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Biomedical subjects

A Ooshima

Publications and source records attributed to A Ooshima.

At least 37 records · Page 2Linked to original sources
PubMed1999

Immunohistochemical and ultrastructural analysis of dysplastic epithelium of human ocular surface: basement membrane and intermediate filament.

PURPOSE: The dysplastic corneal epithelium is characterized by the abnormal proliferation of epithelial cells. The phenotypes of these cells have not been elucidated. We investigated whether such epithelium expresses the phenotypes of corneal or conjunctival epithelial cells. METHODS: The corneas and conjunctivae from four normal subjects and from one patient with epithelial dysplasia of the central cornea were immunostained for IV and VII collagens and for cytokeratins. Monoclonal antibodies against collagen IV reacted to the [alpha1(IV)]2alpha2(IV) or alpha5(IV) molecule. Anti-cytokeratin antibodies were used to define epithelial cell types. The ultrastructure of the basement membrane (BM) of each specimen also was examined. RESULTS: Type VII collagen immunoreactivity was detected in all the specimens of epithelial BM. The anti-collagen IV [alpha1(IV)]2alpha2(IV) antibody labeled the conjunctival BMs, not the BMs of the corneal epithelia, of each subject. The normal corneal epithelial BM, not the BM of the conjunctival or dysplastic corneal epithelium, was immunolabeled with anti-alpha5(IV) antibody. The pattern of cytokeratin expression in the corneal epithelial dysplasia resembled that seen in the normal conjunctivae. Small breaks in the BM of dysplastic corneal epithelium were ultrastructurally revealed. The number of hemidesmosomes in the dysplastic corneal epithelium was decreased as compared with that in the normal BM. CONCLUSION: The composition of collagen types within the BM and the cellular phenotype of the dysplastic epithelium in the cornea resembled those of conjunctival epithelium, not of the cornea.

Adult↗
PubMed1998

Immunolocalization of prolyl 4-hydroxylase subunits, alpha-smooth muscle actin, and extracellular matrix components in human lens capsules with lens implants.

Lens capsules become fibrotic after the extraction of a cataract. To understand this phenomenon, we evaluated the immunolocalization of prolyl 4-hydroxylase (an enzyme involved in procollagen hydroxylation), and extracellular matrix components and cytoskeletal components in a normal human lens capsule and in others with intraocular lenses. Lens capsules containing intraocular lenses were removed from a patient with proliferative vitreoretinopathy and three with proliferative diabetic retinopathy during vitreous surgery. Two circular sections of the anterior capsules with lens epithelial cells were obtained by anterior capsulotomy during cataract surgery. In addition, a lens capsular bag was obtained immediately after phacoemulsification. The lens capsules were processed for light microscopic immunohistochemical detection of the alpha and beta subunits of prolyl 4-hydroxylase, extracellular matrix components (including collagen types, laminin and cellular fibronectin) or cytoskeletal components (such as cytokeratin, vimentin and alpha-smooth muscle actin). Monolayer lens epithelial cells were seen on the inner surface of the normal anterior capsules. Each intraocular lens was found to be fixed in the capsular bag. Light microscopic immunohistochemistry showed that these proliferating cells expressed vimentin and alpha-smooth muscle actin; in contrast, quiescent lens epithelial cells did not stain for alpha-smooth muscle actin. Marked immunostaining for subunits of prolyl 4-hydroxylase was detected in lens epithelial cells proliferating on the capsules, while no or only faint prolyl 4-hydroxylase immunoreactivity was detected in quiescent lens epithelial cells immediately after phacoemulsification. Collagen types I, III and VI and cellular fibronectin were observed diffusely in accumulated connective tissue on a capsule with an intraocular lens. Type IV collagen immunoreactivity was seen both in the capsules and in the connective tissue accumulation on the capsules. Collagen V and laminin were detected in association with cellular proliferation. Collagen VII and VIII and laminin 5 were not seen. We concluded that during wound healing of the lens capsule after cataract extraction, the lens epithelial cells that proliferate on the inner surface of the capsule transform it into a myofibroblastic phenotype, expressing prolyl 4-hydroxylase and alpha-smooth muscle actin. These proliferating cells are involved in the production of collagen on the lens capsule. This results in a postoperative fibrotic process and contraction of the lens capsule.

