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Biomedical subjects

Y M Choi

Publications and source records attributed to Y M Choi.

At least 37 records · Page 2Linked to original sources
PubMed2001

Diagnosis of nut-cracker phenomenon using renal Doppler ultrasound in orthostatic proteinuria.

BACKGROUND: We evaluated the efficacy of non-invasive renal Doppler ultrasound (US) to detect the nut-cracker phenomenon (NCP) and we studied the prevalence of NCP in children with orthostatic proteinuria. METHODS: Among a total 66 cases of orthostatic proteinuria, 39 cases of NCP were found, with 27 cases being detected in a normal control group. Using Doppler US, the anteroposterior (AP) diameter and peak velocity (PV) of the left renal vein (LRV) were measured at the hilar and aortomesenteric portion. We calculated the ratio of AP and PV diameters between the two portions. The parameters were analysed using Student's t-test. RESULTS: The AP diameters and the ratio in the hilar and narrow portions were all significantly different between the two groups (P<0.01). The PV in the narrow portion and the ratio of PV were significantly different (P<0.01), but the PV in the hilar portion was not statistically different between the two groups (P>0.05). If the diagnostic criteria for NCP was that the ratio of PV was more than 5, then 22 subjects (56.4%) in the orthostatic proteinuria group and none in the control group could be diagnosed as NCP. If, however, the cut-off values for the diagnosis of NCP were set at the mean+/-2 SD of the ratio (PV ratio 3.98 and size ratio 4.16), then the orthostatic proteinuria group showed abnormal AP diameter in 25 (64.1%), peak velocity in 28 (71.8%), and both in 21 patients (53.8%), and the control group showed an abnormal AP diameter in one subject (3.7%). CONCLUSIONS: NCP may be one of the leading causes of orthostatic proteinuria, and non-invasive renal Doppler US may be a useful diagnostic tool in the screening of NCP. In the future, the diagnostic criteria of NCP must be redefined in children.

Adolescent↗
PubMed2001

Non-lipid effects of statin on hypercholesterolemic patients established to have coronary artery disease who remained hypercholesterolemic while eating a step-II diet.

BACKGROUND: Results of clinical trials of statin therapy demonstrate that an improvement in incidence of cardiovascular end points and coronary stenosis can be achieved. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that affect endothelial function, such as inflammatory responses, formation of thrombi, and stabilization of plaque. OBJECTIVE: To investigate levels of serologic markers, which may be useful surrogates for activity of vascular disease after administration of statin. METHODS: We administered 20-40 mg simvastatin daily for 14 weeks to 13 patients established to have coronary artery disease who remained hypercholesterolemic during step-II diet therapy. RESULTS: Administration of simvastatin significantly lowered lipoprotein levels and the low: high-density lipoprotein cholesterol level ratio and apolipoprotein B:A-I level ratio compared with pretreatment values (P < 0.01). Administration of simvastatin significantly lowered plasma levels of matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-I [33+/-46 and 13+/-19%, respectively (P = 0.027 and 0.020, respectively)]. Furthermore, administration of simvastatin tended to lower plasma levels of plasminogen activator inhibitor type-1 and tumor necrosis factor-alpha [by 20+/-44 and 13+/-29%, respectively (P= 0.066 and 0.110, respectively)]. There were significant inverse correlations between pretreatment levels of MMP-9 and the degree of change in those levels after administration of simvastatin (r = -0.714, P= 0.005). However, there was no significant correlation between levels of lipoprotein and levels of MMP-9, monocyte chemoattractant protein-I, and plasminogen activator inhibitor type-1 during administration of simvastatin. CONCLUSIONS: Our current data support the hypothesis that nonlipid mechanisms elicited by administration of simvastatin contribute to the decrease in incidence of cardiovascular events and explain the early clinical benefit observed in clinical trials, independent of changes in levels of lipoprotein.

Aged↗
PubMed2000

In vitro characterization of a novel factor Xa inhibitor, RPR 130737.

