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Biomedical subjects

A H Kim

Publications and source records attributed to A H Kim.

At least 19 recordsLinked to original sources
PubMed2001

Physiological modeling of a proposed mechanism of enzyme induction by TCDD.

A physiological model was previously constructed to facilitate extrapolation of surrogates for the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver to doses comparable to human environmental exposures. The model included induction of P450 isozymes and suggested the presence of multiple binding sites with different affinities for the TCDD-liganded Ah receptor at CYP1A1 dioxin responsive elements. The model also indicated that protein synthesis on the mRNA template exhibited saturation kinetics with respect to message levels. In the present work the earlier model was revised to include the increased proteolysis of the Ah receptor on binding TCDD, more realistic representations of gene transcription and mRNA translation, and different stability for each mRNA. The revised model includes multiple TCDD-liganded Ah receptor binding sites for CYP1A1 and CYP1B1 genes, a lag of 0.2 day for production of mRNA and induced proteins, and stabilization of mRNA by a poly(A) tail. The model reproduced the transient depletion of the Ah receptor subsequent to binding ligand and the dose-response of the receptor in rats treated with biweekly oral doses of TCDD in corn oil. The model reproduced tissue TCDD concentrations observed for several dosing scenarios. Such robustness indicates the utility of the model in estimating internal dose. The model also reproduced the observed dose-response patterns for mRNA and protein for CYP1A1, CYP1A2, and CYP1B1 after repeated dosing. Neither of the two dissociation constants for the Ah receptor bound to the CYP1B1 gene is negligible, supporting the assumption of multiple response elements for this gene. The poorer induction of CYP1B1 was predicted to be due to lower affinity of the dioxin responsive elements for binding the liganded Ah receptor, suggesting the involvement of other regulatory factors, and a shorter poly(A) tail on CYP1B1 mRNA, leading to a shorter lifetime. Saturation in the kinetics of protein synthesis was linked to the limited number of ribosomes that could bind to each message molecule, resulting in fewer ribosomes bound per message at higher doses. Predicted induction at low doses was found to vary widely with the assumptions used in the construction of a model. More detailed descriptions of biological processes might provide more reliable predictions of enzyme induction.

Adipose Tissue↗
PubMed2001

The uniqueness of being a neurotrophin receptor.

Neurotrophins rely on Trk tyrosine kinase and p75 receptors for signal transduction. Recently, other roles for these receptors have been identified. Many questions have been raised about the mechanism by which these receptors mediate diverse cellular functions. Studies indicate a great deal of neurotrophin signaling specificity may stem from ligand-receptor selectivity and intracellular protein recruitment.

Animals↗
PubMed2001

Characterization of the mu rhythm during rapid eye movement sleep.

OBJECTIVE: The rolandic mu rhythm, a resting activity of somatosensory cortex, is a striking feature of the waking human electroencephalogram. This study will demonstrate that activity with identical features occurs during rapid eye movement (REM) sleep. METHODS: Eye and chin leads were added during prolonged closed circuit television (video) electroencephalographic (EEG) recording with scalp (12 patients) or subdural electrodes including 64 contract grids over the frontoparietal cortices (5 patients). Sleep staging was performed by reformatting into standard polysomnography montages (using two EEG channels, and eye and chin channels) and applying standard scoring criteria. The recordings were then reviewed using all EEG channels to assess rhythmic EEG activity by a reader blinded to the sleep staging. RESULTS: During scalp recordings, 7-10 Hz central rhythms were seen during wakefulness in 7 patients, with 6 of these also having similar rhythms during REM sleep. Similar activity was seen over somatosensory cortex during wakefulness and REM in all invasively recorded patients. This activity was blocked by contralateral body movement or contralateral somatosensory stimuli, even during REM sleep. It was absent in other sleep stages. CONCLUSIONS: This REM sleep activity recapitulates all the characteristics of the waking rolandic mu rhythm. This demonstrates functional similarity between the states of wakefulness and REM sleep.