Actins↗
PubMed1998

Immunohistochemical evaluation of cellular deposits on posterior chamber intraocular lenses.

PURPOSE: We used immunohistochemistry to characterize cellular and proteinaceous deposits on the surfaces of explanted posterior chamber intraocular lenses (PC-IOLs). METHODS: A total of 30 PC-IOLs were immunostained for the alpha- or beta-subunits of prolyl 4-hydroxylase, which is involved in collagen biosynthesis; cellular fibronectin; alpha B crystalline; and CD68, a macrophage marker, to characterize the cellular deposits that adhere to the IOL surfaces and to evaluate the distribution of cells involved in the deposition of extracellular matrix on IOLs. RESULTS: Cellular or proteinaceous deposits were observed on all 30 PC-IOLs. Cells that showed positive staining for alpha B crystallin were classified as lens epithelial cells; CD68-positive cells were considered to be of macrophagic origin. Positivity for cellular fibronectin, including the macrophages and related cells, appeared to be responsible for the accumulation of fibronectin on the surfaces of PC-IOLs. Prolyl 4-hydroxylase-positive cells were involved in the deposition of collagen on PC-IOLs. CONCLUSION: Immunohistochemical study revealed that macrophages, foreign-body giant cells, and lens epithelial cells adhered to explanted PC-IOLs. Such adherent cells are responsible for the deposition of extracellular matrix on the surfaces of PC-IOLs and may regulate the assembly of the extracellular matrix, influencing the biocompatibility of PC-IOLs.

Adult↗
PubMed1998

Immunolocalization of prolyl 4-hydroxylase in rabbit lens epithelial cells.

PURPOSE: To localize the enzyme prolyl 4-hydroxylase in the crystalline lens and determine the ability of lens epithelial cells (LECs) to synthesize procollagen. SETTING: Research laboratory, Department of Ophthalmology, Wakayama Medical College, Wakayama, Japan. METHODS: Phacoemulsification and aspiration of the crystalline lens followed by implantation of a poly(methyl methacrylate) intraocular lens (IOL) were performed in 1 eye each of 6 albino rabbits; the eye was enucleated 1 or 2 months later. Crystalline lenses were also extracted from the eyes of 2 rabbits. These samples were processed for immunohistochemical detection of the alpha- and beta-subunits of prolyl 4-hydroxylase. RESULTS: A monolayer of LECs was detected on the inner surface of the intact anterior capsule. Antibodies directed against both subunits of prolyl 4-hydroxylase reacted strongly to LECs proliferating on capsules with IOLs, whereas little or no reaction was observed in quiescent LECs or in the regenerated lenticular structure. CONCLUSION: The presence of prolyl 4-hydroxylase in LECs proliferating on the inner surface of the lens capsule suggests that these cells are involved in the production of procollagen and fibrosis during capsular injury and repair. Suppression of prolyl 4-hydroxylase activity may prevent the capsule opacification that results from cataract removal and IOL implantation.

Animals↗
PubMed1998

Immunolocalization of hyaluronan and CD44 in quiescent and proliferating human lens epithelial cells.

PURPOSE: To investigate the role of hyaluronan and its receptor CD44 in capsular repair, their localization in opacified human posterior capsules and in lens epithelial cells (LECs) was assayed. SETTING: Research laboratory, Department of Ophthalmology, Wakayama Medical College, Japan. METHODS: In 8 patients, circular sections of the anterior capsules obtained during cataract surgery, the extracted crystalline lens, and the opacified lens capsules resulting from intraocular lens implantation were examined immunohistochemically to detect hyaluronan or CD44. RESULTS: Both hyaluronan and CD44 were found in the extracellular matrix that accumulated on the inner surface of the capsular bags. In contrast, LECs exhibited immunoreactivity to CD44 but not to hyaluronan. CONCLUSIONS: The cell surface antigen CD44 was expressed ubiquitously by LECs. Expression of its ligand hyaluronan by proliferating LECs suggests that this glycosaminoglycan may be important in the development of posterior capsule opacification.

Adult↗
PubMed1998

Degenerated lens epithelial cells in rabbit and human eyes after intraocular lens implantation.