RPR 130737 inhibited factor Xa (FXa) with a Ki of 2.4 nM and also displayed excellent specificity toward FXa relative to other serine proteases. It showed selectivity of more than 1000-fold over thrombin, activated protein C, plasmin, tissue-plasminogen activator and trypsin. RPR 130737 prolonged plasma activated partial thromboplastin time and prothrombin time in a dose-dependent fashion. In the activated partial thromboplastin time assay, the concentrations required for doubling coagulation time were 0.32 microM (human), 0.61 microM (monkey), 0.44 microM (dog), 0.15 microM (rabbit), and 0.82 microM (rat). The concentrations required to double prothrombin time were 0.86 microM (human), and 1.26 microM (monkey), 1.15 microM (dog), 0.39 microM (rabbit) and 7.31 microM (rat). Kinetic studies revealed that RPR 130737 was a fast binding, reversible and competitive inhibitor for FXa when Spectrozyme FXa, a chromogenic substrate, was used. A coupled-enzyme assay measuring thrombin activity following prothrombinase conversion of prothrombin to thrombin indicated that RPR 130737 was a potent inhibitor for prothrombinase-bound FXa. In this assay, RPR 130737 showed IC50s of 17 nM and 35.9 nM, respectively when artificial phosphatidylserine/phosphatidylcholine (PS/PC) liposomes or gel-filtered platelets were used as the phospholipid source. An FX-deficient plasma clotting-time correction assay further demonstrated that RPR 130737 was a specific inhibitor of FXa. RPR 130737 showed no effect on platelet aggregation in vitro. These results indicate that RPR 130737 has the potential to be developed as an antithrombotic agent based on its potent and selective inhibitory effect against FXa.

Amidines↗
PubMed2000

Rapid-onset intranasal delivery of anticonvulsants: pharmacokinetic and pharmacodynamic evaluation in rabbits.

Intranasal (IN) administration is a promising approach for rapid-onset delivery of medications. In order to assess the feasibility of this approach for the emergency treatment of status epilepticus, three anticovulsants, i.e. diazepam (DZ), clonazepam (CZ), and a monocarbamate-based new compound (MCA) were studied in rabbits for the pharmacokinetics (PK) and pharmacodynamic (PD) response following intravenous (IV) and IN administrations. The animals were intranasally dosed with DZ (1 mg/kg), CZ (0.2 mg/kg), and MCA (5 mg/kg), dissolved in 200 microl of vehicle consisting of propylene glycol (PG), ethanol (EtOH), and water in the presence or absence of 1% sodium glycocholate (SGC) using single and repeated dosing schedules. Both DZ and CZ were absorbed very rapidly from 1% SGC/60% PG-30% EtOH-10% Water after IN single application; the T(max)'s were less than 2 min. The absorption rate of MCA was relatively slower with the peak time of 13-32 min. The bioavailability of single IN administration for DZ, CZ, and MCA determined over the first 2 or 4 h was found to be 77, 45, and 79%, respectively. The peak plasma level of DZ increased linearly with increasing the volume fraction of EtOH in the ternary cosolvent (20% to 60%). A repeated IN application of DZ, 5 min after the first dose, doubled the C(max) and AUC(0-2 h) values of the first one, whereas those of CZ and MCA resulted in an increase of 73-94% of the first dose. A single IN application of DZ- and CZ-containing formulations produced a PD response within 1.5 min, which was comparable to that of an IV injection. These results suggest that single or repeated IN applications of DZ, CZ, and MCA in a hydroalcohol-glycolic formulation might represent a viable approach to achieving a rapid systemic absorption of these anticonvulsants during the emergency treatment of status epilepticus and other types of seizures.

Absorption↗
PubMed2000

Zucchini green mottle mosaic virus is a new tobamovirus; comparison of its coat protein gene with that of kyuri green mottle mosaic virus.