Adult↗
PubMed2001

Induction of hepatic 8-oxo-deoxyguanosine adducts by 2,3,7,8-tetrachlorodibenzo-p-dioxin in Sprague-Dawley rats is female-specific and estrogen-dependent.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a hepatocarcinogen that induces sex-specific hepatic neoplastic alterations in female, but not male, rats. It has been hypothesized that TCDD-induced alterations in estrogen metabolism lead to increased generation of reactive oxygen species. The resulting oxidative damage to DNA may contribute to TCDD-induced tumor promotion and hepatocarcinogenesis. This hypothesis is supported by previous observations of increased 8-oxo-deoxyguanosine (8-oxo-dG) adduct formation in the livers of intact, but not ovariectomized (OVX), rats following chronic exposure to TCDD. The aim of the current study was to more clearly define the roles of hormonal regulation, gender, dose-response, and exposure duration in TCDD induction of 8-oxo-dG adducts. Diethylnitrosamine (DEN)-initiated male and female (both intact and OVX) rats were exposed to TCDD in the presence or absence of 17 beta-estradiol. Following 30 weeks of exposure, hepatic 8-oxo-dG adduct levels were significantly higher in TCDD-treated intact female rats, and TCDD-treated OVX female rats receiving supplemental 17 beta-estradiol, when compared to respective corn oil vehicle controls. In DEN-initiated female rats exposed to a range of TCDD concentrations for 30 weeks, TCDD induced 8-oxo-dG adduct levels in a dose-dependent manner. However, 8-oxo-dG adduct levels were not altered in TCDD-treated male or OVX female rats following 30 weeks of exposure. In noninitiated female rats, the level of 8-oxo-dG adducts 4 days following a single dose of TCDD was not significantly different than in control rats. Additionally, 8-oxo-dG adduct formation was not affected by exposure to TCDD for 20 weeks in intact female rats. These data suggest that the induction of 8-oxo-dG adduct levels by TCDD is likely a response to chronic oxidative imbalance. These studies provide strong evidence that the induction of 8-oxo-dG by TCDD occurs via a chronic, sex-specific, estrogen-dependent mechanism.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1.

The Akt family of serine/threonine-directed kinases promotes cellular survival in part by phosphorylating and inhibiting death-inducing proteins. Here we describe a novel functional interaction between Akt and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase. Akt decreased ASK1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus Akt site at serine 83 of ASK1. Activation of the phosphoinositide 3-kinase (PI3-K)/Akt pathway also inhibited the serum deprivation-induced activity of endogenous ASK1 in L929 cells. An association between Akt and ASK1 was detected in cells by coimmunoprecipitation. Phosphorylation by Akt inhibited ASK1-mediated c-Jun N-terminal kinase and activating transcription factor 2 activities in intact cells. Finally, activation of the PI3-K/Akt pathway reduced apoptosis induced by ASK1 in a manner dependent on phosphorylation of serine 83 of ASK1. These results provide the first direct link between Akt and the family of stress-activated kinases.

Amino Acid Sequence↗
PubMed2001

Screening for major depressive disorders in adolescent psychiatric inpatients with the mood modules from the Primary Care Evaluation of Mental Disorders and the Patient Health Questionnaire.

The mood modules from the Primary Care Evaluation of Mental Disorders (PRIME-MD) and the Patient Health Questionnaire (PHQ) were administered to 17 (52%) female and 16 (48%) male adolescent (13-17 years old) psychiatric inpatients. The internal consistencies of both were good (KR-20 for PRIME-MD=.80, Cronbach coefficient alpha for Patient Health Questionnaire=.85). The correlation between the PRIME-MD and Patient Health Questionnaire total scores was .87 (p<.001), and the point-biserial correlation of both questionnaires' total scores with being diagnosed with a Major Depressive Disorder was .54 (p<.001). Both mood modules appeared to be equally effective in screening for a Major Depressive Disorder.

Adolescent↗
PubMed2000

L-type Ca(2+) channel-mediated Zn(2+) toxicity and modulation by ZnT-1 in PC12 cells.

In view of evidence that Zn(2+) neurotoxicity contributes to some forms of pathological neuronal death, we developed a model of Zn(2+) neurotoxicity in a cell line amenable to genetic manipulations. Exposure to 500 microM ZnCl(2) for 15 min under depolarizing conditions resulted in modest levels of PC12 cell death, that was reduced by the L-type Ca(2+) channel antagonist, nimodipine, and increased by the L-type Ca(2+) channel opener, S(-)-Bay K 8644. At lower insult levels (200 micrometer Zn(2+)+Bay K 8644), Zn(2+)-induced death appeared apoptotic under electron microscopy and was sensitive to the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-CH(2)F (Z-VAD); at higher insult levels (1000 microM+Bay K 8644), cells underwent necrosis insensitive to Z-VAD. To test the hypothesis that the plasma membrane transporter, ZnT-1, modulates Zn(2+) neurotoxicity, we generated stable PC12 cell lines overexpressing wild type or dominant negative forms of rat ZnT-1 (rZnT-1). Clones T9 and T23 overexpressing wild type rZnT-1 exhibited enhanced Zn(2+) efflux and reduced vulnerability to Zn(2+)-induced death compared to the parental line, whereas clones D5 and D16 expressing dominant negative rZnT-1 exhibited the opposite characteristics.