PURPOSE: To evaluate the role of lens epithelial cells (LECs) in posterior capsule opacification. SETTING: Departments of Ophthalmology and Pathology, Wakayama Medical College, Department of Anatomy, Kansai Shinkyu College, and Department of Ophthalmology, Kobe Kaisei Hospital, Japan. METHODS: We examined the presence of degenerated LECs on the capsules of the eyes of rabbits and a patient after intraocular lens (IOL) implantation. Phacoextraction of a crystalline lens and IOL implantation were done in 5 albino rabbits under general anesthesia. The animals were killed after 2 months. Lens capsules were removed and fixed. During vitreous surgery, a lens capsule with an IOL was removed from a patient. Ultrathin sections of specimens were studied by transmission electron microscopy. RESULTS: Presumed LECs proliferated between the posterior capsule and the IOL in association with collagenous matrix. Debris from the degenerated cells and destroyed intracellular organelles was also seen. CONCLUSION: Lens epithelial cells proliferating on the posterior capsule cannot survive indefinitely.

Aged↗
PubMed1998

Recombinant TIMP-1 and -2 enhance the proliferation of rabbit corneal epithelial cells in vitro and the spreading of rabbit corneal epithelium in situ.

PURPOSE: The repair of the corneal epithelium is modulated by matrix metalloproteinases. The present study examined the effects of recombinant (r-) tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and -2) on the proliferation of cultured epithelial cells from rabbit cornea, and on the spreading of a sheet of squamous epithelium of rabbit cornea placed in an organ culture system. METHODS: DNA synthesis of the cells, with or without r-TIMPs, was determined by an immunoassay for BrdU incorporation. Cell proliferation was assayed by measuring MTT mitochondrial activity. Epithelial spreading was evaluated by culturing small corneal blocks for 24 h in the presence or absence of each agent. Cryosections were prepared and the epithelial growth on the cut stromal surface was measured. RESULTS: Each agent, r-TIMP-1 (at 50 and 100 ng/ml) and r-TIMP-2 (at 50 ng/ml) significantly enhanced the DNA synthesis and MTT activity of the corneal epithelial cells in vitro. Relative to the untreated control cells, DNA synthesis was increased 2.4-fold by r-TIMP-1 and 2.3-fold by r-TIMP-2. r-TIMP-1 (at 100 and 200 ng/ml) and r-TIMP-2 (at 10 and 50 ng/ml) each significantly enhanced the spreading of the corneal epithelium. Relative to the untreated control tissue, spreading of the epithelial sheet was increased 1.7-fold by r-TIMP-1 and 1.4-fold by r-TIMP-2. Higher concentrations of r-TIMP-1 and r-TIMP-2 did not further enhance either the DNA synthesis of the cultured cells or the spreading of the epithelium. CONCLUSIONS: Exogenous TIMPs enhanced the spreading of the corneal epithelium and proliferation of cultured corneal epithelial cells. Findings suggest that endogenous TIMPs may influence the healing of corneal epithelium in vivo.

Animals↗
PubMed1998

Ultrastructural examination of corneal epithelium of spontaneously obese, hyperglycemic rats.

PURPOSE: Otsuka Long-Evans Tokushima fatty (OLETF) rats spontaneously become obese and hyperglycemic with age. We investigated whether the development of hyperglycemia would alter the ultrastructure of the corneal epithelium. METHODS: Scanning and transmission electron microscopy (SEM and TEM) were used to examine the morphology of corneal epithelial cells. Fourteen OLETF rats were evaluated, and 9 Long-Evans Tokushima Otsuka (LETO) rats were used as control. Non-hyperglycemic OLETF rats served as controls. RESULTS: SEM showed exfoliative changes in the surface of the central corneal epithelium of the hyperglycemic OLETF rats. These superficial epithelial cells were irregular in shape as compared to polygonal shapes of those of LETO and non-hyperglycemic OLETF rats. The mean anterior surface area of individual superficial epithelial cells was significantly smaller in the hyperglycemic OLETF than that of the LETO or the non-hyperglycemic OLETF rats. Central protrusion(s) could be found in some of the superficial cells of all rats examined, although this phenomenon was more common in the hyperglycemic rats than in the non-hyperglycemic rats. TEM revealed that there were numerous cytoplasmic vacuoles and wide intercellular spaces in the central corneal epithelium of the hyperglycemic OLETF rats, but not in the non-hyperglycemic rats. CONCLUSIONS: The development of spontaneous hyperglycemia in OLETF rats alters the ultrastructure of the corneal epithelium. The alterations included abnormalities of the corneal epithelial surface observed by SEM and the presence of intracellular vacuoles and enlarged intercellular spaces detected by TEM.

