Biomedical subjects
Publications and source records attributed to T Kwon.
A 22-month-old infant developed purulent pleurisy caused by Streptococcus pneumoniae and a hemolytic uremic syndrome. The diagnosis was suggested by the classical triad: hemolytic anemia, renal failure and thrombocytemia confirmed by renal biopsy which demonstrated extensive cortical necrosis. Renal involvement was severe, justifying an indication for renal transplantation.
The protein melanotransferrin (p97) is associated with the brain lesions of Alzheimer's disease (AD) and is a potential marker of the disorder. We measured serum p97 concentrations in 211 subjects: 71 patients with AD, 56 patients with non-AD-type dementia, and 84 normal control subjects. Serum p97 concentrations were elevated 3- to 4-fold in AD (median 15.00 pg/microl, interquartile range 10.20-17.00 pg/microl) as compared to non AD dementia (2.85 pg/microl, 1.93-7.15 pg/microl) and normal controls (3.20 pg/microl, 2.55-3.95 pg/microl). The mean elevation was significant at 13.54 +/- 3.72 pg/microl, even in the 38 subjects with mild AD (CDR stage 0.5-1). Receiver operating characteristic analyses confirmed an optimal diagnostic threshold of 10.0 pg/microl, which yielded over-all accuracy of 0.882 to 0.915. Serum p97 is a candidate marker of AD, even in the early stage when clinical diagnosis is most uncertain.
Rubella is an innocuous illness in adult unless it is contracted by a pregnant woman. We recently observed a case of congenital rubella in the department of neonatology of Abass Ndao hospital in Dakar. It's a female new-born, born after 40 week gestation, with a well followed pregnancy. The first clinical examination shows a severe intrauterine growth retardation and bilateral comeal opacity. Maternal and new-born serologic confirmation is obtained with positive rubella specific IgM and IgG. We also find severe ocular pathology, hearing deficit and associated cardiac disease. This case shows the needs for preventive strategies, such as vaccination against rubella for women of child bearing age.
The inactivation of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor p16INK4A may be caused by gene deletion, mutation or promoter hypermethylation. We have previously reported that p16INK4A in hepatocellular carcinoma (HCC) tissues and cell lines is inactivated predominantly by promoter hypermethylation rather than genomic aberrations. In the present experiments, we have studied the effects of the demethylating agent, 5-aza-2'-deoxycytidine (5-AZA/decitabine), on the expression of aberrant p16INK4A RNA transcripts and the CDK-retinoblastoma gene pathway in HCC cell lines with p16INK4A promoter hypermethylation. The expression of aberrant p16INK4A RNA transcripts was down-regulated and p16INK4A protein was strongly re-expressed in the HCC cell lines, SNU 354, 398, 423 and 475 after 5-AZA/decitabine treatment for 5 days. The re-expressed p16INK4A was functional, because it bound to and inhibited CDK4 kinase activity, and increased the concentrations of the hypophosphorylated form of retinoblastoma protein (pRB) in cells with a wild type RB gene. Moreover, treatment with the demethylating agent led not only to G1 cell cycle arrest, but also to the increased expression of the senescence-associated marker beta-galactosidase. This up-regulation of p16INK4A mRNA and protein correlated with demethylation of the p16INK4A promoter, and with the down-regulation or disappearance of aberrant p16INK4A transcripts. These results suggest that the aberrant p16INK4A RNA transcript can be transcribed from the methylated p16INK4A gene, and endogenous reactivation of functional p16INK4A mRNA by a demethylating agent can restore the pRB pathway in HCC, and foster the terminal differentiation of the malignant cells. Therefore, demethylating agents, such as 5-AZA/decitabine, may have potential in the treatment of HCC.
