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Biomedical subjects

K Kwon

Publications and source records attributed to K Kwon.

At least 19 recordsLinked to original sources
PubMed2005

Decreased insulin sensitivity is associated with the extent of coronary artery disease in patients with angina.

BACKGROUND: Insulin resistance has been proposed as an important risk factor in the development of atherosclerosis. AIM: To evaluate the association of insulin resistance and coronary atherosclerosis, we investigated the correlation between insulin sensitivity and the degree of coronary stenosis in patients with angina pectoris. METHODS: The study population consisted of 74 subjects with angina (54 men and 20 women) aged from 31 to 73 years. Coronary angiograms were evaluated by three semiquantitative scoring systems (vessel score, stenosis score and extent score) to estimate the extent of focal and diffuse coronary artery disease (CAD). Insulin sensitivity (K(ITT)) was determined by the insulin tolerance test. RESULTS: There were significant correlations existed between K(ITT) and all three coronary scores. Multivariate analysis revealed significant and independent correlations of all three coronary scores with K(ITT) (vessel score: beta = -0.349, p = 0.004; stenosis score: beta = -0.487, p < 0.001; extent score: beta = -0.481, p < 0.001), even in patients without diabetes mellitus (vessel score: beta = -0.387, p = 0.008; stenosis score: beta = -0.469, p < 0.001; extent score: beta = -0.559, p < 0.001). K(ITT) was significantly lower in patient with diffuse CAD than without diffuse CAD (2.13 +/- 0.66 vs. 2.57 +/- 0.79%/min, p < 0.05). However, K(ITT) was not different between patients with and without focal CAD. CONCLUSIONS: Insulin sensitivity has statistically significant and independent associations with the extent of coronary stenosis. These results suggest that insulin resistance may play a major role in the development of diffuse coronary artery stenosis.

Adult↗
PubMed2001

Turning On uracil-DNA glycosylase using a pyrene nucleotide switch.

Base flipping is a highly conserved process by which enzymes swivel an entire nucleotide from the DNA base stack into their active site pockets. Uracil DNA glycosylase (UDG) is a paradigm enzyme that uses a base flipping mechanism to catalyze the hydrolysis of the N-glycosidic bond of 2'-deoxyuridine (2'-dUrd) in DNA as the first step in uracil base excision repair. Flipping of 2'-dUrd by UDG has been proposed to follow a "pushing" mechanism in which a completely conserved leucine side chain (Leu-191) is inserted into the DNA minor groove to expel the uracil. Here we report a novel implementation of the "chemical rescue" approach to show that the weak binding affinity and low catalytic activity of L191A or L191G can be completely or partially restored by substitution of a pyrene (Y) nucleotide wedge on the DNA strand opposite to the uracil base (U/A to U/Y). These results indicate that pyrene acts both as a wedge to push the uracil from the base stack in the free DNA and as a "plug" to hinder its reinsertion after base flipping. Pyrene rescue should serve as a useful and novel tool to diagnose the functional roles of other amino acid side chains involved in base flipping.

Catalysis↗
PubMed2001

Corepressor-induced organization and assembly of the biotin repressor: a model for allosteric activation of a transcriptional regulator.

The Escherichia coli biotin repressor binds to the biotin operator to repress transcription of the biotin biosynthetic operon. In this work, a structure determined by x-ray crystallography of a complex of the repressor bound to biotin, which also functions as an activator of DNA binding by the biotin repressor (BirA), is described. In contrast to the monomeric aporepressor, the complex is dimeric with an interface composed in part of an extended beta-sheet. Model building, coupled with biochemical data, suggests that this is the dimeric form of BirA that binds DNA. Segments of three surface loops that are disordered in the aporepressor structure are located in the interface region of the dimer and exhibit greater order than was observed in the aporepressor structure. The results suggest that the corepressor of BirA causes a disorder-to-order transition that is a prerequisite to repressor dimerization and DNA binding.

Allosteric Regulation↗
PubMed2001

Competing protein:protein interactions are proposed to control the biological switch of the E coli biotin repressor.

A model is suggested for the complex between the biotin repressor of Escherichia coli, BirA, and BCCP, the biotin carboxyl carrier protein to which BirA transfers biotin. The model is consistent with prior physical and biochemical studies. Measurement of transfer rates for variants of BirA with single-site mutations in the proposed BirA:BCCP interface region also provides support. The unique feature of the proposed interaction between BirA and BCCP is that it uses the same beta-sheet region on the surface of BirA that the protein uses for homodimerization into a form competent to bind DNA. The resulting mutually exclusive protein:protein interfaces explain the novel feature of the BirA regulatory system, namely, that transcription of the genes involved in biotin synthesis is not determined by the level of biotin, per se, but by the level of unmodified BCCP. The model also provides a role for the C-terminal domain of BirA that is structurally similar to an SH3 domain.