Animals↗
PubMed1998

OPC-15161 suppresses the proliferation of Tenon's capsule fibroblasts and the production of type I collagen and fibronectin stimulated by TGF-beta1 in vitro.

PURPOSE: We investigated the effects of OPC-15161 on the growth of cultured human Tenon's capsule fibroblasts (TCFs), as well as on the production of type I procollagen, fibronectin, and laminin. These effects were examined in the presence or absence of TGF-beta1. METHODS: Cell proliferation was assayed by counting cell number and assay of DNA synthesis. Cytotoxicity was determined by the MTT method. Matrix components were assayed by enzyme immunoassay of material in the medium and in the cell lysate with or without OPC-15161. Total protein content was determined. Cellular ultrastructure was also evaluated. RESULTS: Treatment with OPC-15161 (up to 100.0 microg ml(-1)) significantly reduced the proliferation and DNA synthesis of TCFs. No significant decrease in MTT values was observed in confluent TCF cultures with OPC-15161 (up to 100.0 microg ml(-1)). TGF-beta1 enhanced the TCF production of procollagen I and fibronectin. OPC-15161 significantly decreased the procollagen I content in both the medium, in the cell lysate of TGF-beta1-stimulated cells, and fibronectin content in the lysate. OPC-15161 did not affect the laminin or total protein content, either with or without TGF-beta1. No ultrastructural evidence of cytotoxicity was observed. CONCLUSIONS: OPC-15161 inhibited the proliferation of TCFs, and reduced their production of procollagen I and fibronectin in the presence of TGF-beta1 without evidence of cytotoxicity. OPC-15161 may be useful in inhibiting the excessive fibrosis produced in the wound in response to filtering surgery.

Adult↗
PubMed1998

[Changes in QOL in patients with brain tumors measured by mood changes during and after treatment].

UNLABELLED: Patients with brain tumors are exposed to severe stress which may have an influence on their quality of life (QOL). To measure QOL in those patients, we measure their mood state during and after the treatments. MATERIALS: 16 patients who were admitted to our department for treatment of brain tumors, were included in the study. The tumors included 5 gliomas, 6 meningiomas and others. They were 7 males and 9 females, and age distributed from 19 to 74 years old. All patients presented more than 90% of the Karnofsky performance score (KPS) on discharge, so they were expected to return to their previous social life. METHOD: The self-answering tests were performed on admission (Pre), on discharge (Post 1), and at more than 5 months after the discharge (Post 2). The tests included an original questionnaire asking consent to admission and treatment, and concerning the feeling of disability to cope with conditions of living, Cornell Medical Index (CMI) which measured the neurosis, and Profile of mood state (POMS) which measured the 6 subscales of patients mood states including tension-anxiety (TA), depression (D), anger-hostility (AH), vigor (V), fatigue (F), and confusion (C). RESULTS: The questionnaire showed that the patients feel satisfied with having consented to the treatment. The feeling of disability to cope with living became stronger in Post 2 than in Pre. CMI showed a borderline of neurosis in three patients on admission, and in four patients in Post 2. Only the TA of POMS subscale improved significantly in Post 2. However, other subscales were unchanged. It is characteristic that all of the subscales of POMS showed less disturbance on discharge compared with that on admission, but, they returned to the Prelevel after they returned to social life. CONCLUSIONS: Patients with brain tumors have satisfactory consent to the treatment, however, they feel disability to cope with social life. On discharge, they showed a better mood state compared to that on admission, but the mood state turned for the worse again during the follow-up period. It is evident that patients with brain tumors are exposed to severe stress even after the completion of the treatment. The results necessitate our taking patients' mental health into consideration for our treatment protocol.

Adult↗
PubMed1997

Deposition of extracellular matrix on intraocular lenses in rabbits: an immunohistochemical and transmission electron microscopic study.