Animals↗
PubMed1999

A comparison of the cytoplasmic domains of the Fas receptor and the p75 neurotrophin receptor.

The p75 neurotrophic receptor (p75) shares structural features with the Fas receptor (FasR). Both receptors contain extracellular cysteine-rich repeats, a single transmembrane domain, and intracellular death domains. However, it has not been clearly established whether their death domains are equivalent in their ability to mediate apoptosis. To understand better the role of p75 during apoptosis, we constructed chimeric receptors that contained the extracellular portion of the FasR and the intracellular portion of p75. These chimeric receptors, one containing the p75 transmembrane domain and the other containing the FasR transmembrane portion, as well as wild-type p75 and Fas receptors, were transiently transfected into human U373 glioma cells and human embryonic kidney 293 cells (293 cells), which are both responsive to Fas-mediated apoptosis. Whereas expression of FasR was sufficient to induce apoptosis in U373 and 293 cells, expression of p75 and the chimeric receptors induced only minimal levels of cell death compared to FasR. The results indicate that the magnitudes of FasR- and p75-induced killing are different and suggest that the death domain of p75 does not function in the same manner as the FasR death domain.

Animals↗
PubMed1998

Sonohysterographic screening before in vitro fertilization.

OBJECTIVE: To evaluate the use of sonohysterography for uterine screening before IVF. DESIGN: Prospective screening with sonohysterography and comparison with available hysterosalpingographic and hysteroscopic evaluations. SETTING: Private practice. PATIENT(S): Seventy-two women undergoing IVF-ET using their own or donor eggs. INTERVENTION(S): Sonohysterography was performed by instilling saline into the uterine cavity through an intracervical balloon catheter; there was concurrent vaginal sonographic visualization in all cases. MAIN OUTCOME MEASURE(S): Sonohysterographic findings and pregnancy rates. RESULT(S): Cavitary lesions were detected in 8 (11.1%) of 72 sonohysterographic examinations. Six of 8 cases were confirmed and treated by hysteroscopy. After sonohysterographic evaluation, 35 (48.6%) of 72 patients conceived, resulting in 25 ongoing or delivered pregnancies, 5 chemical pregnancies, and 5 spontaneous abortions. No statistically significant difference was observed in the pregnancy outcome for patients undergoing IVF who had sonohysterography compared with that for patients undergoing IVF during the same period who previously had a uterine evaluation by a different method. The estimated cost savings per patient undergoing sonohysterography instead of in-office hysteroscopy was $275. CONCLUSION(S): Sonohysterography offers advantages over in-office hysteroscopy and hysterosalpingography for evaluation of the uterus before IVF.

Adult↗
PubMed1997

Sonohysterography for screening in recurrent pregnancy loss.

OBJECTIVE: To evaluate the role of sonohysterography for screening of the uterine cavity in patients with recurrent pregnancy loss. DESIGN: Prospective evaluation of sonohysterography, including comparison with available hysterosalpingography and hysteroscopy. SETTING: University referral center. PATIENT(S): Thirty-four reproductive-aged women with at least two consecutive pregnancy losses. INTERVENTION(S): Sonohysterography was performed on all patients, using saline instilled through an endocervically placed balloon catheter with concurrent vaginal sonography. RESULT(S): Seventeen of 34 sonohysterograms (50.0%) demonstrated intrauterine abnormalities. Eighteen of 34 cases have undergone hysteroscopy or, in 1 case, laparoscopy. All confirmed the positive or negative sonohysterographic finding, resulting in a sensitivity and specificity of 100%. Additionally, 100% (12/12) of the defects were diagnosed accurately at sonohysterography when confirmed by surgery. Twenty-seven of 34 patients also had a hysterosalpingogram that demonstrated a 90.0% sensitivity and 20.0% specificity based on hysteroscopic findings, yet only 5 of 11 (45.5%) defects were diagnosed accurately at hysterosalpingography when compared with surgery. CONCLUSION(S): Sonohysterography is a highly sensitive, specific, and accurate screening tool for the evaluation of uterine cavitary defects associated with recurrent pregnancy loss and offers several advantages over hysterosalpingography.

