Biomedical subjects

T Okamura

Publications and source records attributed to T Okamura.

At least 109 records · Page 6Linked to original sources

PubMed2000

Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart.

OBJECTIVE: Caspase family proteases are recognized as key mediators of apoptosis. However, the role of caspases in the ischemia-reperfused heart remains uncertain. We evaluated the effect of caspase inhibitors on myocardial infarct size and the myocyte DNA fragmentation in the ischemia-reperfused rat hearts. METHODS: Three groups of Sprague-Dawley rats (n = 7, each) were subjected to 30 min of ischemia followed by 6 h of reperfusion. One of the following drugs: (1) YVAD-aldehyde, a caspase-1-like protease inhibitor (3.5 mg/kg; YVAD), (2) DEVD-aldehyde, a caspase-3-like protease inhibitor (3.5 mg/kg, DEVD), (3) vehicle (140 microliters/kg) was administered intravenously 5 min prior to the ischemia in each group. Myocardial infarct size was defined by triphenyltetrazolium chloride (TTC) staining. Immunohistochemical staining by in situ nick end labeling (TUNEL) of cardiomyocytes and DNA electrophoresis were used for detecting DNA fragmentation. Ultrastructural analysis was done by electron microscopy. The caspase activity was measured in the myocardium of both groups. RESULTS: The percentage of TUNEL-positive myocyte nuclei (%AP) was quantified by microscopy. A ladder pattern was detected by electrophoresis of DNA from the risk area and TUNEL-positive myocytes were seen in the risk area. The %AP was significantly reduced from 20 +/- 1% to 12 +/- 3% by YVAD and to 10 +/- 3% by DEVD (both P < 0.01). However, caspase inhibitors did not significantly change the infarct size. Electronmicrograph showed similar salcolemmal and mitochondrial damage in both group. The caspase activity was blocked by DEVD at 4 h after reperfusion. CONCLUSION: Myocyte DNA fragmentation and caspase activation was inhibited by caspase inhibitors without reduction of the infarct size in ischemia-reperfused rat hearts.

Analysis of Variance↗

PubMed2000

Presence of pituitary adenylate cyclase-activating polypeptide (PACAP) and its relaxant activity in the rectum of a teleost, the stargazer, Uranoscopus japonicus.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide and a member of the secretin/glucagon superfamily of peptides that include vasoactive intestinal polypeptide. PACAP is not only present in the central nervous system but also in peripheral organs, such as the gastrointestinal tract, gonads and adrenal glands, and plays various roles in mammals. Recently, we isolated and characterized PACAP, which is very similar to PACAP of mammalian origin, from the brain of a teleost, the stargazer, Uranoscopus japonicus. In the present study, the expression of PACAP mRNA was detected in the stargazer rectum using the reverse transcriptase/polymerase chain reaction (RT-PCR) method. The distribution of PACAP-like immunoreactivity in the rectum was also examined immunohistochemically, using an antiserum raised against PACAP 27, and PACAP-like immunoreactive neuronal cell bodies and fibers were found in the myenteric plexuses and the smooth muscle layers of the rectum. The present study also investigated the relaxant activity of synthesized homologous PACAP on rectal contraction. Stargazer PACAP, like that of mammalian origin, inhibited contractions stimulated by acetylcholine or potassium chloride. PACAP-induced inhibition was not affected by preincubation with atropine, propranolol, or phentolamine. These results suggest that PACAP may act directly as an inhibitory neuropeptide in the stargazer rectum.

Acetylcholine↗

PubMed2000

Cerebral vasodilatation induced by stimulation of the pterygopalatine ganglion and greater petrosal nerve in anesthetized monkeys.