BACKGROUND: We examined by transmission electron microscopy the accumulation of extracellular matrix on intraocular lenses (IOLs) implanted experimentally into rabbit eyes, and evaluated the immunolocalization of such extracellular matrix components as collagen types I, III, and IV, and cellular fibronectin on these IOLs. METHODS: Phacoemulsification and aspiration of the crystalline lens were performed and an IOL was implanted into the capsular bag of each eye of each of 16 adult albino rabbits under general anesthesia. After up to 12 weeks, the animals were killed and the IOLs were removed. Specimens were processed for transmission electron microscopy or for immunohistochemical detection collagen types I, III, and IV, and cellular fibronectin. RESULTS: Transmission electron microscopy revealed an accumulation of extracellular matrix between the residual anterior lens capsule and the surface of an IOL explanted 4 weeks after surgery. Collagen types I and III and cellular fibronectin were detected immunohistochemically on each IOL in association with cellular deposits. Type IV collagen-immunoreactive matrix was not seen on the optic portion, but was detected on the haptic portion of one of six IOLs examined. CONCLUSION: Each component of the extracellular matrix that is deposited on the IOL supplies scaffolding for the adhesion and proliferation of cells. These components are considered to be produced by cells such as lens epithelial cells and macrophages that adhere to the IOL surface.

Animals↗
PubMed1997

Deposition of extracellular matrix on silicone intraocular lens implants in rabbits.

PURPOSE: To examine the deposition of extracellular matrix on silicone intraocular lenses (IOLs) implanted experimentally into rabbit eyes by electron microscopy and to determine the immunolocalization of extracellular matrix components, including collagen types and cellular fibronectin, on these IOLs. METHODS: We performed phacoemulsification and aspiration of the crystalline lens and implanted a foldable silicone IOL in the capsular bag of one eye of each of 26 adult albino rabbits under general anesthesia. After 8 weeks the animals were killed and the eyes were enucleated. The silicone IOLs were processed for electron microscopy and for immunohistochemical detection of collagen types I, III, and IV and cellular fibronectin. RESULTS: Electron microscopy revealed deposition of a presumed cell matrix complex on the optic portion of all silicone IOLs, as well as the adhesion of presumed macrophages and foreign-body giant cells. Cellular deposits showed immunoreactivity for cellular fibronectin. Fibrous or membranous deposits exhibited immunoreactivity for cellular fibronectin and collagen types I and III. A few type IV collagen-immunoreactive deposits were also seen. CONCLUSION: Deposits of extracellular matrix components were observed on silicone IOLs. These deposits may form the scaffolding for the adhesion and proliferation of cells. These matrix components appeared to be the products of cells adhering to the surfaces of IOLs, including lens epithelial cells, macrophages and foreign-body giant cells, indicating that the process of granulation was incomplete.

Animals↗
PubMed1997

Cell proliferation on the outer anterior capsule surface after extracapsular lens extraction in rabbits.

PURPOSE: To use light microscopy to evaluate the presence and distribution of cells that proliferate on the outer surface of the anterior capsule after experimental lens extraction in rabbit eyes. SETTING: Research Laboratory, Department of Ophthalmology, Wakayama Medical College, Wakayama, Japan. METHODS: Extracapsular lens extraction, with or without implantation of a poly(methyl methacrylate) intraocular lens, was performed in 10 adult albino rabbits under general anesthesia. Animals were killed 1 month postoperatively. Each eye was embedded in paraffin and examined by light microscopy. RESULTS: A capsular bag composed of the anterior and posterior capsules was observed. Mononuclear cells, presumed to be lens epithelial cells (LECs), had proliferated in the space between the capsules as well as on the outer surface of the anterior capsules, in association with an accumulation of extracellular matrix. CONCLUSION: After lens extraction, LECs migrated to and proliferated on the anterior surface of the anterior capsule.

Animals↗
PubMed1997

Light and scanning electron microscopy of rabbit lens capsules with intraocular lenses.