A novel virus we call zucchini green mottle mosaic virus (ZGMMV) was isolated from zucchini squash and its properties were determined. The size and shape of its virions, and other properties suggest that the virus is a tobamovirus. The coat protein (CP) genes of ZGMMV and kyuri green mottle mosaic virus (KGMMV), which also infects zucchini squash plants, were cloned and their nucleotides sequences were determined. The CP genes of ZGMMV and KGMMV are composed of 161 amino acid residues, and they share 77.6% amino acid identity. Western blot analysis showed that the two viruses are serologically related but not identical. Comparison of the sequences with those of sixteen other tobamoviruses revealed that the two viruses had much higher identity to cucumber green mottle mosaic virus (CGMMV), another tobamovirus infectious to cucurbit plants, than other tobamoviruses. The nucleotide and amino acid sequences of ZGMMV were from 29.5 to 78.4% and from 29.3 to 77.6% identical, respectively, to those of other tobamoviruses. The predicted virion assembly origins of the two tobamoviruses were located in the CP region of the genomic RNAs, and the predicted secondary structures were more similar to that of CGMMV than those of other tobamoviruses. The seventeen tobamo-viruses could be classified into three main subgroups based on the phylogenetic tree analysis on the CP gene, and ZGMMV and KGMMV formed a third subgroup together with CGMMV and sunn-hemp mosaic virus (SHMV). These results show that ZGMMV is a previously unknown member of the Tobamovirus genus.

Base Sequence↗
PubMed2000

Association of the vitamin D receptor start codon polymorphism (FokI) with bone mineral density in postmenopausal Korean women.

We undertook this study in order to examine the association between bone mineral density (BMD) and a polymorphism at the first of two potential translation initiation codons in the vitamin D receptor (VDR) gene. This polymorphism was detected by restriction fragment length polymorphism analysis, using polymerase chain reaction (PCR) and the restriction endonuclease FokI. The f allele indicates the presence of the FokI site, and the F allele its absence. The FokI genotype was determined in 174 postmenopausal Korean women, aged 43-71 years. The distribution of FokI genotypes in Koreans was found not to differ significantly from those found in Caucasians and Japanese, although it does differ significantly from that found in the black American population. We observed a significant association between the FokI polymorphism and lumbar BMD; P = 0.048, analysis of covariance [ANCOVA], but no association with femoral neck BMD (P = 0.505, ANCOVA). Those with the ff genotype had a 13.3% lower BMD in the lumbar spine than the FF subjects. In addition, a significantly higher prevalence of the ff genotype was observed in osteoporotic compared with osteopenic or normal women (P = 0.036, chi2 test). These data suggest that the ff genotype of the VDR gene correlates with decreased BMD in the lumbar spine in postmenopausal Korean women.

Base Sequence↗
PubMed2000

Carrier detection and prenatal diagnosis of hemophilia A in a Korean population by PCR-based analysis of the BclI/intron 18 and St14 VNTR polymorphisms.

We have undertaken this study to identify the usefulness of polymerase chain reaction (PCR)-based analysis of DNA polymorphisms in the BclI/intron 18 and St14 variable number of tandem repeats (VNTR) loci for carrier detection and prenatal diagnosis of hemophilia A in the Korean population. We have analyzed these polymorphisms in members of 105 unrelated Korean families with severe hemophilia A. The observed heterozygosity rates for the BclI/intron 18 and St14 VNTR polymorphisms were 21.0% and 71.3%, respectively. The BclI/intron 18 polymorphism was less informative in Koreans when compared with Caucasians and Japanese. The allele frequencies for St14 VNTR in Koreans were different from those in Caucasians. Compared with Caucasians, there was a markedly higher occurrence of low molecular weight alleles in Koreans. The observed heterozygosity for the St14 VNTR polymorphism in combination with the BclI/intron 18 polymorphism was 81.9%. These two polymorphisms were applied to determine the carrier status of 107 women from 65 unrelated families, and to assess fetal status in 37 pregnancies. So far, we have experienced one case of misdiagnosis of carriership. Our study demonstrated that the PCR-based analysis of the BclI/intron 18 and St14 VNTR polymorphisms was useful in the carrier detection and prenatal diagnosis of hemophilia A in the Korean population.

DNA↗
PubMed2000

Insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP-3 protease activity in the peritoneal fluid of patients with and without endometriosis.