Although brain cell viability depends largely on cerebral circulation, mechanisms of blood flow control, such as autoregulation, or of the pathogenesis of functionally impaired blood supply to brain regions, such as in cerebral vasospasm after subarachnoid hemorrhage, have not been clearly defined. Our recent studies support the hypothesis that nitric oxide, released from nitrergic nerves, plays a crucial role as a neurotransmitter in vasodilating cerebral arteries from primate and subprimate mammals. In the present study, we demonstrated, by using arterial angiography, that electrical stimulation of the pterygopalatine ganglion produced vasodilatation of ipsilateral cerebral arteries of anesthetized Japanese monkeys. The response was abolished by intravenous injections of N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor. Denervation of the ganglion elicited cerebral vasoconstriction, indicating that vasodilator nerves from the vasomotor center were tonically active. Stimulation of the greater petrosal nerve, upstream of the pterygopalatine ganglion, also elicited cerebral vasodilatation, which was abolished by treatment with the nitric oxide synthase inhibitor and with hexamethonium, indicating that the nerve is in connection via synapses with the nitrergic nerve innervating cerebral arteries. Endogenous nitric oxide released from the nerve may contribute to the maintenance of blood flow in major cerebral arteries necessary to supply blood to the different brain regions. Without this influence, cerebral arteries might be constricted to the extent that blood flow is impeded. This is the first direct evidence indicating an important role of nitric oxide liberated by pre- and postganglionic nerve stimulation in the control of cerebral arterial tone in primates.

Animals↗

PubMed2000

Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function.

Janus kinases (Jaks) play an important role in signal transduction via cytokine receptors. Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo. Tyk2-deficient mice show no overt developmental abnormalities; however, they display a lack of responsiveness to a small amount of IFNalpha, although a high concentration of IFNalpha can fully transduce its signal even in the absence of tyk2. Furthermore, IL-12-induced T cell function is defective in these mice. In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro. These observations demonstrate that tyk2 plays only a restricted role in mediating IFNalpha-dependent signaling while being required in mediating IL-12-dependent biological responses.

Animals↗

PubMed2000

A fatal case of hyperthermia due to tricyclic antidepressant intoxication.

We report here an autopsy case of a 49-year-old woman with depression who died of hyperthermia, probably due to amitriptyline intoxication. She was found dead in bed with several empty amitriptyline pill containers. Her rectal temperature was 41.5 degrees C approximately 3 hours after death. Plasma levels of amitriptyline and nortriptyline were 0.51 and 0.74 mg/l, respectively. Possible mechanisms of fatal hyperthermia are discussed.

Journal Article↗

PubMed2000

Development of mushrooms for thrombosis prevention by protoplast fusion.

With thrombosis a major cause of death in Japan and the Western world, thrombin-inhibitory agents that constrain the formation of fibrin are sought. We screened for basidiomycetes showing anti-thrombin activity and isolated Laetiporus sulphureus. However, it was difficult to cultivate and its form was not satisfactory. We therefore used protoplast fusion between L. sulphureus and the commonly cultivated basidiomycete Hypsizygus marmoreaus to obtain cultivable basidiomycetes that produced an anti-thrombin substance. For the protoplast fusion of L. sulphureus and H. marmoreaus, the protoplast concentration, alternating electric field intensity, dielectrophoresis duration, and field pulse intensity used were of 1 x 10(7) protoplasts/ml, 100 V/cm.1 MHz, 60 s, and 8 kV/cm, respectively. The number of regenerated colonies obtained was 4961, from which 43 strains were selected for electrophoretic analysis. Four of the fusants were found to have a band from each parent in isozyme patterns obtained using their crude extract. The fruiting bodies of the fusants were very similar to those of H. marmoreaus. Crude extract from each of the fusants and from L. sulphureus showed anti-coagulative activity in terms of the thrombin clotting time. We thus obtained improved basidiomycetes that produce an anti-thrombin substance, are easily cultivated, and whose form resembles H. marmoreaus, a commonly used culinary mushroom.

Journal Article↗

PubMed2000

Molecular cloning and characterization of mouse testis poly(A) binding protein II encoded by the Pabp3 gene, which transcomplements meiotic mutant sme2 of S. pombe.

