Long-term outcome of IgA nephropathy in living related kidney transplantation.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
H T Kim
Publications and source records attributed to H T Kim.
Comparison of the safety and efficacy of mycophenolate mofetil, prednisolone and cyclosporine and conventional cyclosporine and prednisolone in kidney transplantation.
Explore the source record for details and available documents.
Adrenal Cortex Hormones↗
Interferon tau-induced hepatocyte apoptosis in sheep.
Clinical applications of Type I interferon (IFN) are limited by adverse side effects mediated largely by unknown mechanisms. This study examined the mechanisms of acute hepatic injury in lambs treated with systemic administration of IFN-tau, a Type I IFN. Liver tissues were collected at 24, 48, or 96 hours after treatment with either IFN-tau or saline. Histopathology revealed acute hepatopathy including cellular swelling, cytoplasmic aggregates, and apoptosis in all IFN-tau-treated lambs, which were accompanied by elevation of aspartate transaminase (AST) (P <.01). The number of apoptotic hepatocytes in IFN-tau-treated lambs was higher than for control lambs (P <.001). Immunohistochemistry for proliferating cell nuclear antigen (PCNA) revealed that IFN-tau induced hepatocyte growth arrest at the G0/G1 phase of the cell cycle and that the majority of hepatocytes in S or G2 phase were eliminated by apoptosis. We investigated expression of bax-alpha and bcl-2, acting as pro- and antiapoptotic molecules, in IFN-tau-induced apoptosis. Northern blot analysis revealed increased expression of bax-alpha messenger RNA (mRNA) in IFN-tau-treated lambs (P <.01) compared with control lambs, consistent with the expression pattern for bax-alpha protein. However, there was no detectable difference in expression of bcl-2 proteins between control and IFN-tau-treated lambs. The levels of bax-alpha associated with the mitochondria also increased during IFN-tau treatment. Bax-alpha immunostaining showed scattered immunoreactive hepatocytes with morphological hallmarks of apoptosis. These results suggest that IFN-tau induces growth arrest as well as apoptosis by regulating bax-alpha expression. These pathological effects of IFN-tau on sheep liver indicate potential mechanisms of Type 1 IFN-induced hepatotoxicity in animals and humans.
Animals↗
Protein disulfide isomerase in Alzheimer disease.
There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.
Adolescent↗
Influence of phonation on basement membrane zone recovery after phonomicrosurgery: a canine model.
The process of wound healing at the basement membrane zone of the vocal folds after phonomicrosurgery was investigated. The influence of phonation and the implied optimal period of voice rest were considered. Phonomicrosurgery was performed on both vocal folds of 20 adult dogs. In 10 dogs, the left recurrent laryngeal nerve was simultaneously resected to simulate iatrogenic voice rest; the remaining 10 dogs were allowed to phonate normally. The healing process of the vocal folds of each group was observed at 1, 2, 4, 8, and 12 weeks after surgery with immunohistochemical staining and transmission electron microscopy. In the voice rest group, the basement membrane was completely re-formed in 2 weeks, and the "cover" appeared completely rearranged by 8 weeks. The results of the phonation group were characterized by a delayed healing process and basement membrane changes. These results suggest that voice rest of at least 2 weeks after surgery may be beneficial and that vocal hygiene should be maintained for as long as 8 weeks.
Animals↗
9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic mice.