Abortion, Habitual↗
PubMed1996

Polymerase chain reaction-based diagnosis of del (5q) in acute myeloid leukemia and myelodysplastic syndrome identifies a minimal deletion interval.

Loss of all or part of the long arm of human chromosome 5 is a recurrent abnormality in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), especially after chemotherapy for a prior malignancy. It is one of the worst prognostic indicators in AML, associated with chemotherapy resistance and short survival. These deletions center at band 5q31, which has thus been proposed as the location of a tumor suppressor gene; this site is to be distinguished from that observed in 5q- syndrome, centering at 5q32. To define the molecular extent and the clinical prevalence of 5q31 deletions, we collected a series of AML and MDS cases of mixed karyotype, taking care to exclude MDS cases with 5q- syndrome. The samples were analyzed for loss of heterozygosity (LOH) using a panel polymerase chain reaction (PCR)-based microsatellite markers from 5q, comparing malignant cells with normal tissue derived from lymphoblastoid cell lines or buccal mucosa scrapings. Losses were detected in seven of 29 matched samples, including four of 17 with MDS, and three of 12 with AML; six of these seven also had a cytogenetically-visible del(5q) or -5. The one case without a cytogenetic deletion showed molecular loss of three contiguous markers, with retention of flanking markers interleukin-9 (IL-9) and D5S414, and thus contained a small deletion that is below cytogenetic resolution. PCR failed to detect 5q loss in two cases with large cytogenetic deletions, but both had been treated and contained low percentages of malignant cells in the samples. This study thus led to the identification of a case with a minimal deletion for the 5q31 tumor suppressor gene, specified by IL-9-D5S414, that is approximately 1 Mb (2 cM) in extent. Additionally, we demonstrate that PCR-based allelotyping is a reliable method for the detection of chromosomal deletion in myeloid malignancy, providing the specimens contain a high proportion of malignant cells. These studies will help to identify the tumor-suppressor gene at 5q31, and will help to develop molecular methods for diagnosis and monitoring of these disorders.

Acute Disease↗
PubMed1996

Reproductive outcome after tubal reversal in women 40 years of age or older.

OBJECTIVE: To determine the reproductive outcome of women who received a microsurgical tubal anastomosis operation at age 40 years or older. DESIGN: Multicenter retrospective cohort study. SETTING: Four university teaching hospitals. PATIENTS: Fifty-two women having undergone tubal sterilization reversal at age > or = 40 years. MAIN OUTCOME MEASURES: Pregnancy and live birth rate. RESULTS: Of the 52 women, 10 were lost to follow-up. Of those traced, 18 of 42 (42.8 percent) conceived. Of those 18, 6 patients had a live birth, 10 patients had a first trimester spontaneous abortion, 1 patient had an ectopic pregnancy, and 1 patient had an elective termination. Overall, the live birth rate was 14.3 percent, spontaneous abortion rate was 23.8 percent, and ectopic pregnancy rate was 2.4 percent. CONCLUSIONS: Microsurgical tubal anastomosis is a justifiable alternative to IVF-ET in women age 40 years or older.

Adult↗
PubMed1996

Cytokine induction of heat shock protein in human granulosa-luteal cells.