A cDNA clone from a mouse testis cDNA library was isolated by the transcomplementation method using a Schizosaccharomyces pombe meiotic mutant (sme2) that is defective in meiosis I. The cDNA clone isolated has an open reading frame encoding 302 amino acids constituting a protein with a strong similarity to mouse poly(A) binding protein II (mPABII) and bovine poly(A) binding protein II (PABII). PABII is known to bind to the growing poly(A) tail and stimulates poly(A) polymerase, which catalyzes the polymerization of the mRNA poly(A) tail. Northern blot analysis of the cDNA clone identified as mPABII revealed a single transcript of 1.2 kb. This was detectable exclusively in adult testis. Immunohistochemical analysis using a polyclonal antibody demonstrated that mPABII protein was expressed in the nucleus at specific stages from late pachytene spermatocytes to round spermatids. Genetic mapping showed the Pabp3 gene encoding mPABII to be located near position 19.5 on mouse chromosome 14. These results suggest that mPABII might be involved in specific spermatogenetic cell differentiation.

Animals↗

PubMed2000

Expression of H type 1 antigen of ABO histo-blood group in normal colon and aberrant expressions of H type 2 and H type 3/4 antigens in colon cancer.

We have immunohistochemically examined the distribution of the H antigens of type 1, type 2 and type 3/4 chains of the ABO(H) histo-blood group system in human normal colon and in colon cancer using three monoclonal antibodies specific for each of the H type 1/2, H type 2, and the H type 3/4 chain. We unexpectedly found that mucosa of the normal colon from secretors but not that from nonsecretors expressed only H type 1 and did not express H type 2 or H type 3/4. The H type 1 was expressed in goblet cells. Positive goblet cells expressing H type 1 were decreased in number progressively from the proximal colon to the rectum. In tumors, 4 (57%) of 7 cancer tissues of the proximal colon from secretors expressed no H type 1, whereas all 8 cancer tissues of the distal colon from secretors expressed H type 1. The aberrant expressions of H type 2 and H type 3/4 (47 and 67%, respectively) were found in cancer tissues from both the proximal and the distal colon. Tumors from nonsecretors did not express any H antigens. Our results suggested that the expression of H type 1 in the normal colon and the aberrant expressions of H type 2 and H type 3/4 in colon cancer tissues were regulated by FUT2-encoded Se type alpha(1,2)fucosyltransferase. However, UEA-I-positive substance(s) rather than H type 2 were uniquely expressed throughout the normal colon and in colon cancers from both secretors and nonsecretors.

ABO Blood-Group System↗

PubMed2000

Acquired Pelger-Huët anomaly in association with concomitant tacrolimus and fluconazole therapy following allogeneic bone marrow transplantation.

A 38-year-old Japanese woman with severe aplastic anemia received an allogeneic bone marrow transplant from her serologically HLA-identical father. Cyclosporine and methotrexate were administered to prevent graft-versus-host disease (GVHD). However, grade III acute GVHD developed on day 44, which was successfully treated with methylprednisolone and tacrolimus. Fluconazole therapy was started for oral candidiasis on day 112, but she complained of headache soon after. In addition to glycosuria and increased serum creatinine levels, Pelger-Huët anomaly of granulocytes was found in her blood, which disappeared after discontinuation of tacrolimus. Transient occurrence of Pelger-Huët cells may be associated with tacrolimus toxicity due to drug interaction with fluconazole.

Adult↗

PubMed2000

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro.

Precursor cells that migrate into the thymus are still multipotent. Therefore, thymic epithelial cells (TECs) may provide microenvironments not only for T-cell development, but also for maintenance of multipotent precursor cells until they undergo T-cell commitment. In the present study, we performed long-term cultures of CD34+ bone-marrow (BM) cells on TEC lines that were derived from cortical epithelial cells of post-natal thymus, to investigate whether human TECs could maintain long-term nonlymphoid haematopoiesis. Haematopoietic cells maintained in direct contact with established TEC lines were able to generate clonogenic progeny to both myeloid and erythroid cells for periods in excess of 5 weeks. Their abilities to support colony-forming units of granulocytes-macrophages (CFU-GM) and burst-forming units of erythroids (BFU-E) were almost equal to those of BM stromal cells. We observed similar results by using cloned TEC lines derived by limiting dilution, as well as those by using parental TEC lines. Colony-forming activities were maintained even when haematopoietic progenitor cells were physically separated from TEC lines and cultured on microporous membrane. These observations indicate that haematopoiesis maintained in TEC-contact long-term cultures may depend on soluble factors produced by TEC lines. Our results suggest that thymic cortical epithelial cells have the ability to support not only the differentiation of haematopoietic cells, but also long-term survival of clonogenic myeloid/erythroid progenitor cells.