Retinoids have been investigated as potential agents for the prevention and treatment of human cancers. These compounds play an important role in regulating cell growth, differentiation, and apoptosis. 9-cis-Retinoic acid (9cRA) is a naturally occurring ligand with a high affinity for both the retinoic acid receptors and the retinoid X receptors. We hypothesized that treatment with 9cRA would prevent mammary tumorigenesis in transgenic mice that spontaneously develop mammary tumors. To test this hypothesis, C3(1)-SV40 T antigen (Tag) mice, which develop mammary tumors by the age of 6 months, were treated daily p.o. with vehicle or two different dose levels of 9cRA (10 or 50 mg/kg) from 5 weeks to 6 months of age. Tumor size and number were measured twice each week, and histological samples of normal and malignant tissue were obtained from each mouse at time of sacrifice. Our results demonstrate that 9cRA suppresses mammary tumorigenesis in C3(1)-SV40 Tag-transgenic mice. Time to tumor development was significantly delayed in treated mice; median time to tumor formation for vehicle-treated mice was 140 days versus 167 days for mice treated with 50 mg/kg 9cRA (P = 0.05). In addition, the number of tumors per mouse was reduced by >50% in mice treated with 9cRA (3.43 for vehicle, 2.33 for 10 mg/kg 9cRA, and 1.13 for 50 mg/kg 9cRA, P < or = 0.002). Histological analysis of the mammary glands from vehicle and treated mice demonstrated that 9cRA treatment also did not affect normal mammary gland development. Immunohistochemical staining of normal and malignant breast tissue and Western blot analysis demonstrated that SV40 Tag expression was not affected by treatment with retinoids. Single doses of 10 and 50 mg/kg resulted in peak plasma concentrations of 3.4 and 6.71 microM, respectively. Daily doses of 9cRA for 28 days resulted in plasma concentrations of 0.86 and 1.68 microM, respectively, concentrations consistent with that seen in humans treated with 9cRA in clinical trials. These results demonstrate that 9cRA suppresses mammary carcinogenesis in transgenic mice without any major toxicity and suggest that retinoids are promising agents for the prevention of human breast cancer.
Alitretinoin↗
Synthesis and evaluation of 2-amino-9-(1, 3-dihydroxy-2-propoxymethyl)- 6-fluoropurine mono- and diesters as potential prodrugs of ganciclovir.
A series of 2-amino-9-(1,3-dihydroxy-2-propoxymethyl)-6-fluoropurine mono- and diesters, 6a-h, were synthesized as potential prodrugs of ganciclovir and evaluated for their oral ganciclovir bioavailability in rats. Treatment of 2-amino-6-chloro-9-(1, 3-dihydroxy-2-propoxymethyl)purine (4) with Me3N in DMF/THF (1/4) followed by the reaction of the resulting trimethylammonium chloride salt 5 with KF in DMF gave 2-amino-9-(1, 3-dihydroxy-2-propoxymethyl)-6-fluoropurine (2) in 83% yield. Esterification of 2 with an appropriate acid anhydride (Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O) (6 equiv for 6a-d or 1 equiv for 6e-h) in DMF in the presence of a catalytic amount of DMAP produced the diesters 6a-d in 92-98% yields and the monoesters 6e-h in 37-44% yields. Of the prodrugs tested in rats, the monoisobutyrate 6h achieved the highest ganciclovir bioavailability (45%) that is 15-fold higher than that from ganciclovir (3%), followed in order by the diisobutyrate 6d (42%), the diacetate 6a (41%), the monobutyrate 6g (41%), the monopropionate 6f (39%), the dipropionate 6b (35%), the dibutyrate 6c (35%), and the monoacetate 6e (29%). The prodrugs 6e-h were found to be quite stable at pH 6.0 (t1/2 = >29 days), 7.4 (t1/2 = >7 days), and 8.0 (t1/2 = >2 days) but had relatively short half-lives at pH 1.2 (t1/2 = 60-83 min).
Animals↗
Synthesis and evaluation of 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine mono- and diesters as potential prodrugs of penciclovir.
2-Amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7), and its mono- and diesters 8-15 were prepared and evaluated for their potential as prodrugs of penciclovir. Treatment of 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (5) with trimethylamine in THF followed by a reaction of the resulting trimethylammonium chloride salt 6 with KF in DMF afforded 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7) in 80% yield. Esterification of 7 with an appropriate acid anhydride [Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O] in DMF in the presence of a catalytic amount of DMAP produced the mono-esters 8-11 in 42-45% yields and diesters 12-15 in 87-99% yields. Of the prodrugs tested in rats, the monoisobutyrate 11 was the most efficiently absorbed and metabolized to 7, showing the mean maximum total concentration of penciclovir (5.5 microg/mL) and 7 (10.8 microg/mL) in the blood was much higher than the mean maximum concentration of penciclovir (11.5 microg/mL) from famciclovir. However, the mean concentrations of penciclovir from 11 were lower than those from famciclovir because of the limited conversion of a major metabolite 7 to penciclovir by adenosine deaminase.