OBJECTIVE: To compare levels of insulin-like growth factor (IGF) components in the peritoneal fluid of patients with and without endometriosis. DESIGN: Patients with endometriosis were compared with control patients. SETTING: Seoul National University Hospital, Korea. PATIENT(S): Forty-three patients with endometriosis and 20 patients without endometriosis. INTERVENTION(S): Peritoneal fluid specimens were collected. MAIN OUTCOME MEASURE(S): Insulin-like growth factors, IGF binding protein (IGFBP) profiles and IGFBP-3 protease activity. RESULT(S): The IGF-I levels in peritoneal fluid were significantly higher in patients with endometriosis than in control patients, while the IGFBP-3 levels and the relative proportion of IGFBP-2 in peritoneal fluid were significantly lower in patients with endometriosis than in control patients. However, IGF-II levels, IGFBP-4 profiles, and IGFBP-3 protease activity did not differ significantly between the two groups. No correlation between these IGF components in peritoneal fluid and the stage of endometriosis was noted. CONCLUSION(S): The profiles of IGF components in peritoneal fluid of patients with pelvic endometriosis may play an important role in the growth of ectopic endometrium and endometriosis-induced infertility.

Adult↗
PubMed1999

Myeloid differentiation of human cord blood CD34+ cells during ex vivo expansion using thrombopoietin, flt3-ligand and/or granulocyte-colony stimulating factor.

We investigated the phenotypic changes of human umbilical cord blood (CB) CD34+ cells during ex vivo expansion using thrombopoietin (TPO), flt3-ligand (FL), and/or granulocyte-colony stimulating factor (G-CSF). During ex vivo expansion of CD34+ cells isolated from human CB for up to 5 weeks, surface expression of molecules on the cultured cells including CD64 (Fc gammaRI), CD32 (Fc gammaRII), CD16 (Fc gammaRII), CD11b (MAC-1) and CD18 (beta2-integrin) was analysed by flow cytometry along with simultaneous measurement of apoptosis by 7-aminoactinomycin D staining method. CD64, CD32 and/or CD18 expressing cells appeared in the cultures both with and without the addition of G-CSF until the tenth day. However, without G-CSF, CD16+ fractions did not appear and CD11b+ fractions were not maintained. With G-CSF, the CD16+ or CD11b+ fractions appeared only from the second week. These results suggest that G-CSF is necessary for the late stage of myeloid maturation during which CD16 and CD11b are expressed.

Antigens, CD34↗
PubMed1999

The relationship among circulating insulin-like growth factor components, biochemical markers of bone turnover and bone mineral density in postmenopausal women under the age of 60.

OBJECTIVES: The changes in circulating IGF components after the menopause and the potential role of new markers of bone turnover and circulating IGF components in predicting bone mass in postmenopausal women are still controversial and the relationship between these two systems has not been investigated. The aims of this study were to investigate the changes in circulating IGF components after the menopause, to evaluate whether new markers of bone turnover and circulating IGF components reflect bone mass in postmenopausal women under the age of 60 and to study the relationship between these two systems. DESIGN, PATIENTS AND MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, osteocalcin (OST), bone specific alkaline phosphatase (BAP), urinary deoxypyridinoline (DPYD) and N-telopeptide of type I collagen (NTX) were measured in 31 premenopausal women aged 31-43 and 65 postmenopausal women aged 47-60: this latter group comprised 30 normal healthy women and 35 osteoporotic women. RESULTS: Compared with premenopausal women or normal postmenopausal women, serum IGF-1 and IGFBP-3 levels were significantly lower in osteoporotic postmenopausal women while no significant differences in serum levels of IGF-II, IGFBP-1 and IGFBP-2 were observed. The correlations between bone turnover markers and circulating IGF components (except between serum BAP and IGF-II), and between bone turnover markers and bone mineral density (BMD) in postmenopausal women were not significant. However, serum IGF-I and IGFBP-3 correlated positively with BMD of the lumbar spine and/or Ward's triangle even if age, BMI and menopause duration were taken into account in a multiple regression analysis model. CONCLUSIONS: Circulating IGF-I and IGFBP-3 may be involved in the mechanism of bone loss in postmenopausal women under the age of 60. They may also provide indirect information on the current bone microenvironment different from that provided by new markers of bone turnover.

Adult↗
PubMed1999

Experimental autoimmune myasthenia gravis and CD5+ B-lymphocyte expression.