Antigens, CD34↗

PubMed2000

Positron emission tomographic imaging of acoustic neuromas.

Positron emission tomography (PET) examination with both [11C]methyl-l-methionine (Met) and [18F]fluoro-2-deoxyglucose (FDG) was performed in the same patients with acoustic neuroma wherever possible in order to compare the usefulness of the two methods. The study included six patients who visited the Osaka City University Hospitals, between April 1994 and October 1998, for complaints associated with acoustic neuroma. All patients were examined by magnetic resonance imaging (MRI) and Met-PET. Four patients were examined by FDG-PET. The tumor's region of highest accumulation was selected as the region of interest; the tumor/normal ratio (T/N ratio) was defined as the ratio of radioisotope counts for tumor and normal gray matter. All tumors in this series were detected by MRI. In the Met-PET images, four tumors were easily identified, with a high T/N ratio. However, two tumors could not be identified using Met-PET. On FDG-PET, no cases could be identified. The T/N ratio for the four patients with positive Met-PET findings averaged 1.694 +/- 0.266. PET, especially Met-PET, is a powerful means of examination providing functional information on tumors in acoustic neuroma. Met-PET may therefore be useful for acoustic neuroma, which is known to proliferate slowly, as for malignant tumors, in evaluating the proliferating potential of a tumor, in determining patients in whom to perform radiological treatment and in monitoring post-treatment progress.

Adult↗

PubMed2000

Preganglionic and postganglionic neurons responsible for cerebral vasodilation mediated by nitric oxide in anesthetized dogs.

The authors performed investigations to functionally determine the route of efferent innervation in vivo responsible for cerebral vasodilation mediated by nitric oxide (NO). In anesthetized beagles, electrical stimulation of the pterygopalatine ganglion vasodilated ipsilateral cerebral arteries such as the middle cerebral and posterior communicating arteries. Intravenous injections of NG-nitro-L-arginine (L-NA) markedly inhibited the response to nerve stimulation, and the effect was reversed by L-arginine. Stimulation of the proximal portion of the greater superficial petrosal nerve, upstream of the pterygopalatine ganglion, also produced cerebral vasodilation, which was abolished by L-NA and restored by L-arginine. Treatment with hexamethonium abolished the response to stimulation of the petrosal nerve but did not affect the response to pterygopalatine ganglion stimulation. Destruction of the pterygopalatine ganglion by cauterization constricted the cerebral arteries. Postganglionic denervation abolished the vasodilation, lacrimation, and nasal secretion induced on the ipsilateral side by stimulation of the pterygopalatine ganglion and petrosal nerve. The vasodilator response was suppressed by L-NA but unaffected by atropine, whereas lacrimation and nasal secretion were abolished solely by atropine. It is concluded that postganglionic neurons from the pterygopalatine ganglion play crucial roles in cerebral vasodilation mediated by NO from the nerve, and preganglionic neurons, possibly from the superior salivatory nucleus through the greater superficial petrosal nerve, innervate the pterygopalatine ganglion. Tonic discharges from the vasomotor center participate significantly in the maintenance of cerebral vasodilation.

Animals↗

PubMed2000

Conserved smooth muscle contractility and blood pressure increase in response to high-salt diet in mice lacking the beta3 subunit of the voltage-dependent calcium channel.

Voltage-dependent calcium channels are crucially important for calcium influx and the following smooth muscle contraction. Beta subunits of these channels are known to modify calcium currents through pore-forming alpha subunits. Among the four reported independent beta subunits, the beta3 subunit is expressed in smooth muscle cells and thought to compose L-type calcium channels in the tissue. To determine the role of the beta3 subunit in the cardiovascular system, we have analyzed beta3-null mice. Electrophysiological examinations proved the existence of dihydropyridine (DHP)-sensitive. L-type calcium channels in the smooth muscle cells. Beta3-null mice show no apparent changes in smooth muscle contraction and sensitivity to DHP, and normal blood pressure when they are raised on a normal diet, but the 13 subunit deficient mice show elevated blood pressure in response to a high-salt diet, with significant reductions in plasma catecholamine concentrations. Our finding strongly suggests a close relationship between voltage-dependent channels and high blood pressure.