Acyclovir↗
Retinoic acid receptor antagonist BMS453 inhibits the growth of normal and malignant breast cells without activating RAR-dependent gene expression.
To elucidate the role of RAR-dependent gene transcription in inhibiting breast cell growth, we have investigated the ability of retinoids to suppress growth of normal, immortal, and malignant breast cells. We compared the ability of all trans retinoic acid (atRA) to activate retinoid receptors in normal, immortal, and malignant breast cells, with its ability to inhibit the growth of these cells. Our studies demonstrate that normal breast cells are more sensitive to the growth inhibitory effect of atRA than are immortal nonmalignant breast cells and breast cancer cells. atRA activated RAR-dependent gene transcription in both atRA-sensitive and -resistant breast cells as determined by transfection of a RARE-containing reporter gene. These results demonstrate that activation of RAR-dependent gene transcription by atRA is not sufficient to inhibit growth in atRA-resistant breast cancer cells. To determine whether activation of RAR-dependent gene transcription by atRA is necessary for growth inhibition, we tested the growth suppressive effect of a retinoid (BMS453) which binds RAR receptors and transrepresses AP-1 but does not activate RAR-dependent gene expression. This retinoid inhibited the growth of normal breast cells (HMEC and 184) and T47D breast cancer cells. Breast cancer cells which were resistant to atRA, were also resistant to BMS453. Normal human breast cells were most sensitive to the anti-proliferative effects of BMS453. These results indicate that in some breast cells RAR-dependent transactivation is not necessary for retinoids to inhibit growth. Instead, retinoids may suppress growth by inhibiting transcription factors such as AP-1 through transcription factor crosstalk.
Antineoplastic Agents↗
Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats.
Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. We attempted to identify the subtype of alpha-adrenergic receptor (alpha-AR) that is responsible for the sympathetic (adrenergic) dependency of neuropathic pain in the segmental spinal injury (SSI) model in the Lewis strain of rat. This model was chosen because our previous study showed that pain behaviors in this condition are particularly sensitive to systemic injection of phentolamine (PTL), a general alpha-AR blocker. We examined the effects of specific alpha1- and alpha2-AR blockers on 1) behavioral signs of mechanical allodynia, 2) ectopic discharges recorded in the in vivo condition, and 3) ectopic discharges recorded in an in vitro setup. One week after tight ligation of the L5 and L6 spinal nerves, mechanical thresholds of the paw for foot withdrawals were drastically lowered; we interpreted this change as a sign of mechanical allodynia. Signs of mechanical allodynia were significantly relieved by a systemic injection of PTL (a mixed alpha1- and alpha2-AR antagonist) or terazosin (TRZ, an alpha1-AR antagonist) but not by various alpha2-AR antagonists (idazoxan, rauwolscine, or yohimbine), suggesting that the alpha1-AR is in part the mediator of the signs of mechanical allodynia. Ongoing ectopic discharges were recorded from injured afferents in fascicles of the L5 dorsal root of the neuropathic rat with an in vivo recording setup. Ongoing discharge rate was significantly reduced after intraperitoneal injection of PTL or TRZ but not by idazoxan. In addition, by using an in vitro recording setup, spontaneous activity was recorded from teased dorsal root fibers in a segment in which the spinal nerve was previously ligated. Application of epinephrine to the perfusion bath enhanced ongoing discharges. This evoked activity was blocked by pretreatment with TRZ but not with idazoxan. This study demonstrated that both behavioral signs of mechanical allodynia and ectopic discharges of injured afferents in the Lewis neuropathic rat are in part mediated by mechanisms involving alpha1-ARs. These results suggest that the sympathetic dependency of neuropathic pain in the Lewis strain of the rat is mediated by the alpha1 subtype of AR.