Myasthenia gravis is one of the typical organ specific autoimmune disease and the CD5+ B-lymphocytes are known to be associated with the secretion of autoimmune antibodies. The authors performed the study to establish an animal model of experimental autoimmune myasthenia gravis (EAMG) by immunizing the nicotinic acetylcholine receptor (AChR) and to understand CD5+ B-lymphocyte changes in peripheral blood of EAMGs. Lewis rats weighing 150-200 g were injected subcutaneously three times with 50 microg AChR purified from the electric organ of Torpedo marmorata and Freund's adjuvant. The EAMG induction was assessed by evaluating clinical manifestations. The CD5+ B-lymphocyte was double stained using monoclonal PE conjugated anti-CD5+ and FITC conjugated anti-rat CD45R antibodies and calculated using a fluorescence-activated cell sorter (FACS). In three out of ten Lewis rats injected with purified AChR, the EAMG models were established. The animals showed definite clinical weakness responded to neostigmine; they had difficulty in climbing the slope, or easily fell down from a vertical cage. The range of CD5+ B-lymphocytes of peripheral blood in the EAMG models was 10.2%-17.5%, which was higher than in controls. In conclusion, the EAMG models were successfully established and the CD5+ B-lymphocyte expression in peripheral blood increased in EAMGs. This provided indirect evidence of the autoimmune pathomechanism of human myasthenia gravis.

Animals↗
PubMed1998

OK-432 and 5-fluorouracil, doxorubicin, and mitomycin C (FAM-P) versus FAM chemotherapy in patients with curatively resected gastric carcinoma: a randomized Phase III trial.

BACKGROUND: The streptococcal agent OK-432 is used widely as a potent biologic response modifier. Accumulated evidence suggests that OK-432 exerts antineoplastic effects by a direct cytotoxic or inhibitory effect on tumor cells. The clinical efficacy of OK-432 has been reported for various tumors. In this randomized Phase III study, the authors compared 5-fluorouracil (5-FU), doxorubicin, mitomycin C, and the intradermal administration of OK-432 (FAM-P) with the standard FAM regimen in patients with gastric carcinoma who underwent curative resection. METHODS: From May 1988 until November 1991, a total of 99 patients were entered into this randomized trial. The patients were stratified according to the American Joint Committee on Cancer stage of disease (i.e., Stage IB, II, and III). Fifty patients were treated with the FAM regimen here and throughout text.: 5-FU, 750 mg intravenously (i.v.), on Days 1, 8, 29, and 36; doxorubicin, 30 mg/m2 i.v., on Days 1 and 29; and mitomycin C, 10 mg/m2 i.v., on Day 1. Forty-nine patients received the FAM-P regimen: 5-FU, 750 mg i.v., on Days 1, 8, 29, and 36; doxorubicin, 30 mg/m2 i.v., on Days 1 and 29; mitomycin C, 10 mg/m2 i.v., on Day 1; and OK-432 5.0 Klinishe Einheit (clinical unit) injected intradermally weekly. RESULTS: The survival difference was statistically significant between the patients receiving the FAM and FAM-P regimens (5-year survival of 52% vs. 62%; P = 0.04). A comparison between disease free survival in FAM and FAM-P patients showed a borderline advantage for the FAM-P group (P = 0.053). When Stage IB, Stage II, and Stage III patients were analyzed separately, the difference in survival between two regimens was significant in Stage III patients (P = 0.049) and the disease free survival was of borderline significance (P = 0.06), but not in patients with Stage IB and II disease. The significant toxicity of OK-432 was mild fever, which was controlled with acetaminophen. CONCLUSIONS: The results of this study show that OK-432 may be an active, well tolerated agent for the treatment of curatively resected gastric carcinoma. However, these findings should be confirmed by a multicenter randomized study with a large sample size.

Adenocarcinoma↗
PubMed1998

Anticholinesterase induces nicotinic receptor modulation.

The effects of carbamate anticholinesterases, pyridostigmine and physostigmine, on the function of the nicotinic receptor (nAChR) in TE671 cells was studied, precluding their inhibition of acetylcholine hydrolysis by carbachol usage. In radioassay, the simultaneous application of carbachol and carbamates dose-dependently decreased carbachol-induced 22Na+ influx, compared with carbachol activation alone. Increasing cell preincubation in the presence of carbamates, however, potentiated influx at low concentrations in a time-dependent manner. This facilitating effect of carbamates, even at high concentrations, was significantly increased by washing out these drugs and was blocked by pretreatment with diisopropylfluorophosphate. Similar results were also obtained in whole-cell patch-clamp study. There were insignificant changes in desensitization properties during facilitation. It is thus supposed that facilitation cannot be explained by the inhibition of acetylcholine hydrolysis. These results support a previous hypothesis that acetylcholinesterase might modulate nAChR by an unknown mechanism. In addition, the clinical effects of carbamates may be partly attributed to this facilitation.