Animals↗

PubMed2000

Comparison of endothelium-dependent relaxation in carotid arteries from Japanese white and Watanabe heritable hyperlipidemic rabbits.

Modifications by atherosclerosis of endothelium-dependent and -independent relaxations were evaluated in carotid arteries isolated from Watanabe heritable hyperlipidemic (WHHL; age 20-29 months) and age-matched Japanese white (JW) rabbits. Marked, patchy atherosclerotic lesions were observed in all WHHL rabbit arteries. Endothelium-dependent relaxations induced by acetylcholine, partly depressed by N(G)-nitro-L-arginine (L-NA), were significantly inhibited in the WHHL rabbit arteries with atherosclerosis, compared with those in the arteries without atherosclerotic lesions from JW and WHHL rabbits. No difference was observed in the relaxation caused by superoxide dismutase in these arteries. Conversely, endothelium-dependent relaxations by substance P were greater in the arteries with and without atherosclerosis from WHHL rabbits than in the arteries from JW rabbits. Endothelium-independent relaxations elicited by sodium nitroprusside and 2,2-(hydroxynitrosohydrazino)bis-ethanamine (NOC18) did not differ in the arteries from JW and WHHL rabbits. The responses to acetylcholine and substance P of JW rabbit arteries with the endothelium were not attenuated by treatment with pertussis toxin. L-NA-resistant, endothelium-dependent relaxations by substance P were almost abolished by charybdotoxin, and atherosclerosis did not alter the response. It is concluded that endothelial functions, evaluated by substance P, in rabbit carotid arteries are not impaired by atherosclerosis and by long exposure to hyperlipidemia in vivo. Dysfunction of muscarinic receptors may be involved in the depressed response to acetylcholine. As far as the arteries used in the present study are concerned, responses mediated possibly by endothelium-derived hyperpolarizing factor (EDHF) are unlikely to be modulated by atherosclerosis.

Acetylcholine↗

PubMed2000

Evidence for nitroxidergic innervation in monkey ophthalmic arteries in vivo and in vitro.

In anesthetized monkeys, electrical stimulation (ES) of the pterygopalatine or geniculate ganglion dilated the ipsilateral ophthalmic artery (OA). The induced vasodilatation was unaffected by phentolamine but potentiated by atropine. Intravenous N(G)-nitro-L-arginine (L-NNA) abolished the response, which was restored by L-arginine. Hexamethonium-abolished vasodilator responses induced solely by geniculate ganglionic stimulation. The L-NNA constricted OA; L-arginine reversed the effect. Destruction of the pterygopalatine ganglion constricted the ipsilateral artery. Helical strips of OA isolated under deep anesthesia from monkeys, denuded of endothelium, responded to transmural ES with relaxations, which were abolished by tetrodotoxin and L-NNA but were potentiated by atropine. It is concluded that neurogenic vasodilatation of monkey OA is mediated by nerve-derived nitric oxide (NO), and the nerve is originated from the ipsilateral pterygopalatine ganglion that is innervated by cholinergic neurons from the brain stem via the geniculate ganglion. The OA appears to be dilated by mediation of NO continuously liberated from nerves that receive tonic discharges from the vasomotor center. Acetylcholine liberated from postganglionic cholinergic nerves would impair the release of neurogenic NO.

Animals↗

PubMed2000

Reduced expression of manganese superoxide dismutase mRNA may correlate with invasiveness in esophageal carcinoma.

Little is known about the expression and antioxidant function of manganese superoxide dismutase (Mn-SOD) in esophageal squamous cell carcinoma. To determine the significance of Mn-SOD in esophageal squamous cell carcinomas, Mn-SOD mRNA expression was examined in 45 esophageal squamous cell carcinomas and the corresponding normal mucosal tissues by reverse transcription-polymerase chain reaction. The tumor/normal (T/N) ratio of 45 patients with esophageal carcinoma was calculated, and the data were clinicopathologically analyzed. The T/N ratio of Mn-SOD mRNA expression was less than 0.5 in 11 (32.4%) of 34 esophageal carcinoma cases without any preoperative treatments, while none of 11 cases who underwent preoperative chemotherapy showed a T/N ratio of <0.5 (p < 0.05). There was an inverse correlation between the Mn-SOD expression level and the degree of venous invasion (p < 0.05) as well as lymphatic invasion (p < 0.05). Furthermore, poorly differentiated squamous cell carcinoma showed significantly lower Mn-SOD mRNA expression levels than well differentiated carcinoma (p < 0.05). Our results suggest that Mn-SOD mRNA was frequently reduced in esophageal carcinoma when compared to the normal mucosa and the reduced expression levels of Mn-SOD mRNA may lead to an accumulation of superoxide radicals in conjunction with the increased invasiveness of esophageal carcinoma.

