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Biomedical subjects

J D Kim

Publications and source records attributed to J D Kim.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effect of 2-amino oleic acid exposure conditions on the inhibition of calcification of glutaraldehyde cross-linked porcine aortic valves.

Postimplant calcific degeneration is a frequent cause of clinical failures of glutaraldehyde cross-linked porcine bioprosthetic heart valves (BPHV). It was demonstrated previously that 2-amino oleic acid (AOA) used as a bioprosthesis treatment was highly effective in mitigating aortic valve cusp but not aortic wall calcification. Our main objective was to study the efficacy of various AOA exposure conditions for inhibiting calcification of both cusps and aortic wall tissues using rat subdermal implants. BPHV tissues were treated with a saturated AOA solution for different time intervals before experimental. Aortic wall AOA levels were consistently lower than that of the cusps after the same exposure times. The diffusion of calcium ion across both cusp and aortic wall tissues was evaluated, and the results demonstrated that there was an AOA exposure time-dependent retardation of calcium ion penetration for cusp but not aortic wall. An 8-month extraction study was performed to determine the stability of AOA binding. When Tween 80 was used as an extraction medium, cusp and aortic wall retained 12.9 and 48.7%, respectively, of their initial AOA levels. AOA inhibition of calcification in rat subdermal implants (60 days) was found to be exposure time-dependent with maximum treatment time (120 h), resulting in the lowest calcium levels (20.1 +/- 10.3 and 71.4 +/- 5.4 micrograms/mg of cusp and aortic wall, respectively) as compared with controls (219.1 +/- 6.8 and 104.9 +/- 8.5 micrograms/mg of cusp and aortic wall, respectively). The significance of AOA binding on BPHV tissue was determined by either blocking or reducing BPHV's (cusp and aortic wall) free aldehyde residues with lysine or NaBH4, respectively, before AOA treatment. For aortic cusps, the AOA contents after 72 h were 98.3 +/- 2.7, 34.2 +/- 3.6, and 54.1 +/- 3.0 nM/mg of tissue for AOA (control), lysine-pretreated (plus AOA) and NaBH4-pretreated (plus AOA) tissues, respectively. However, their calcium levels after 60 days of rat subdermal implant were all comparable (i.e., 48.1 +/- 6.2, 38.2 +/- 9.1, and 47.0 +/- 15.0 micrograms calcium per mg of tissue). Similar results were observed on BPHV aortic wall. It can thus be concluded that AOA inhibition of BPHV calcification is exposure time-dependent, but the efficacy of AOA for aortic wall is less than that noted for aortic cusps, perhaps because of lower AOA binding and differences in calcium diffusion kinetics.

Animals↗
PubMed1994

Effects of n-3 and n-6 fatty acids on the activities and expression of hepatic antioxidant enzymes in autoimmune-prone NZBxNZW F1 mice.

Menhaden fish oil (FO) containing n-3 fatty acids dramatically extends the life span and delays the onset and progression of autoimmune disease in (NZBxNZW)F1 (B/W) female mice as compared to those fed corn oil (CO) rich in n-6 lipids. As an inefficient antioxidant defense system has been linked to autoimmune diseases, the present study was undertaken to determine whether the protective action of n-3 lipids is mediated through their antioxidant defense system. Weanling B/W mice were fed a nutritionally adequate, semipurified diet containing CO or krill oil (KO) or FO at 10% level (w/w) ad libitum until the mice were 6.5 months old. All diets contained the same level of vitamin E (21.5 mg/100 g diet). We compared the effects of feeding n-6 and n-3 lipids on survival, kidney disease, hepatic microsomal lipid composition, peroxidation, and on the activity and mRNA expression of the antioxidant enzymes catalase, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in 6.5-month-old B/W mice. The results showed that when compared to livers from CO-fed mice, livers from KO- and FO-fed mice showed: (i) significantly higher (P < 0.001) activities and expression of CAT, GSH-Px and SOD; (ii) significantly lower (P < 0.001) arachidonic acid (20:4n-6) and linoleic acid (18:2n-6) and higher (P < 0.001) eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) levels in hepatic microsomes; and (iii) significantly lower (P < 0.001) estimated peroxidation indices and thiobarbituric acid reactive substances generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Nuclear protein binding patterns in the 5'-upstream regulatory elements of HLA class I genes.