PURPOSE: To examine postoperative changes in the lens capsules of rabbit eyes after phacoemulsification and aspiration of the crystalline lens and implantation of posterior chamber intraocular lenses (IOLs) using light and scanning electron microscopy. SETTING: Research Laboratory, Department of Ophthalmology, Wakayama Medical College, Japan. METHODS: The crystalline lens was emulsified and aspirated and an IOL implanted in the capsular bag or ciliary sulcus of each eye in adult albino rabbits under general anesthesia. Animals were killed after 4 weeks, and the lens capsules were removed. The specimens were observed under phase-contrast microscopy and processed for light and scanning electron microscopy. RESULTS: Phase-contrast microscopy revealed presumed lens epithelial cells (LECs) on the central posterior capsules in association with regenerating lenticular fibers and Elschnig pearls in the peripheral capsules. Scanning electron microscopy showed the accumulation of fibrous extracellular matrix on the surface of the posterior capsule in eyes in which the IOL was implanted in the ciliary sulcus. Deposition of packed material attached to the surface of IOLs and of Soemmering's ring were observed in eyes with in-the-bag IOL fixation. At a higher magnification, a parallel arrangement of lenticular fibers was seen in the regenerated lens structure on posterior capsules. An identical structure was observed under light microscopy. Outgrowth of presumed LECs from residual anterior lens capsules and adhesion of macrophages and giant cells were observed on the IOL surface. CONCLUSION: Two types of postoperative changes were observed in lens capsules after implantation of IOLs: accumulation of fibrous extracellular matrix and newly formed lenticular fibers. These changes are attributed to the proliferation of LECs and can induce posterior capsule opacification after IOL implantation.

Animals↗
PubMed1997

Increased laminin-1 expression in hydatidiform mole.

To investigate the aetiology of hydatidiform mole, laminin-1 expression was determined in human villous tissues obtained from normal pregnancies (n = 17) and complete hydatidiform moles (n = 10). Indirect immunofluorescent staining was performed to detect laminin-1, and Northern blot analysis was performed to assess expression of laminin mRNA. Serum concentrations of laminin P-1 were also measured. Immunohistochemical analysis revealed stronger staining of the trophoblastic basement membrane in hydatidiform mole than in normal pregnancy. Northern blot analysis revealed that villous expression of laminin mRNA was significantly increased in hydatidiform mole compared with normal pregnancy (P < 0.05). The serum laminin P-1 concentration was also significantly higher in those patients with hydatidiform mole than in normal pregnancy (P < 0.05). These results suggest that laminin-1 might play an important role in determining the pathophysiology and structure of hydatidiform mole. In addition, measurement of serum laminin P-1 in combination with human chorionic gonadotrophin might be useful in the diagnosis of hydatidiform mole, to evaluate the prognosis, and to detect the presence of metastatic or recurrent disease.

Adult↗
PubMed1997

Increase in the relative level of type V collagen in the placentae of patients with pre-eclampsia.

To obtain some insight into the extracellular matrix in the human placenta, we investigated the composition of collagens purified from the placentae of patients with pre-eclampsia and compared it with normal placentae. Collagen was extracted from the placentae of both normal and pre-eclampsia pregnancies during the third trimester. The relative amounts of various collagens were evaluated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The ratio of the intensity of the band corresponding to the alpha 1 (III) chain with that of the alpha 1 (I) chain in placentae of pre-eclampsia was significantly lower than in normal placentae (P < 0.05). In contrast, the ratio of the intensity of the band corresponding to the alpha 1 (V) chain with that of the alpha 1 (I) chain in placentae of pre-eclampsia was significantly higher than in normal placentae (P < 0.05). The results suggest that an increased level of type V collagen relative to type I collagen in the placentae of pre-eclampsia might be closely associated with the disturbance to trophoblastic cell functions and the supply of nutrients to the developing fetus necessary for the maintenance of pregnancy.

Adult↗
PubMed1997

Increased serum concentrations of type IV collagen and laminin associated with granulosa cell tumour of the ovary.

A 65 year old woman presented with an ovarian mass. Ultrasonography and computed tomography findings, and an increased serum oestrogen concentration were suggestive of an oestrogen producing ovarian tumour. The tumour was removed surgically and weighed 460 g. The pathological diagnosis was adult-type granulosa cell tumour. Strong immunohistochemical staining specific for type IV collagen and laminin was observed, and these components were localised to the pericellular region of the granulosa cells. The serum concentrations of these basement membrane components (measured by radioimmunoassay) were very high before surgery, but decreased rapidly thereafter. Serial measurement of type IV collagen and laminin, in conjunction with other tumour markers and oestrogen concentrations, might be helpful in evaluating prognosis of ovarian granulosa cell tumours, in detecting metastatic or recurrent lesions and in monitoring response to treatment.

Aged↗