Carcinoma, Squamous Cell↗

PubMed2000

Mechanisms underlying contraction and relaxation induced by nerve stimulation in monkey uterine arteries.

We investigated the mechanisms of contractile and relaxant responses to nerve stimulation by electrical pulses and nicotine in isolated monkey uterine artery strips denuded of the endothelium. In the strips contracted with prostaglandin F(2alpha), transmural electrical stimulation (5 Hz, 40 s) produced a contraction which was partially attenuated by prazosin and abolished or reversed to a relaxation by additional treatment with alpha,beta-methylene ATP. The relaxation was abolished by N(G)-nitro-L-arginine (L-NA) and restored by L-arginine but not by D-arginine. Atropine, D-NA, aminophylline and suramin, an inhibitor of P(2Y) purinoceptors, were without effect. The neurogenic relaxation was abolished by 1H-(1,2, 4)oxadiazolo(4,3)quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Nicotine (10(-4) mol/l) elicited contraction or relaxation of uterine arteries; the contraction was reversed by combined treatment with prazosin and alpha,beta-methylene ATP. Nicotine-induced relaxations were abolished by L-NA and restored by L-arginine. The relaxation induced by exogenously applied NO (acidified NaNO(2) solution) was not influenced by L-NA but abolished by ODQ. It is concluded that contractions induced by nerve stimulation are mediated by norepinephrine and ATP liberated from sympathetic nerves that stimulate alpha(1)-adrenoceptors and P(2x) purinoceptors, respectively. The neurogenic relaxation seems to be mediated exclusively by nitric oxide synthesized from L-arginine in perivascular nerves that activates guanylate cyclase and produces cyclic GMP in smooth muscle.

Adenosine Triphosphate↗

PubMed2000

Relationship between urinary albumin excretion and glomerular filtration rate in normotensive, nonproteinuric patients with type 2 diabetes mellitus.

BACKGROUND/AIM: In patients with type 2 diabetes mellitus, the relationship between glomerular filtration rate (GFR) and urinary albumin excretion remains an unresolved issue. In order to investigate the early renal function abnormalities, GFR and urinary albumin excretion were assessed, and their relationship was examined in normotensive patients with type 2 diabetes mellitus. METHODS: In a cross-sectional study of 85 nonhypertensive Japanese patients with type 2 diabetes mellitus not showing overt proteinuria, the GFR was measured using (99m)Tc-diethylenetriamine pentaacetate renography. Fifty-one diabetic patients lacked microalbuminuria (albumin excretion <30 mg/day), while 34 patients showed microalbuminuria (between 30 and 300 mg/day). Fifteen healthy subjects served as controls. RESULTS: The three groups were well matched with regard to gender, age, and body mass index. The GFR in microalbuminuric patients (134 +/- 23 ml/min/1.48 m(2)) was significantly higher than in patients without microalbuminuria (108 +/- 21 ml/min/1.48 m(2)) and in controls (109 +/- 18 ml/min/1.48 m(2); p < 0.0001). In type 2 diabetic patients, the GFR positively correlated with the logarithmically transformed urinary albumin excretion. Multiple regression analysis showed that the urinary albumin excretion was significantly and independently affected by GFR (beta = 0.548), duration of diabetes (beta = 0.297), and systolic blood pressure (beta = 0.232; R(2) = 0.409; p < 0.0001). CONCLUSION: It is suggested that one of the mechanisms underlying increased urinary albumin excretion in early nephropathy in normotensive type 2 diabetes is glomerular hyperfiltration.

Adult↗