The expression of MHC class I genes has been thought to be regulated by two major cis-acting regulatory elements. The first region, enhancer A (Enh A) spanning from positions -210 to -165 contains perfect palindrome (PP), TGGGGATTCCCCA. The PP is well-conserved both in mouse and human MHC class I genes, even though the PP is disrupted by 2 bp substitutions (TGAGGATTCTCCA) in HLA-C genes. Three proteins binding to the Enh A of HLA-A and -B locus genes, but very weakly or nearly not to the Enh A of HLA-C locus gene have been identified. To determine functional importance of the PP for binding of trans-acting protein, mutant DNA probes were made by site-directed in vitro mutagenesis and then electrophoretic mobility shift assay was performed. HLA-A mutant DNA probe, in which the PP is disrupted, shows the same nuclear protein binding pattern as that of the HLA-C gene, and HLA-C mutant DNA probe, in which the PP is introduced, shows the same nuclear protein binding pattern as that of the wild type HLA-A gene. These data suggest that the perfect palindrome and its cognate DNA binding nuclear protein play an important role in the HLA class I gene regulation, and thus the lower expression of HLA-C antigen may be ascribed to no or very weak factor binding to the nonpalindromic sequences of HLA-C upstream DNA.

Animals↗
PubMed1993

Diagnosis of tuberculous meningitis by detection of immunoglobulin G antibodies to purified protein derivative and lipoarabinomannan antigen in cerebrospinal fluid.

Enzyme-linked immunosorbent assay of immunoglobulin G (IgG) activity in cerebrospinal fluid (CSF) and sera was conducted prospectively in 27 patients with tuberculous meningitis (TBM) by using purified protein derivative (PPD) and lipoarabinomannan (LAM) antigens, from January 1989 to August 1990. 29 patients with aseptic meningitis and 49 patients with non-inflammatory neurological illnesses served as controls. All patients had a computed tomography (CT) scan of the head before a lumbar puncture. The IgG antibodies to the antigens were significantly elevated in TBM, and the reactivity was more frequently positive in the CSF than in the sera, suggesting a local synthesis of IgG in the central nervous system (CNS). The sensitivity and the specificity for the diagnosis of TBM were 59.2% and 93.9% for PPD antigen, and 85.2% and 95.9% for LAM antigen, respectively. Assay of IgG reactivity to LAM antigen was clinically very useful for the early diagnosis of TBM and was superior to PPD for detecting the serological evidence of TBM.

Adolescent↗
PubMed1993

Evaluation of polymerase chain reaction amplification of Mycobacterium leprae-specific repetitive sequence in biopsy specimens from leprosy patients.

Biopsy specimens were obtained from 102 leprosy patients before chemotherapy and examined by polymerase chain reaction (PCR) using the primers amplifying the 372-bp DNA of a repetitive sequence of Mycobacterium leprae. The PCR results were then compared with bacterial indices (BI) of slit-skin smears and biopsy specimens. The intensities of DNA bands were in general correlated with the numbers of acid-fast bacilli, and even a sample with only one organism gave a PCR positive result. Ten 5-micron sections from each frozen tissue sample were pooled and processed for DNA preparation. PCR was positive for 11 (73.3%) of 15 biopsy specimens with BI of 0 determined for the paraffin sections from the same biopsy samples. PCR also gave positive results for 84 (96.6%) of 87 BI positive biopsy samples. Although the difference in overall results between the two methods was not statistically significant, PCR seemed to have an advantage over microscopic examination in detecting M. leprae in biopsy specimens negative for acid-fast bacilli. Further evaluation of PCR using more specimens from leprosy patients who are bacteriologically negative is warranted to ensure PCR's advantage over the conventional microscopic examination for the diagnosis of leprosy.

Base Sequence↗
PubMed1993

Evidence for pituitary regulation of somatic growth, insulin-like growth factors-I and -II, and their binding proteins in the fetal rat.