The aims of this study were to determine the cellular and subcellular localization of aquaporin-9 (AQP9) in different rat organs by immunoblotting, immunohistochemistry and immunoelectron microscopy. To analyze this, we used rabbit antibodies to rat AQP9 raised against three different AQP9 peptides (amino acids 267-287, 274-295, and 278-295). In Cos7 cells transfected with rat AQP9, the affinity-purified antibodies exhibited marked labeling, whereas nontransfected cells and cells transfected with aquaporin-8 (AQP8) exhibited no labeling, indicating the specificity of the AQP9 antibodies. Immunoblotting revealed a predominant band of 28 kDa in membranes of total rat liver, epididymis, testes, spleen, and brain. Preabsorption with the immunizing peptides eliminated the labeling. Immunohistochemistry showed strong anti-AQP9 labeling in liver hepatocytes. The labeling was strongest at the sinusoidal surface, and there was little intracellular labeling. Immunoelectron microscopy revealed that the labeling was associated with the plasma membrane of the hepatocytes. In testes Leydig cells exhibited anti-AQP9 labeling, and in epididymis, the stereocilia of the ciliated cells (principal cells) exhibited significant labeling, whereas there was no labeling of the nonciliated cells (basal cells). This was confirmed by immunoelectron microscopy. In spleen strong labeling of cells was observed of leukocytes in the red pulp, whereas there was no labeling of cells in the white pulp. In rat brain, AQP9 immunolabeling was confined to ependymal cells lining the ventricles and to the tanycytes of the mediobasal hypothalamus. Antibody preabsorbed with the immunizing peptide revealed no labeling. In conclusion, AQP9 proteins is strongly expressed in rat liver, testes, epididymis, spleen, and brain.
A putative Akt kinase phosphorylation site ((64)ydRIRplSYp(73)) was found in Rac1/CDC42 and Rho family proteins (RhoA, RhoB, RhoC, and RhoG). Phosphorylation of Rac1 by Akt kinase was assayed with recombinant Rac1 protein and the fluorescein-labeled Rac1 peptide. It was shown that the Rac1 peptide and the recombinant protein were phosphorylated by the activated recombinant Akt kinase and the lysate of SK-MEL28 cells, a human melanoma cell line. The phosphorylation of Rac1 inhibited its GTP-binding activity without any significant change in GTPase activity. Both the GTP-binding and GTPase activities of Rac1 S71A protein (with the serine residue to be phosphorylated replaced with alanine) were abolished regardless of the treatment of Akt kinase. Akt kinase activity and Rac1 peptide phosphorylation were down-regulated by the treatment of SK-MEL28 cells with wortmannin or LY294002 (a phosphoinositide 3-kinase inhibitor), but JNK/SAPK kinase activity was up-regulated. Thus, the results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation.
With the amino acid sequences of all reported Akt kinase physiological substrates, the possible Akt kinase substrate specificity has been suggested. The serine/threonine residue to be phosphorylated in these proteins is placed within stretches of amino acids with homology, and the arginine residues on the -5 and -3 positions and a hydrophobic amino acid on the +2 position are conserved relative to those of serine/threonine residues (XXRXRXXS/TXX). We noticed two putative Akt kinase phosphorylation sites (220GARRRGGSAS229) and (817AVRIRGKSYV826) in human telomerase reverse transcriptase (hTERT) subunit. To demonstrate that hTERT is an Akt kinase substrate protein, we performed the nonradioactive protein kinase assay with the fluorescein hTERT peptide (817AVRIRGKSYV826). We observed the phosphorylation of hTERT peptide by the human melanoma cell lysate or the activated recombinant Akt kinase proteins in vitro. With the treatment of the growth factor deprivation or okadaic acid, we also observed the up-regulation of both hTERT peptide phosphorylation and the telomerase activity. We noticed that Wortmannin down-regulates hTERT peptide phosphorylation and telomerase activity together. In addition, we observed the enhancement of telomerase activity with the pretreatment of Akt kinase in vitro. Thus, these observations suggest that Akt kinase enhances human telomerase activity through phosphorylation of hTERT subunit as one of its substrate proteins.