Acetyl-CoA Carboxylase↗
PubMed2000

Multiple disordered loops function in corepressor-induced dimerization of the biotin repressor.

Cooperative association of the Escherichia coli biotin repressor with the biotin operator is allosterically activated by binding of the corepressor, bio-5'-AMP. The corepressor function of the adenylate is due, in part, to its ability to induce repressor dimerization. Since a high-resolution structure of only the apo or unliganded repressor is currently available, the location of the dimerization interface on the protein structure is not known. Here, five mutants in the corepressor-binding domain of the repressor have been analyzed with respect to their DNA-binding and self-assembly properties. Results of these studies reveal that four of the mutant proteins exhibit defects in DNA binding. These same proteins are compromised in self-assembly. Furthermore, in the three-dimensional structure of the apo protein the mutations all lie in partially disordered surface loops, one of which is known to participate directly in corepressor binding. These results suggest that multiple disordered surface loops function in the corepressor-induced dimerization required for sequence-specific DNA binding by the biotin repressor.

Adenosine Monophosphate↗
PubMed2000

Function of a conserved sequence motif in biotin holoenzyme synthetases.

The biotin holoenzyme synthetases (BHS) are essential enzymes in all organisms that catalyze post-translational linkage of biotin to biotin-dependent carboxylases. The primary sequences of a large number of these enzymes are now available and homologies are found among all. The glycine-rich sequence, GRGRXG, constitutes one of the homologous regions in these enzymes and, based on its similarity to sequences found in a number of mononucleotide binding enzymes, has been proposed to function in ATP binding in the BHSs. In the Escherichia coli enzyme, the only member of the family for which a three-dimensional structure has been determined, the conserved sequence is found in a partially disordered surface loop. Mutations in the sequence have previously been isolated and characterized in vivo. In this work these single-site mutants, G115S, R118G, and R119W, of the E. coli BHS have been purified and biochemically characterized with respect to binding of small molecule substrates and the intermediate in the biotinylation reaction. Results of this characterization indicate that, rather than functioning in ATP binding, this glycine-rich sequence is required for binding the substrate biotin and the intermediate in the biotinylation reaction, biotinyl-5'-AMP. These results are of general significance for understanding structure-function relationships in biotin holoenzyme synthetases.

Adenosine Monophosphate↗
PubMed2000

Expression of osteopontin in calcified coronary atherosclerotic plaques.

Advanced atherosclerosis is often associated with dystrophic calcification and remodeling of extracellular matrix of vascular wall. Recently many studies have documented a general relationship between calcification and severity of coronary disease, and discussed the feasibility of electron beam computed tomography for detecting and quantifying the coronary artery calcification in the patients. The present study investigated the expression and the localization of osteopontin, one of noncollagenous bone matrix protein, within the calcified coronary arteries. Autopsy-derived coronary artery specimens were scanned and reconstructed to visualize the pattern of coronary calcification using a novel microscopic computed tomography technique. The localization of the osteopontin were evaluated by immunohistochemial stain with LF7. The present study showed that the pattern of coronary calcification is variable and the expression of osteopontin is localized mainly to calcified lesion. The smooth muscle cells in addition to macrophage expressed osteopontin protein in human coronary atherosclerotic plaques. Soluble osteopontin released near to the sites of vascular calcification may represent an adaptive mechanism aimed at regulating the process of vascular calcification.

Aged↗
PubMed1999

Complete myocardial revascularization on the beating heart.

BACKGROUND: Complete myocardial revascularization with excellent visualization, exposure, and stabilization can be accomplished on the beating heart without cardiopulmonary bypass (CPB). METHODS: Three hundred patients were totally revascularized via median sternotomy with myocardial stabilization using the CardioThoracic System. All patients who underwent coronary artery bypass grafting were considered for the off-pump procedure. Pericardial sutures were placed at the level of the left atrial appendage and were pulled upwards to the right. The stabilizer was applied sequentially from circumflex, obtuse marginal, intermediate, diagonal, left anterior descending, and right coronary artery. Coronaries were occluded using the Calafiore technique, and multiple arterial grafts were inserted. RESULTS: The average number of grafts was 3.4 per patient. Six percent had to be converted to standard CPB. Comorbidity was not a limiting factor with 8% redos, 48% having diabetes, and acute myocardial infarctions in 28%. The unadjusted mortality was 2.3%, and stroke rate was 0.7%. CONCLUSIONS: These results indicate that complete revascularization can safely be accomplished without CPB.