We investigated pituitary regulation of late-gestation fetal growth in the spontaneous dwarf rat, a strain with an autosomal recessive mutation (gene symbol dr) in the growth hormone (GH) gene resulting in complete isolated GH deficiency. GH-normal/GH-deficient (Dr/dr) females were crossed with Dr/dr or dr/dr males, producing both GH-deficient and GH-normal fetuses within the same litter. Pups were killed within 3 h after birth to approximate the developmental state of a late-gestation fetus. The body weight of GH-deficient fetuses was inhibited by 14% in comparison to GH-normal animals, but tail length remained unaffected. The brain and lungs were the only organs whose growth appeared to be pituitary-independent. Other organs showed moderate pituitary dependence in proportion to body weight. Serum IGF-I and IGF-II were reduced by 73% and 52%, respectively, in the absence of GH. The major IGF-binding proteins (IGFBP) were analyzed by Western ligand blot. The predominant 26- to 30-kD IGFBP band normally seen in neonatal rat serum was greatly increased in GH-deficient sera, to 250% of GH-normal sera as measured by densitometry. However, addition of alpha-Hec 1 antibody to IGFBP-2, which has been used to identify IGFBP-2 as the major neonatal IGFBP, resulted in immunoprecipitation of only a small amount of the 26- to 30-kD band from the GH-deficient fetuses, suggesting the presence of an additional IGFBP. Northern analysis of GH-deficient livers did not reveal any visible increase in IGFBP-1, IGFBP-2, or IGFBP-4 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Studies on IL-2 production and T-cell colony forming unit in patients with chronic renal failure.

To elucidate the nature of altered cellular immunity seen in patients with chronic renal failure, the values of interleukin-2 (IL-2), a kind of lymphokine, and T-cell colony forming units were measured in controls (N = 10), predialysis uremic patients (N = 14), patients undergoing chronic hemodialysis (HD, N = 11) and patients on continuous ambulatory peritoneal dialysis (CAPD, N = 9). Dialytic patients were selected as relatively stable cases receiving dialysis for more than 3 months. The duration of dialysis was 25.5 +/- 5.5 months in HD and 14.7 +/- 3.0 months in CAPD groups. The mean age was 30.3 years in the control, 36.1 years in the predialysis, 32.9 years in the HD and 41.1 years in the CAPD groups; all 4 groups showed male predominance. The serum creatinine concentration of each group was 1.2 +/- 0.1 mg/dl in the control, 14.1 +/- 0.9 mg/dl in predialysis, 13.5 +/- 1.3 mg/dl in HD and 14.7 +/- 0.9 mg/dl in CAPD groups. The level of IL-2 in the predialysis group was markedly lower compared to the control, HD and CAPD groups (as 3.1 +/- 0.8 unit vs. 8.8 +/- 2.2 unit, 11.8 +/- 3.0 unit and 14.9 +/- 3.4 unit, respectively, p < 0.05); the difference between the control and dialytic groups was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Serologic responses to nerve antigens in sooty mangabey monkeys with experimental leprosy.

Eight sooty mangabey monkeys were inoculated intravenously and intradermally with varying doses of Mycobacterium leprae from 4.8 x 10(7) to 4.8 x 10(10). Serum samples were obtained from the animals at intervals of about 3 months for 90 months, and were examined for IgM and IgG antibodies to nerve antigens, including ceramide, galactocerebroside (GC), and asialo-GM1 (AGM1), using an enzyme-linked immunosorbent assay (ELISA). The serological results were then compared with clinical findings, particularly nerve involvement. Of 8 mangabey monkeys inoculated with M. leprae, 7 animals had clinical leprosy; 6 of them had nerve damage, including neurologic deformities in 4 monkeys and nerve enlargement in 2. Median time for the initial signs of leprosy was 10 months postinoculation (p.i.), a range from 4 to 35 months. In contrast, nerve damage was noted rather late, about 35 to 86 months p.i. (median 54 months). The major immunoglobulin class to ceramide, GC, and AGM1 antigens was IgM, and the antibody responses to the nerve antigens appeared from 15 to 63 months p.i. (median 37 months). Antineural antibodies were thus detectable about 18 months (range -2 to 60 months) prior to observable nerve damage. In addition, elevation of antineural antibody levels were predictive of clinical exacerbation of the disease and neuritic damage. This study suggests that antineural antibodies are produced during the course of M. leprae infection and may be indicative of nerve damage, such as neurological deformities or nerve enlargement, in leprosy patients.