Carbachol↗
PubMed1998

Chemometric applications of thermally produced compounds as time-temperature integrators in aseptic processing of particulate foods.

The chemometric principle was used to derive a guideline for obtaining a simple "yes or no" answer about the sterility of food particulates heated at aseptic processing temperatures. A quadratic temperature pulse model was used to estimate bacterial destruction from the fractional yield of thermally produced chemical marker compounds (2,3-dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-one, M-1, and 4-hydroxy-5-methyl-3(2H)-furanone, M-2) and the rate constants and the activation energies of the chemical and bacterial systems. The model yielded a conservative estimate of lethality at the center of meat-balls heated under different time-temperature conditions. A scheme for determining the minimum marker yield for a designated Fo-value is provided.

Food Analysis↗
PubMed1998

In vitro inhibition of biophysical surface properties and change in ultrastructures of exogenous pulmonary surfactant by albumin or fibrinogen.

In order to observe the effects of serum albumin and fibrinogen on biophysical surface properties and the morphology of pulmonary surfactant in vitro, we measured the surface adsorption rate, dynamic minimum and maximum surface tension (min-, max-ST) by Pulsating Bubble Surfactometer, and demonstrated ultrastructures on a series of mixtures with varying concentrations of albumin or fibrinogen and Surfactant-TA. The albumin and fibrinogen significantly inhibited the adsorption rate and ST-lowering properties of surfactant through increasing STs of adsorption rate, min-ST, and max-ST. The characteristic morphology of the Surfactant-TA changed from lamellar rod-like structure with open ends into spherical structures with loss of their open ends by mixing with albumin or fibrinogen. These inhibitory effects of albumin and fibrinogen on surface properties of surfactant were dependent upon the increasing concentration of albumin or fibrinogen. We concluded that albumin and fibrinogen significantly altered surfactant function and its ultrastructural morphology in vitro. These findings support the concept that albumin and fibrinogen-induced surfactant dysfunction may play an important role in the pathophysiology of adult respiratory distress syndrome, and this adverse effect of albumin and fibrinogen on surfactant might be overcome by administration of large doses of exogenous surfactant.

Adsorption↗
PubMed1997

Anionic- and lipophilic-mediated surface binding inhibitors of human leukocyte elastase.

We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inhibitors of human leukocyte elastase (HLE). The enzyme inhibition is regulated by the size of the oligomer, as well as, the number of charges. Lipophilicity is an important element in determining potency and specificity against other basic enzymes. Compounds whose scaffolds contain three phenoxyacetic acid groups and three alkyl ethers are competitive and specific inhibitors of HLE with Ki = 20 nM. The mechanism of action of this class of compounds is believed to involve multidendate interactions with the surface of HLE near the active site which prevents substrate access to the catalytic site.

Benzhydryl Compounds↗
PubMed1997

Sphingomyelinase activity is enhanced in cerebral cortex of senescence-accelerated mouse-P/10 with advancing age.

The cerebral cortical sphingomyelinase (SMase) activities were detected in the cytosolic and the membrane fractions of cerebral cortex, hippocampus, cerebellum, brainstem, and thalamus/midbrain of senescence-accelerated mouse-prone/10 (SAM-P/10) and SAM-resistant/1 (SAM-R/1) with advancing age, respectively. The SMase activity was increased uniquely in the membrane fraction of the cerebral cortex of SAM-P/10 in an age-dependent manner; The enzyme activities of 10 and 17 months of age were about 25 and 30% higher than those of 2 months of age, respectively. This observation implicates that the membrane-associated SMase activity might be related with accelerated senescence. The cerebral cortical SMase was eluted in a molecular mass of approximately 400 kDa on a gel filtration chromatography and was active in a broad range of pH from 4 to 9. It was also suggested that phosphorylation may be one of the mechanisms regulating the enzyme activity, but not responsible for the increased activity with advancing age.

Aging↗