The serratus anterior muscle has been suggested as a versatile and reliable flap for reconstruction of head and neck and extremity injuries. The adipofascial layer overlying the serratus anterior muscle is the anatomic layer, which is supplied by the same branch of thoracodorsal artery. Even though great progress has occurred in the prevention of postoperative adhesion of extremity injuries, the problem has not been completely solved and is still of special importance in complex injuries. Between March of 1995 and February of 1996, seven patients underwent reconstructive operation as a result of soft-tissue defects of the upper or lower extremities or the scalp. We transferred free adipofascial tissue overlying the serratus anterior muscle in three patients and both serratus anterior muscle and adipofascial tissue in four patients. A free adipofascial flap overlying serratus anterior muscle was transferred when a gliding surface was required, owing to the exposure of tendons and neurovascular structures. The average duration from operation to follow-up examination was 8 months (from 4 to 16 months). The results of the operations were satisfactory in functional and cosmetic aspects. This kind of flap was very effective in reconstruction of soft-tissue defects and gliding surfaces for these reasons: easy dissection, the capability of obtaining a long vascular pedicle, large-sized flap, composite flap including muscle or rib, and the fact that there was no serious functional or cosmetic deficit at the donor site.
Novel steroidal antiinflammatory antedrugs, 11 beta,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)-isoxazolino[16,17 - d]pregna-1,4-diene (2a) and 9-fluoro-11 beta,20-dihydroxy-3,20-dioxo-3'-ethoxy- carbonylisoxazolino[16,17-d]pregna-1,4-diene (2b) were prepared in 97% yield via 1,3-dipolar cycloaddition of carbethoxyformonitrile (CEFNO) to 11 beta,21-dihydroxy-3,20-dioxopregna-1,4,-16-triene (1a) and 11 beta,21-dihydroxy-3,20-dioxo-9-fluoropregna-1,4,16-triene (1b), respectively, which were prepared via five steps from prednisolone and 9-fluoroprednisolone, respectively. The treatment of steroids 2a and 2b with acetic anhydride in pyridine led to the corresponding 21-acetates 3a and 3b, respectively, in 95% yield. Dose-response profiles of the croton oil-induced ear edema bioassay in rats were used to calculate the following ID50 values (nmol/ear resulting in a 50% reduction of edema): prednisolone (P), 540 nmol; 2b, 135 nmol; and 3b, 101 nmol. Inhibition of edema did not exceed 50% following application of either 2a or 3a. Relative potency calculations indicated that 2b was 4-fold and 3b 5.3-fold more potent than the parent compound P when applied topically. No significant adverse systemic effects were seen following treatments with 3b. These results suggest that C-9-fluorination, side-chain hydroxy group esterification, and [16 alpha,17 alpha-d]-3'-carbethoxyisoxazoline additions to the conventional steroid P improve topical antiinflammatory activity without concomitant increases in adverse systemic activity.
In a continuing effort to minimize the systemic adverse effects of potent anti-inflammatory steroids, a series of 16 alpha-alkoxycarbonyl-17-deoxyprednisolone derivatives: methyl (8a), ethyl (8b), isopropyl (8c), and benzyl (8d) 11 beta,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16 alpha-carboxylate, was synthesized and evaluated for their topical and local anti-inflammatory activities. In the acute croton oil-induced ear edema dose-response bioassay, the topical anti-inflammatory potencies of these esters relative to prednisolone, 1, were: 8a:1.0, 8b:1.3, 8c:4.0, 8a:4.7 and 1:1.0. The putative metabolite, 11 beta,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16 alpha-carboxylic acid, 7, was inactive in this test. A seven day cotton pellet granuloma bioassay was employed to study the local and systemic anti-inflammatory activities of these steroids. The local anti-inflammatory potencies of these esters relative to prednisolone, 1, were 1.3, 1.5, 2.3, 2.5, and 1.0 for 8a, 8b, 8c, 8d, and 1, respectively. In this semi-chronic study, only prednisolone exhibited significant untoward side effects, such as reduction in thymus weights, normal body weight gain, and normal plasma corticosterone levels. The increase in the topical and local potencies of these steroid esters was consistent with the increase in their 1-octanol/buffer partition coefficient. The ratio of local to systemic anti-inflammatory activity of 8c and 8d was four times that of prednisolone. The effects of increasing the size of the alkoxy group of these new steroids on both topical and local anti-inflammatory activity and their concomitant decrease in untoward systemic effects were unequivocally demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
Several stable, water soluble cyclohexa-2,4-dien-1-ones have been prepared and their photolytic coupling reactions in aqueous solution at 28 degrees C with various amino acids and dipeptides investigated. This procedure represents a new and high yielding method for the labeling of the terminal amino functionality of peptides and amino acids.