Animals↗
PubMed1992

Induction of vesicle-to-micelle transition by bile salts for DOPE vesicles incorporating immunoglobulin G.

The vesicle-to-micelle transition of immunoliposomes formed by dioleoylphosphatidyl-ethanolamine (DOPE) and palmitoyl-immunoglobulin G (p-IgG) was investigated in the presence of bile salts and conjugated bile salts. Turbidity and the release of calcein from liposomes were measured as a function of the amount of bile salts added and compared with the solubilizing profiles of the salts according to the number and configurational state of hydroxy groups in the cholate. The solubilizing phenomena by bile salts conjugated with glycine or taurine were investigated in comparison with non-conjugated bile salts. The solubilizing effect of bile salts on the bilayer of immunoliposomes increased remarkably with the number of hydroxy groups, but was not influenced by the configurational state of the hydroxy group. The half-maximal concentration of bile salts, defined as the concentration giving the half-maximum turbidity of liposome solutions, decreased with hydrophobicity in the phosphatidylcholine (PC) bilayer. The increase in the hydrophobicity of bile salts induces the ability to permeabilize and solubilize phospholipid vesicles. In the case of PC or PE liposome bilayers with inserted protein, bile salts conjugated with taurine or glycine had lower hydrophobicity than non-conjugated bile salts and showed a lower half-maximal concentration. The conjugated bile salts are believed to interact with lipids and solubilize the bilayers, while the head groups of bile salts interact with the inserted protein and extract it from the lipid bilayer.

Bile Acids and Salts↗
PubMed1992

Detection of antibodies to human nerve antigens in sera from leprosy patients by ELISA.

Anti-neural antibodies have been implicated to play a role in the pathogenesis of nerve damage in leprosy patients. To find the relationship between anti-neural antibodies and clinical findings, we attempted to detect antibodies against neurofilament-enriched proteins by ELISA in sera from leprosy patients. Of 289 sera from leprosy patients, 74 (25.6%) had significant anti-neural antibodies; in contrast, 1 (5.0%) of 20 tuberculosis patients and 11 (7.1%) of 154 controls were seroreactive to nerve antigen. When clinical types were considered, a significant level of anti-neural IgG antibodies was detectable in 53 (30.1%) of 176 sera from lepromatous patients compared with 21 (18.6%) of 113 sera from tuberculoid patients, indicating that lepromatous patients were more likely to be seropositive to nerve antigens in ELISA. Some of the ELISA-reactive sera showed antibody reactivity with 38-kD, 40-kD and 43-kD nerve antigens in Western blotting analysis. There was no apparent correlation between seroreactivity to nerve antigens and bacterial load in leprosy patients. Although there was no statistical significance, anti-neural antibodies were detectable more often among the patients on chemotherapy than the untreated and among the patients with erythema nodosum leprosum than without. The results, therefore, suggest that anti-neural antibodies are elicited during the course of leprosy and may be associated with the extensiveness of nerve involvement in the patients.

Animals↗
PubMed1992

Production of monoclonal antibody to a phenolic glycolipid of Mycobacterium tuberculosis and its use in detection of the antigen in clinical isolates.

A monoclonal antibody (MAbIII604) specific to phenolic glycolipid Tb (PGL-Tb), a Mycobacterium tuberculosis-specific antigen, was produced and used in the detection of the antigen. MAbIII604 reacted with the PGL-Tb antigen but not with other phenolic glycolipids from Mycobacterium leprae, M. bovis, and M. kansasii, thus indicating the specificity of the monoclonal antibody to PGL-Tb. A dot enzyme-linked immunosorbent assay with MAbIII604 was employed to detect the PGL-Tb antigen in lipids purified from M. tuberculosis clinical isolates. Of 50 isolates, 32 (64.0%) showed clear evidence of the PGL-Tb antigen by the dot enzyme-linked immunosorbent assay, but there were marked variations in the intensities and sizes of spots. This suggests differences in PGL-Tb antigen production among M. tuberculosis strains even when they are grown in the same culture media and conditions. This was most evident from the fact that in only eight (16.0%) of the isolates examined was the PGL-Tb antigen detectable by thin-layer chromatography, which is much less sensitive for the detection of glycolipid antigens. This study shows that monoclonal antibodies specific to PGL-Tb are useful in detecting the antigen in lipid extracts and that there is a marked variation in the PGL-Tb production among M. tuberculosis clinical isolates.