Adrenergic alpha-Agonists↗
Frequent loss of imprinting of the H19 and IGF-II genes in ovarian tumors.
Several human imprinted genes have been identified and are implicated in genetic diseases and tumorigenesis. We studied alterations of two imprinted genes, the paternally imprinted H19 and maternally imprinted IGF2, in 15 ovarian tumors with various cell types. To know allele-specific expression of the two genes, we analyzed restriction fragment length polymorphisms (RFLPs) at the 3'-untranslated region (UTR) in their cDNA, compared with those in the respective genomic DNA. As a result, biallelic H19 and IGF2 expression was observed in 8 (62%) of 13 informative (heterozygous) ovarian cancers and in 6 of 11 informative cases, respectively. H19 loss of imprinting (LOI) was most frequently observed in malignant serous cystadenocarcinoma (in four of six cases), whereas IGF2 LOI was not common in malignant epithelial cancers because three of six such LOI events occurred in benign mucinous cystadenomas and non-cancerous endometriotic cyst. Our data suggest that the alteration of H19 and IGF2 imprinting plays differential roles in tumorigenesis and progression of ovarian tumors, depending on the tissue type as well as the developmental stage. Our data may argue against tumor suppressor activity of H19 in ovarian cancers.
Alleles↗
Liver-specific enhancer II is the target for the p53-mediated inhibition of hepatitis B viral gene expression.
Here, we established the inhibitory mechanism of p53 on hepatitis B viral gene expression using HepG2 cells. Our results are as follows. First, p53 down-regulated the activities of all four promoters of hepatitis B virus (HBV), suggestive of the presence of a common element mediating the p53-dependent transcriptional repression. Second, employing the 5'-deletion constructs of the pregenomic/core promoter, the liver-specific enhancer II region was localized as a target for the p53-mediated transcriptional repression. Third, in a detailed analysis of the enhancer II region, the 5'-proximal 31-base pair region was defined as a p53-repressible element. Throughout the study, p53-mediated repression was rescued upon coexpression of the X-gene product, HBx. Finally, in an electrophoretic mobility shift assay, the defined p53-repressible element did not bind purified p53 directly, but shifted three bands in HepG2 nuclear extract, two of which was supershifted upon addition of p53 monoclonal antibody. These results display a novel mechanism of p53-dependent transcriptional repression in which p53 negatively regulates the viral-specific DNA enhancer through protein to protein interaction with an enhancer-binding protein. At the same time, the results indicate that p53 plays a defensive role against HBV by transcriptionally repressing the HBV core promoter through liver-specific enhancer II and HBx is required to counteract this inhibitory function of p53.
Adaptor Proteins, Signal Transducing↗
Influence of exposure and infusion times on the cytotoxicity and pharmacokinetics of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) .
The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.
Adenocarcinoma↗
Significance of IL-2, IL-2R, IL-6, and TNF-alpha as a diagnostic test of acute rejection after renal transplantation.
Explore the source record for details and available documents.
Acute Disease↗
The asystolic donor syndrome.
Explore the source record for details and available documents.
Accidents, Traffic↗
Lesion of the cerebellar interpositus nucleus or the red nucleus affects classically conditioned neuronal activity in the hippocampus.
1. The cerebellum and the hippocampus have been known to be neural structures involved in classical conditioning of the nictitating membrane response in rabbits. The neuronal activities related to conditioning are observed in both structures. It is uncertain, however, whether these conditioning-related neuronal activities are established in parallel or hierarchically. 2. The present study was conducted to observe the effects of lesions of the cerebellar interpositus nucleus(INT) or the red nucleus(RN) on conditioned hippocampal neuronal activity. 3. Rabbits in the first experiment were trained by standard delay conditioning and then given INT lesion by injecting the kainic acid through a cannula previously implanted. Lesions of INT abolished conditioned neuronal responses in the hippocampal CA1 area, which had been established before lesioning, as well as behavioral conditioned responses(CRs). 4. The second experiment was to examine if conditioning-related activities in the hippocampus would develop after RN was lesioned with INT intact. Rabbits were first given unilateral electrolytic lesions of RN followed by conditioning sessions. Besides a few CRs, they failed to show an increase in hippocampal CA1 activity. When training was switched to the contralateral eye, animals showed robust CRs and hippocampal responses immediately. However, training reswitched to the original eye, behavioral and neuronal responses disappeared again. 5. These results suggest that conditioned neuronal activities in the hippocampus depends on the cerebellum and that conditioning-related inputs from INT via RN may be critical for these conditioned neuronal response in the hippocampus.