The infiltration of leukocytes is a characteristic feature of luteolysis in humans. Leukocytes are known to generate physiological inducers of cell stress such as cytokines which have been implicated as mediators of functional luteal regression. In cells exposed to stress, a response characterized by an increase in heat shock protein (HSP) synthesis occurs. Recently, the induction of HSP-70 in rat luteal cells has been shown to inhibit luteinizing hormone (LH) and cAMP-sensitive progesterone production, possibly by interfering with the translocation of cholesterol to the mitochondrial cytochrome P450scc. We therefore investigated whether HSP-70 is induced in human granulosa-luteal cells and its relationship to steroidogenesis. [35S]Methionine labelling showed an increase in a 70 kDa protein after heat treatment which was demonstrated to be HSP-70 by Western analysis using monoclonal antibodies against the constitutive and inducible forms of HSP-70. Induction of HSP-70 in human granulosa-luteal cells was also seen with interferon (IFN) gamma (10 ng/ml), tumour necrosis factor (TNF)-alpha (100 ng/ml) and a combination of IFN gamma/TNF-alpha (10/50 ng/ml). Interleukin-1 beta (IL-1 beta) (30 ng/ml) showed minimal induction of HSP-70 above control values. An increase in activated heat shock factor, which binds to the heat shock transcriptional control element, was detected after heat shock, IFN/TNF, and IFN treatment. Coincident with the induction of HSP-70 by heat shock was the inhibition of progesterone production compared with non-shocked granulosa-luteal cells. Heat shock inhibition of progesterone synthesis was partially reversed by the cell- and mitochondria-permeant cholesterol analogue, 22R-hydroxycholesterol. Cell viability was unaffected by heat treatment. White blood cell-depleted granulosa-luteal cell cultures treated with IFN demonstrated a significant reduction in progesterone production. Treatment with IFN/TNF, TNF, and IL-1 also decreased progesterone secretion, although statistical significance was not achieved. These findings provide evidence that a stress response occurs in human granulosa-luteal cells in response to heat and cytokines. The inhibition of gonadotrophin-sensitive steroidogenesis coincident with the induction of HSP-70 synthesis by physiological agents which are present in the corpus luteum implicates HSP-70 as a potential mediator of luteolysis in the human.

Animals↗
PubMed1995

Dilutional hyponatremia during hysteroscopic myomectomy with sorbitol-mannitol distention medium.

To determine the frequency of hyponatremic complications during hysteroscopic myoma resections using sorbitol-mannitol distending medium and its relationship to operative time, fluid balance, and myoma size, we reviewed all operative hysteroscopic procedures performed by the Section of Reproductive Endocrinology and Fertility at Yale-New Haven Hospital over a 1-year period during which that medium was used. Twenty-six cases were identified of which seven involved hysteroscopic myoma resections. Hyponatremia occurred in four of the seven patients, and in one it was associated with severe posttransurethral prostatic resection (post-TURP) syndrome. The degree of hyponatremia varied roughly in direct proportion to fibroid volume and fibroid volume as a percentage of uterine volume. No relationship was found between the degree of hyponatremia and operating time, estimated submucosal volume, and uterine volume. We conclude that dilutional hyponatremia and the post-TURP syndrome may occur with the use of sorbitol-mannitol distension medium during hysteroscopy. They occur more frequently during operative hysteroscopy to resect myomata, with myoma size and myoma volume expressed as a percentage of uterine volume possibly influencing the degree of hyponatremia.

Abdominal Pain↗
PubMed1995

Large bowel-to-pelvic sidewall adhesions associated with chronic pelvic pain.

STUDY OBJECTIVES: To assess retrospectively the prevalence of colon-to-pelvic sidewall adhesions associated with pelvic pain or pelvic endometriosis, and to evaluate prospectively their prevalence compared with controls. DESIGN: A retrospective review of all patients undergoing laparoscopy for chronic pelvic pain between August 1992 and September 1993; and abased on a power analysis, a prospective comparison of women undergoing laparoscopy for chronic pelvic pain with those undergoing laparoscopy for tubal sterilization between October 1994 and December 1995. SETTING: A university-associated teaching hospital. PATIENTS: Fifty women in the retrospective portion, and 30 women (15 in each group) in the prospective portion. MEASUREMENTS AND MAIN RESULTS: Of the 50 women undergoing laparoscopy for pelvic pain, 47 (94%) had either right- or left-sided colon-to-sidewall adhesions, and these adhesions were more common than any other type of intraabdominal adhesion, 94% versus 58%. Thirty-eight (76%) of these women had visual and 25 (50%) histologic evidence of endometriosis. The prospective study revealed that women with pelvic pain had a higher rate of colon-to-sidewall adhesions than controls (93.3% vs 13.3%) and a correspondingly higher rate of visualized endometriosis (73.3% vs 6. 7%). Right-sided paracolic adhesions were both more common than left-sided adhesions (87.7% vs. 46.7%) and were more often extensive than minimal (46.7% vs 6.7%). CONCLUSIONS: Colon-to-sidewall adhesions occur in the majority of patients with chronic pain, whereas they are an uncommon finding in the general population. The lateral gutters are dependent regions of the abdominal cavity that are susceptible to the spread of peritoneal endometriosis or other inflammatory processes, and should be evaluated at diagnostic laparoscopy for chronic pelvic pain.

Chronic Disease↗