressure levels than those after trabeculotomy alone.

Female↗

Phenotypic characteristics and cyclin-dependent kinase inhibitors repression in hyperplastic epithelial pathology in idiopathic focal segmental glomerulosclerosis.

Hyperplastic glomerular epithelial lesion is an important determinant of the progression of idiopathic focal segmental glomerulosclerosis (FGS). The proliferation and differentiation of glomerular epithelial cells and parietal epithelial cells (PECs) are regulated differently by cyclin and cyclin-dependent kinase inhibitors (CKIs) during nephrogenesis. To access the cellular mechanism underlying epithelial hyperplasia in the development of FGS, the present study applied immunohistochemistry to 21 cases of FGS to demonstrate expression of cell-cycle molecules and phenotypic characterization in proliferative epithelial lesions in FGS. The materials included segmental sclerosis (18.1%), which was divided into monolayer epithelial lesions (64.6%) and cellular lesions (35.4%). All of the cellular lesions expressed cytokeratin, frequently with Ki-67 (82.4%) and less frequently with cyclin A (17.7%), but were invariably negative for podocyte markers (PHM-5 and synaptopodin) and CKIs (p27kip1 and p57kip2). Podocytes in nonsclerotic tuft in the same glomeruli with cellular lesions strongly expressed CKIs and podocyte markers. Moreover, electron microscopy showed that some large proliferating cells with prominent nucleoli have a broad cell base attached to Bowman's capsule. These cells have cilia and a junctional complex with neighboring hyperplastic cells, some of which directly cover the glomerular basement membrane. This suggests that cellular lesions are of PEC origin. Monolayer epithelial lesions also exclusively exhibited a PEC phenotype with reciprocal expression of podocyte markers and cytokeratin. In addition, CKIs are weakly expressed in monolayer epithelial lesions, suggesting a re-entry of cell-cycle quiescent. In conclusion, proliferation of PEC, sustained by repression of CKIs in nature and simultaneous activation of cyclin A, is the actual molecular background to the cellular lesions in FGS. Cellular lesions may result in monolayer epithelial lesions that retain the PEC phenotype and enter a common pathway to glomerulosclerosis.

Adolescent↗

Hydrogen peroxide augments eosinophil adhesion via beta2 integrin.

During eosinophil (EOS) accumulation at sites of allergic inflammation, an initial step is the binding of EOS to adhesion molecules expressed on vascular endothelial cells (EC). We have previously observed that adhesion of peripheral blood EOS to recombinant human vascular cell adhesion molecule-1 (rh-VCAM-1) stimulates the respiratory burst of EOS. Although the biological consequence of this activation remains to be elucidated, reactive oxygen species such as hydrogen peroxide (H2O2) may modify the adhesive property of EOS. In the present study, we examined whether H2O2 modifies the adhesive property of EOS. EOS were isolated from the peripheral blood of healthy subjects. Adhesion of the EOS to paraformaldehyde-fixed human umbilical vein EC (HUVEC), stimulated or not stimulated with tumour necrosis factor-alpha (TNF-alpha; 100 pM for 24 hr), was examined in the presence or absence of H2O2. H2O2 significantly enhanced adhesion of EOS to both resting and TNF-alpha-stimulated fixed HUVEC (P < 0.01, respectively). Such enhancing effects were inhibited by anti-beta2 integrin antibody or anti-CD11b antibody, but not by anti-CD11a or anti-alpha4 integrin antibody. H2O2 also enhanced EOS adhesion to rh-intracellular cell adhesion molecule-1 (ICAM-1) but not to rh-VCAM-1. Finally, H2O2 enhanced the expression of both CD11b and CD18 on EOS. These results indicate that H2O2 directly augments the adhesive property of EOS through beta2 integrin.

Adult↗

The expression of a novel natural killer inhibitory molecule, Cho-1, on the chorionic cytotrophoblast cells of successful pregnancy, but not of spontaneous abortion.