Aged↗
PubMed1998

Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas.

The transforming growth factor-beta (TGF-beta) type II receptor (RII) is a colon cancer suppressor gene that is inactivated by mutation in 90% of human colon cancers arising via the microsatellite instability (MSI) pathway of carcinogenesis. To determine the pathophysiological consequence of RII mutations, we have determined the timing of their onset among 22 MSI human colon adenomas of varying stages. No RII mutations were detected in any early MSI adenoma, including all those with simple tubular or villous histology. The earliest RII mutation detected was in a region of high-grade dysplasia but was absent from the surrounding simple adenoma. Six additional RII mutations were all found in highly progressed adenomas that contained regions of frankly invasive adenocarcinoma. These RII mutations were detected in both the advanced adenomas and their adjacent regions of carcinoma. RII mutation is a late event in MSI adenomas and correlates tightly with progression of these adenomas to cancer.

Adenoma↗
PubMed1998

Analysis of the gene encoding cyclomaltodextrinase from alkalophilic Bacillus sp. I-5 and characterization of enzymatic properties.

The gene encoding cyclomaltodextrinase (CDase) was cloned from alkalophilic Bacillus sp. I-5. The nucleotide sequence of the gene was determined and the physicochemical properties of the enzyme were investigated. The gene had an open reading frame of 559 amino acids with a predicted molecular weight of 64,884. The enzyme was purified to near homogeneity from Escherichia coli cells carrying a recombinant plasmid that contained the CDase gene. The enzyme hydrolyzed cyclomaltoheptaose (beta-CD) 13 times better than starch and 33 times better than pullulan, and it had transglycosylation activity. The enzyme also hydrolyzed acarbose, a pseudotetrasaccharide inhibitor of glucosidases. The enzyme was stabilized by Ca2+ and the activity was increased more than twofold in the presence of 5 mM EDTA. The optimum temperature of the enzyme was elevated from 40 to 50 degrees C by Ca2+ ion and the thermal activity was maintained more than 80% at 60 degrees C in the presence of Ca2+. Comparison of known amino acid sequences of several amylolytic enzymes with cyclomaltodextrinase activity, site-directed mutagenesis of the enzyme, and substrate specificity of the enzyme imply that the region between the third and the fourth conserved regions of the enzyme may play an important role in binding and degradation of cyclomaltodextrin.

Acarbose↗
PubMed1997

Detection of a dup(17q) and inv(16) by fluorescence in situ hybridization in acute myelomonocytic leukemia.

Two cases of acute myelomonocytic leukemia (AMMoL) of FAB type M4Eo are described in which a primary subclone containing a dup(17)(q21q25) and a subclone containing dup(17)(q21q25), inv(16)(p13q22) were seen in one patient, and -7, dup(17)(q21q25) in another. Fluorescence in situ hybridization (FISH) was carried out for the confirmation of the duplicated segment and breakpoint of inv(16). Inv(16) is a well known anomaly in AMMoL, whereas dup(17q) is rare though as not yet confirmed, this anomaly could be a nonrandom or novel change in AMMoL.

Child↗
PubMed1997

Outcome of clozapine therapy for elderly patients with refractory primary psychosis.

OBJECTIVE: The objective was to analyze outcome of clozapine therapy in elderly patients with treatment refractory primary psychosis. DESIGN: This was an open-label clozapine trial in elderly patients. Patient psychopathology was assessed before and after clozapine therapy. SETTING: A psychiatry service at a large urban/suburban Veterans Administration Medical Center. PATIENTS: Inpatients and outpatients age 65 years or older with primary psychotic disorders established to be resistant to conventional antipsychotic therapy (Kane et al., 1988). Ten patients met study inclusion criteria out of a total of 134 patients receiving clozapine at the Cleveland VAMC (7.5%). Mean age of the group was 70.6 years. MEASURES: Patients were rated with the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962). Additional data on patient demographics, comorbid non-psychiatric diagnoses and concurrent psychotropic medication were collected via chart review. RESULTS: Mean clozapine dosage was 204 mg/day for a mean duration of 430 days. 7/10 patients had some degree of clinical improvement and 3/10 patients had significant improvement documented by BPRS change of 20% or greater. Patients had a mean of 1.4 comorbid physical illnesses, which were not worsened by clozapine therapy. 4/10 patients discontinued clozapine therapy due to adverse effects or inability to comply with bloodwork; however; only 2/10 were truly treatment intolerant. CONCLUSIONS: Clozapine is a useful alternative treatment option for elderly individuals with refractory primary psychosis. As in younger patients, inability to tolerate drug-related adverse effects or weekly bloodwork may lead to drug discontinuation.