Animals↗
Usefulness of electron beam computed tomography scanning for distinguishing ischemic from nonischemic cardiomyopathy.
OBJECTIVES: This study was undertaken to evaluate the ability of electron beam computed tomography (EBCT) to distinguish ischemic from nonischemic causes of cardiomyopathy by evaluating heart failure patients for coronary calcification (CC). BACKGROUND: The etiology of heart failure, whether coronary-induced or nonischemic, may be difficult to discern clinically. Differentiation of ischemic from nonischemic etiology is clinically important for both therapeutic and prognostic implications. With its ability to noninvasively discern and quantitate coronary artery calcification, EBCT correlates well with angiographic stenosis and thus may be useful in distinguishing ischemic and nonischemic cardiomyopathies. METHODS: One hundred and twenty-five patients with cardiomyopathy (ejection fraction <0.40) and known coronary anatomy underwent EBCT coronary scanning to evaluate for CCs within 3 months of coronary angiography. RESULTS: Of the 72 patients who were found to have ischemic cardiomyopathy, 71 patients had CC by EBCT (sensitivity 99%, p < 0.001), mean score 798+/-899. In comparison, among the 53 patients without significant coronary artery disease (CAD) (nonischemic cardiomyopathy), the mean score was significantly lower (17+/-51; p < 0.0001), and 44 patients had a CC score of 0 (no CC present). The specificity of EBCT to exclude CAD in patients with cardiomyopathy was 83%, using a threshold CC score of 0, and 92% for scores <80 (p < 0.001). Overall accuracy for determining the etiology of cardiomyopathy (differentiating ischemic from nonischemic) was 92% for this technique. CONCLUSIONS: This prospective, blinded study indicates that EBCT detected CC accurately and can noninvasively distinguish between cardiomyopathy because of CAD and nonischemic causes of left ventricular dysfunction.
Adult↗
The T cell receptor subsets of lymphocytes in bronchoalveolar lavage in patients with active pulmonary tuberculosis.
STUDY OBJECTIVE: To determine whether or not the levels of gamma/delta lymphocytes increase in bronchoalveolar lavage (BAL) fluid from patients with pulmonary tuberculosis. DESIGN: Prospective data collection relating to cells in BAL fluid and peripheral blood mononuclear cells (PBMC) from patients with pulmonary tuberculosis and control subjects. SETTING: A university hospital, from March 1990 to December 1993. PATIENTS: Thirteen patients with pulmonary tuberculosis who were diagnosed by culture of Mycobacterium tuberculosis from their sputum of BAL fluid and/or clinical response were enrolled in the study. Fifteen healthy volunteers participated as control subjects. MEASUREMENTS AND RESULTS: The differential cell counts in BAL fluid were made by Diff-Quik stain. The percentages of T-cell receptor (TCR) (gamma/delta and alpha/beta)-positive lymphocytes and interleukin 2 (IL-2) receptor-positive CD3 lymphocytes in BAL fluid and peripheral blood were measured by dual scan with flow-cytometry. The percentage and absolute number of lymphocytes and the percentages of CD3+, IL2R+ lymphocytes in BAL fluid significantly increased in patients with tuberculosis when compared with those of control subjects. The percentages and numbers of gamma/delta and alpha/beta TCR-positive lymphocytes in BAL fluid and PBMC from patients with tuberculosis and indistinguishable from those of control subjects. CONCLUSIONS: gamma/delta Lymphocytes do not appear to have as much meaning in patients as they do in animal studies.
Adult↗