The regulatory mechanism of the recognition and cytotoxicity by natural killer (NK) cells in placental tissue remains unclarified. Previous reports indicated that monoclonal antibody Cho-1-defined molecule (Cho-1 molecule) may act as the negative regulator in the cytotoxicity by human NK cells. The Cho-1 molecule is composed of non-covalently associated cell surface molecules of approximately 200 kDa and 40 kDa. In the present study we analyzed the expression of this novel molecule in extravillous cytotrophoblast cells, which are presumed to be exposed to the cytotoxic action by maternal NK cells, from clinical cases of successful pregnancy and spontaneous abortion. By using monoclonal antibody Cho-1, our immunohistochemical data indicated that the Cho-1 molecule is clearly expressed in the cytotrophoblast cells of the early phase of successful pregnancy, but only weakly expressed in those from spontaneous abortion. The cytotrophoblast cells in the late phase (9-10 months) of pregnancy also expressed this molecule. Fluorescence-activated cell sorter analysis also showed that it is expressed on the cytotrophoblast cell surface of successful pregnancy but not on that of spontaneous abortion, suggesting that Cho-1 antigen may act as a negative regulator of the cytotoxicity by NK cells in successful pregnancy of the fetus.

Abortion, Spontaneous↗

Carcinosarcoma with rhabdoid features of the urinary bladder in a 2-year-old girl: possible histogenesis of stem cell origin.

A case of carcinosarcoma of the urinary bladder in a 2-year-old girl is reported. The tumor, measuring 34 x 20 x 18 mm, was located in the peri-trigone area of the urinary bladder with polypoid features. Histologic examination revealed transitional cell carcinoma at the tumor surface with downward invasion. Concurrently, a sarcomatous area was found beneath the carcinoma, with these two different malignant components sharing on apparent transition without distinct boundaries. Sarcomatous components included immature round cells focally showing rhabdoid features. No rhabdomyomatous component was observed. Immunohistochemistry disclosed vimentin and cytokeratin-double positive cells at the transposition between carcinoma and sarcomatous components. In addition, ultrastructural analysis revealed that the epithelial cells had a distinct junctional complex, and the sarcomatous cells occasionally had a meshwork of cytoplasmic intermediate filaments, indicating bidirectional cytodifferentiation to epithelial and mesenchymal elements. The extremely young age at which this case of carcinosarcoma occurred suggests that the tumor may be of mesodermal stem cell origin.

Carcinosarcoma↗

Corresponding distributions of increased endothelin-B receptor expression and increased endothelin-1 expression in the aorta of apolipoprotein E-deficient mice with advanced atherosclerosis.

Endothelin (ET)-1 causes proliferation of vascular smooth muscle cells (VSMC). Although it has been reported that stimulation of ET(B) receptors as well as ET(A) receptors promote proliferation of VSMC, the precise distribution of each receptor subtype in atherosclerotic vessels is unknown. Previous studies demonstrated that apolipoprotein E (apoE)-deficient mice have hypercholesterolaemia and develop severe atherosclerosis. To investigate the pathophysiological roles of vascular ET system in atherosclerosis, we examined preproET-1 messenger ribonucleic acid expression in the aorta of apoE-deficient mice, and performed immunohistochemical staining for ET-1 and each ET receptor subtype (ET(A) and ET(B) receptors) in the atherosclerotic lesions of these mice. The level of preproET-1 mRNA in the aorta was significantly higher in the apoE-deficient mice than in the control mice. Strong ET-1 staining was observed in the macrophage-foam cells, intimal and medial VSMC in the atherosclerotic lesions of the apoE-deficient mice. In addition, in the atherosclerotic lesions, strong ET(B) receptor staining was observed in the macrophage-foam cells, intimal and medial VSMC, which distribution corresponded closely to that of ET-1. ET(A) receptor staining was observed in the medial VSMC of both groups, but not in the macrophage-foam cells of the apoE-deficient mice. ET(A) receptor staining in the medial VSMC was stronger in the apoE-deficient mice than in the control mice. These results suggest that the vascular ET system, including ET-1 and ET receptors, is activated in the atherosclerotic lesions of apoE-deficient mice. Since the distribution of strong ET(B) receptor staining corresponded closely to that of ET-1, it is suggested that the ET system, mediated by ET(B) receptors, has an important role in the pathophysiology of the atherosclerotic lesions of apoE-deficient mice.

Animals↗

Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies.