The synthesis and pharmacological evaluation of 6-(methoxycarbonyl)prednisolone (11) (a 3:1 mixture of 6 alpha-isomer 11a and 6 beta-isomer 11b), its 21-ol acetates 13a (6 alpha-isomer) and 13b (6 beta-isomer), and 17,21-diol acetonide 14 (a 6:1 mixture of 6 alpha-isomer 14a and 6 beta-isomer 14b) as local antiinflammatory steroidal antedrugs are described. The lead compound 11 was prepared via 12 steps from hydrocortisone (1). In the croton oil-induced ear edema assay, the topical antiinflammatory activity of 13a was higher than that of its epimer 13b. Except for 13a, the compounds (11, 13b, and 14) showed less activity than prednisolone. The systemic activities were assessed after 5 days of consecutive administration of these compounds at equiactive doses. Neither 11 nor 14 depressed plasma corticosteroid levels or significantly altered adrenal weights. Thymic involution was absent for 14, 15% for 11, and 47% for prednisolone at the equiactive doses. Both 13a and 13b showed significant reduction of adverse systemic effects assessed as the increase of body weight and the decreases of adrenal and thymus weights. The putative metabolite, carboxylic acid 12, showed 26 times less topical antiinflammatory activity than prednisolone. These results suggest that introduction of a labile methoxycarbonyl group at the C-6 position of prednisolone results in retention of antiinflammatory activity while reducing systemic effects noted following topical application of the parent compound prednisolone.
The authors "estimate the volume and rate of net internal migration in [South] Korea for each five-year age group for the period between 1985 and 1990, adopting the forward census survival ratio method.... Two sets of [estimates] are made: (1) net internal migration for administratively defined provinces and equivalent districts with urban-rural distinction and (2) net internal migration for each of 73 cities in 1990." Extensive tables contain the estimates.
Very late recurrent invasive squamous cell carcinoma of the cervix (over 10 years) after successful initial radiation treatment is a very rare occurrence (approximately 0.5%). Even though the treatment of choice has been radical surgery, there are a number of patients in whom surgery was regarded as undesirable. Ten such patients were reirradiated for these late recurrences after the full course of irradiation some 10 or more years ago. Six patients (six of ten) survived disease-free several years, while the remainder experienced relief of their symptoms. Factors determining success and failure are: (1) the extent of the recurrence (clinical stage); (2) the degree of tumor necrosis; (3) status of normal surrounding tissues; and (4) radiation treatment and doses, integration and individualization of the external beam and brachytherapy. Criteria for patient selection and treatment technique are discussed.
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One hundred ninety-one cases of histopathologically confirmed invasive carcinoma of the cervix were available to study. Until early diagnosis is made routinely and treatment instituted with a predictable promise for cure, attention must be devoted to studying the natural history of disease, its histologic and nuclear grading, stromal reaction, and whether lymphatics and/or blood vessels are involved. The results are impressive since patients with Stage IB carcinoma with lymphatic and/or blood vessel involvement treated by radical hysterectomy have had a 59.4% 5-year survival rate which has increased dramatically to 90% when there was no involvement. Other features which were analyzed, including tumor type, histologic and nuclear grades, size and number of nucleoli, and stromal leukocyte reactions showed no significant statistical relationship to survival. This may represent a bias because of the small number of cases in each group. This study helped identify the patient at high risk. The high-risk group as outlined by the parameters listed should receive additional therapy. Since the cancer had invaded a vascular channel, the authors selected these patients for combination anticancer chemotherapy. Those patients for combination anticancer chemotherapy. Those patients have not been followed long enough to evaluate the results of the treatment.
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