Antibodies, Bacterial↗
PubMed1992

Comparative analysis of lipopolysaccharide and lipid antigens of Leptospira interrogans serovars.

Lipopolysaccharide (LPS) or glycolipid antigens of Leptospira interrogans have been candidates as serogroup or serotype specific antigen. In this study, therefore, we prepared the LPS and lipid antigens from L. interrogans serovars lai, icterohaemorrhagiae, copenhageni, canicola, pomona, grippotyphosa, and a Korean isolate 30R. The LPS antigens were analyzed by a polyacrylamide gel electrophoresis and lipid antigens by thin-layer chromatography, respectively. The seroreactivity of the antigens were also examined with homologous or heterologous antisera using an enzyme-linked immunosorbent assay. The LPS antigens from serovar lai and the strain 30R were closely related but different from serovar icterohaemorrhagiae. Particularly, the LPS antigens from serovars icterohaemorrhagiae and grippotyphosa were reactive only with the homologous antisera, thus indicating serovar specificity. However, the LPS antigens of the other serovars were reactive to the heterologous antisera. The lipid antigen of serovar icterohaemorrhagiae reacted only with the homologous antisera. In contrast, lipids of other serovars reacted broadly with heterologous antisera, particularly among serovars lai, copenhageni, canicola, pomona, and the strain 30R. The results thus indicated that the LPS and lipid antigens of L. interrogans may contain serovar-specific as well as cross-reactive epitopes.

Antigens, Bacterial↗
PubMed1992

Detection of Mycobacterium tuberculosis in clinical samples from patients with tuberculosis or other pulmonary diseases by polymerase chain reaction.

Polymerase chain reaction (PCR) using primers targeting the IS6110 repetitive sequence was employed to detect Mycobacterium tuberculosis in 228 samples from patients with tuberculosis or other pulmonary diseases and controls, and the results were compared with culture and clinical findings. None of culture negative samples from 17 healthy controls were PCR positive. Of 109 active tuberculosis patients under chemotherapy, 88 (80.7%) were PCR positive and were significantly higher than 63 (57.8%) positive by culture. Fifty-nine (93.7) of 63 culture positive and 29 (63.0%) of 46 culture negative specimens contained M. tuberculosis detectable by PCR. In 41 specimens from inactive tuberculosis patients who visited to the chest clinic because of chest problems, 16 (39.0%) also gave PCR positive results. In addition, 14 (46.7%) of 30 specimens submitted for M. tuberculosis culture from patients with pulmonary diseases were PCR positive. Presumptive diagnosis of these PCR positive patients was bronchitis, pneumonia, bronchial asthma, etc. Therefore, this study suggests that PCR is sensitive and specific in detecting M. tuberculosis in clinical specimens. However, the interpretation of the PCR results in specimens from patients with pulmonary diseases should be done cautiously in areas with a high prevalence of tuberculosis.

Base Sequence↗
PubMed1992

Prevalence of IgM antibodies to phenolic glycolipid I among household contacts and controls in Korea and the Philippines.

Phenolic glycolipid I (PGL-I) is a Mycobacterium leprae-specific antigen and the antibodies to the antigen may suggest an M. leprae infection. To compare the M. leprae transmission among the populations, we compared the prevalence of anti-PGL-I IgM antibodies among household contacts and controls between Korea and the Philippines. In Korea (prevalence of leprosy--0.04: 1000), the prevalence of anti-PGL-I antibodies were 4.8% among controls and 8.0% among contacts, respectively. On the other hand, the seroprevalence rate was 10.8% among controls and 13.4% among contacts in the Philippines (prevalence of leprosy--0.70: 1000). Interestingly, a marked difference was noted in the prevalance of anti-PGL-I antibodies among children between the countries; 10-14% among children under 10 years old and 15-18% among those aged between 10 and 19 in the Philippines compared to 0% and 2.9-6.4% in Korea, respectively. This study, therefore suggests that a high prevalance of anti-PGL-I IgM antibodies among children may indicate an active transmission of M. leprae, resulting in a higher incidence of leprosy in the population.