Aged↗
PubMed1996

Clozapine reduces water-drinking behavior in schizophrenic patients with polydipsia.

Disordered water balance, or polydipsia, is an underassessed and underreported phenomenon present in the severely psychiatrically disabled population. Prevalence rates for polydipsia range from 6.2 to 20%. We followed up five male patients (mean age 43) with chronic schizophrenia who met the Kane criteria for being treatment nonresponders and who, in addition, had marked polydipsia. Three patients had previously received medical care for hyponatremia and had to be placed on fluid restriction when admitted to the hospital. All patients exhibited polydipsia despite high doses of typical antipsychotic drugs. Each patient was treated openly with clozapine (range 450-800 mg/day) for at least 6 months. In each case, there was a decline in the Brief Psychiatric Rating Scale score (preclozapine mean, 63; postclozapine mean, 46), and a marked reduction in fluid-seeking behavior. All fluid restrictions could be lifted, and the patients were discharged from the hospital. During a mean follow-up period of 17 months, during which patients were evaluated weekly, polydipsic behavior that required intervention had not been noted. We conclude that clozapine may be a highly effective treatment for polydipsia in patients with treatment-refractory schizophrenia. Future studies may aim to delineate neurobiologic mechanisms.

Adult↗
PubMed1996

Clozapine-induced urinary incontinence: incidence and treatment with ephedrine.

BACKGROUND: Treatment with the atypical antipsychotic drug clozapine appears to be associated with an increased incidence of urinary incontinence (UI). We posited that the potent anti-alpha-adrenergic effects of clozapine were involved, and hence that an alpha-adrenergic agonist would reduce UI. We tested this hypothesis by using ephedrine, an approved alpha-adrenergic agonist. METHOD: Fifty-seven inpatients with schizophrenia or schizoaffective disorder (DSM-IV) who met the Kane criteria for being treatment refractory were treated with clozapine (75-900 mg/day). Patients who developed UI were then openly treated with ephedrine in increasing doses until UI was attenuated or a dose of 150 mg/day was attained. RESULTS: Seventeen patients developed UI as evidenced by either urine-stained sheets/clothing or direct patient reports. In 2 cases, the UI was sufficiently severe that adult diapers had to be used. Comparison of patients who developed UI and those who did not showed that UI was associated with female gender and with concomitant treatment with typical antipsychotic drugs. One patient was treated with a behavioral program, but the remaining 16 patients were treated with ephedrine. Ephedrine treatment was very effective, with 15/16 patients showing improvement within 24 hours after reaching maximum ephedrine dosage. Twelve of 16 (including the 2 most severe) eventually had a complete remission of their UI. In the remaining 4 patients, 3 had a reduction in the frequency of UI and 1 showed no response. These benefits have been maintained over the course of 12 months of subsequent treatment for several patients. There were no side effects associated with the use of ephedrine nor were there any changes in neuropsychiatric status. CONCLUSION: Ephedrine appears to be a safe and effective treatment clozapine-associated UI. By inference, it is likely that clozapine may cause UI via its anti-alpha-adrenergic properties.

Adrenergic alpha-Agonists↗
PubMed1991

The unstable ST segment early after thrombolysis for acute infarction and its usefulness as a marker of recurrent coronary occlusion.

To investigate the incidence of early recurrent ST elevation after intravenous thrombolytic therapy for acute myocardial infarction, 12-lead electrocardiograms were continuously monitored for 571 +/- 326 minutes in 31 patients presenting within 4 hours of symptom onset. The study group comprised 9 women and 22 men (mean age +/- standard deviation 53 +/- 12 years), with ST elevation (anterior in 15, inferior in 16) on the initial electrocardiogram, who were given either tissue plasminogen activator (22 patients) or streptokinase (9 patients). Angiography was performed in 30 of 31 patients at 7 to 10 days. Early (less than 3 hours) resolution of ST elevation occurred in 19 patients (61%) at a median of 94 minutes (interquartile range 57 to 113) after thrombolysis, whereas 12 (39%) had no or late (greater than 6 hours) resolution. Eleven of the 19 with early resolution (58%) had either transient (5 patients) or sustained (6 patients) recurrences of ST elevation. Recurrent ST elevation was equal to or more than the initial peak elevation in 9 of 11 patients, and greater than 75% of initial peak in 2. A total of 25 episodes of recurrent ST elevation were observed in the 11 patients (19 transient and 6 sustained episodes), of which 8 (32%) were silent. The proportion of silent episodes was similar for transient (35%) and sustained (33%) recurrences. All patients with sustained recurrent ST elevation had at least 1 preceding transient recurrence. The median duration of transient recurrent ST elevation was 43 minutes (28 to 63).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Angiography↗