BACKGROUND: Mature podocytes are growth-arrested because of the expression of cyclin-dependent kinase inhibitors. Under pathological conditions, podocytes may undergo mitosis, but not cell division. Exceptions to this rule are collapsing glomerulopathies (CGs), including HIV-associated nephropathy (HIVAN) and idiopathic CG, where podocytes undergo a dysregulation of their differentiated phenotype and proliferate. METHODS: To shed light on the mechanism underlying podocyte proliferation in CG, we analyzed the expression of the proliferation marker Ki-67, cyclins (A, D1), cyclin-dependent kinase inhibitors (p27, p57), and podocyte differentiation marker synaptopodin in eight cases of HIVAN and two cases of idiopathic CG. Normal fetal and adult kidneys served as controls. RESULTS: Both HIVAN and idiopathic CG showed a marked reduction in the expression of p27, p57, and cyclin D1 (absent in 69, 62, and 80% of all glomeruli, respectively). Cyclin A and Ki-67 were expressed in 11 and 29% of all glomeruli. Moreover, there was partial loss of synaptopodin and cyclin D1 expression in nonaffected glomeruli. CONCLUSIONS: The loss of p27 and p57 leading to expression of cyclin A may account for the activation of podocyte proliferation in CG. Furthermore, the loss of cyclin D1 from histologically normal glomeruli suggests a possible role of cyclin D1 in mediating the dysregulation of the podocyte cell cycle in CG. These novel findings offer insight into the molecular regulation of mature podocyte differentiation. Podocyte proliferation in CG provides evidence in support of a previously underestimated plasticity of mature podocytes.

AIDS-Associated Nephropathy↗

Induction of cytotoxic T lymphocytes from peripheral blood of human histocompatibility antigen (HLA)-A31(+) gastric cancer patients by in vitro stimulation with antigenic peptide of signet ring cell carcinoma.

Antigenic peptides have been used as a cancer vaccine in melanoma patients and have led to a drastic regression of metastatic tumors. However, few antigens have been identified in non-melanoma tumors. We recently purified a new natural antigenic peptide, designated F4. 2, by biochemical elution from a human gastric signet cell carcinoma cell line and showed that it is recognized by an autologous human histocompatibility antigen (HLA)-A31-restricted cytotoxic T lymphocyte (CTL) clone. Here we describe in vitro induction of F4. 2-specific CTLs from peripheral blood T lymphocytes of HLA-A31( +) gastric cancer patients. The T cells of seven HLA-A31( +) patients with gastric cancers were stimulated in vitro by F4.2-pulsed autologous dendritic cells which had been induced from peripheral blood of each patient by incubation in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-4. We tested the cytotoxicity of the T cells against F4.2-loaded C1R-A*31012 by a 6-h (51)Cr release assay after 3 stimulations with F4.2-pulsed dendritic cells. F4.2-specific cytotoxicity was detectable in the stimulated T cells from two of the seven HLA-A31( +) patients. Further, both F4.2-specific CTLs also lysed the gastric cancer cell line, HST-2, from which F4.2 was derived. These results suggest that F4.2 peptide may be useful as an HLA-A31-restricted peptide vaccine in certain patients with gastric cancer.

Adjuvants, Immunologic↗

[Three cases of tuberculosis complicating acute respiratory distress syndrome].

In this report, we describe three patients with pulmonary tuberculosis with acute respiratory failure with an extensive tuberculous consolidation in bilateral lung fields. Disseminated intravascular coagulation (DIC) was present in one patient and miliary tuberculosis in two patients. They all developed acute respiratory distress syndrome (ARDS), nessecitating management by mechanical ventilation with a combination therapy of antituberculous agents and methylprednisolone (m-PSL) pulse therapy. Only one patient survived in whom the PaO2/FiO2 ratio recovered rapidly after the initiation of therapy. Two patients whose systemic condition upon admission was critically ill eventually died of hepatic failure and bacterial pneumonia, even though ARDS and pulmonary tuberculosis were successfully treated. Prognosis of pulmonary tuberculosis complicating ARDS and DIC is poor, and these patients need systemic intensive treatment, in which m-PSL therapy may be beneficial.

Aged↗