Adolescent↗
PubMed1991

Influence of extract of Rosa rugosa roots on lipid levels in serum and liver of rats.

The effects of the methanol extract of Rosa rugosa roots on serum and liver lipids were studied in rats. The rats were fed the purified diets with or without the methanol extract at the 1% level for 4 weeks. The concentrations of serum and liver total cholesterol were not significantly affected by the feeding of extract. Feeding of the extract, on the other hand, reduced the liver triacylglycerol content without influencing the serum triacylglycerol level. The effects of the extract on lipids profiles were diminished markedly by dietary cholesterol. The results suggest an existence of component in the extract which may ameliorate the accumulation of triacylglycerol in rat liver.

Administration, Oral↗
PubMed1991

Vesicle to micelle transitions of egg phosphatidylcholine liposomes induced by nonionic surfactants, poly(oxyethylene) cetyl ethers.

Vesicle to micelle transitions of sonicated liposomes of egg yolk phosphatidylcholine (EPC) induced by a homologous series of nonionic surfactants, poly(oxyethylene) cetyl ethers [POE(n) cetyl ether], were investigated by using the method of turbidity titrations. The turbidities of the mixed dispersions of sonicated vesicles and surfactant were systematically measured as a function of the surfactant added for a wide range of lipid concentrations (from 0.51 to 6.35 mM EPC). From the titration curves, two threshold points representing onset and complete solubilization of liposomal membranes were determined as a probe for the effect of the length of ethylene oxide (EO) moiety on the phase behavior of ternary system of POE(n) cetyl ethers-EPC-excess water. Patterns of turbidity curves and the surfactant concentrations at two threshold points as well as widths of region between two transitions, where lamellar sheets and mixed micelles may coexist, mainly depended on the length of EO head group. With changing the lengths, solubilization of liposomes and phase diagram showed optimal behavior. That is, in the middle range of EO numbers, it resulted in narrowest coexistence region between onset and complete solubilization. Assuming the equilibrium partitioning model, critical effective molar ratios of surfactant to lipid, Rsat, free surfactant concentrations, Dw, and the partition coefficient of surfactant between bilayer and aqueous phase, K, in surfactant-saturated liposomes were quantitatively determined as a function of EO number. Effective ratios, Rsol, and free surfactant concentration in mixed micelles were also determined. In addition, the effects of CMC and HLB of surfactants on the solubilization of liposome were discussed.

Egg Yolk↗
PubMed1991

Ontogeny of pituitary regulation of growth in the developing rat: comparison of effects of hypophysectomy and hormone replacement on somatic and organ growth, serum insulin-like growth factor-I (IGF-I) and IGF-II levels, and IGF-binding protein levels in the neonatal and juvenile rat.

We investigated pituitary regulation of growth during two critical stages of development in the rat, using hypophysectomy (Hx) with replacement of GH and/or T4. In the neonatal period (Hx on day 6), body weight and tail length were inhibited by 60% and 50%, respectively, while these parameters were inhibited by 80% and 85% by Hx in the juvenile period (Hx on day 45). Administration of T4 alone significantly increased skeletal growth (tail length) in neonatal Hx rats, while T4 alone proved ineffective in promoting somatic growth in juvenile Hx rats. GH effects were greater on body weight than on tail length at both stages of development. Replacement of both GH and T4 restored somatic growth to normal values during both time periods. The brain was the sole organ whose growth appeared to be independent of the pituitary. Hx reduced serum insulin-like growth factor-I (IGF-I) and -II in both age groups, and GH alone restored IGF-I and -II levels to the control range. The major IGF-binding proteins (IGFBPs) were analyzed by Western ligand blots. The effect of Hx on the predominant IGFBP was greater in the juvenile rat. T4 replacement in the neonate and GH replacement in the juvenile rat restored IGFBPs to control levels. We conclude that somatic growth in the rat is less pituitary dependent in the neonatal period. There are also important age-specific differences in organ response to GH and T4. Serum IGFs and their binding proteins are pituitary dependent even in infancy, and GH is their primary regulator. The neonatal Hx rat is an important model for the study of the dynamic development of the pituitary-dependent growth.

Aging↗