Absence of factor V Leiden mutation in Koreans.
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Asian People↗
Biomedical subjects
S Park
Publications and source records attributed to S Park.
Mechanism for coupling free energy in ATPase to the myosin active site.
Acrylamide quenching of tryptophan 510 (Trp510) fluorescence in rabbit skeletal myosin subfragment 1 (S1) indicates the conformation of the probe binding cleft, containing the highly reactive thiol (SH1) and Trp510, in the presence of nucleotides or nucleotide analogs trapped in the active site of S1 [Park et al. (1996) Biochim. Biophys. Acta 1296, 1-4]. The Trp510 quenching efficiency shows that the probe binding cleft closes slightly in the presence of beryllium fluoride trapped MgADP (MgADPBeFx-S1) and most tightly in the presence of vanadate trapped MgADP (MgADPVi-S1) with aluminum fluoride and scandium fluoride trapped MgADP (MgADPA1F4-S1 and MgADPScFx-S1) falling in between in the order MgADPBeFx > MgADPA1F4 > MgADPScFx > MgADPVi. These nucleotide analogs are identified with sequential structural changes in MgATP during hydrolysis in the same order with beryllium fluoride occurring earliest in the ATPase cycle. Correlation of the separation distance of the gamma-phosphate analog metal from the oxygen connecting it to the beta-phosphate in ADP, to the extent of cleft closure, suggests that this distance in the nucleotide transition state determines the conformation of the probe binding cleft. Trp510 quenching efficiency was also measured as a function of the base moiety of the vanadate trapped Mg-nucleotide diphosphate (MgNDPVi-S1). The extent of cleft closure is largest in the presence of the natural substrate NDP and follows the order MgADPVi > MgCDPVi > MgUDPVi > MgIDPVi > MgGDPVi with very little difference between MgADPVi and MgCDPVi. These data follow the order of the effectiveness of the corresponding nucleotide triphosphates to support force production in muscle fibers [Pate et al. (1993) J. Biol. Chem. 268, 10046-10053]. In both the fiber and S1, it appears that the 6-position amino group of the bases of ADP and CDP is required to properly anchor the nucleotide in the active site, possibly at tyrosine 135 as suggested by X-ray crystallographic studies [Fisher et al. (1995) Biochemistry 34, 8960-8972]. Finally, the Trp510 quenching efficiency was measured as a function of the size of the divalent cation trapped in the active site of S1 with ADPVi. These data failed to show a correlation suggesting that the divalent cation is not involved with the propagation of influence from the active site to the probe binding cleft. The forgoing experiments suggest that the changing conformation of ATP during hydrolysis, parameterized by the increasing distance between the beta- and the gamma-phosphate, stresses the active site of S1 through protein-nucleotide contacts at the gamma-phosphate and nucleotide base. The stress-induced strain in the cross-bridge may be the mechanism by which energy in ATP is transferred to the myosin structure.
Adenosine Diphosphate↗
The Eek receptor, a member of the Eph family of tyrosine protein kinases, can be activated by three different Eph family ligands.
The Eph family of receptors, the largest subgroup within the tyrosine protein kinase receptor family, are comprised of at least thirteen members, many of which are predominantly expressed in the developing and adult nervous system. In this study, we have isolated a full-length cDNA, encoding the mouse homologue of a previous partially characterized Eek protein, a member of Eph receptor tyrosine kinase family. In a comparison of the amino acid sequences of various Eph family members, Eek is most similar to Ehk-3/MDK1, Sek/Cek8, Ehk-2, Hek/Mek4/Cek4, and Bsk/Ehk1/Rek7/Cek7, which are predominantly expressed in the nervous system. Additionally, we have used a low-stringency PCR cloning technique to identify ligands, related to B61, that may interact with Eek. Three different GPI-linked ligands, namely Elf-1/Cek7-L, Ehk1-L/Efl-2/Lerk3 and AL-1/RAGS, were isolated from mouse brain. To study the functional interactions between these ligands and the Eek receptors, we have constructed chimeric ligands consisting of the Fc portion of human IgG fused to their carboxyl-terminus. These chimeric ligands bound to, and activated both the Eek receptors and the Eek-TrkB chimeric receptors expressed in NIH3T3 cells. These findings suggest that Eek receptor can be activated by at least three different GPI-linked ligands.
3T3 Cells↗
Synthesis and utilization of GDP-D-arabinopyranoside.
We describe a procedure for the enzymatic synthesis of labeled or unlabeled GDP-D-arabinopyranoside. This method uses two enzymes purified from pig kidney: an L-fucokinase and a GDP-L-fucose pyrophosphorylase. The isolated GDP-D-[3H]arabinose served as a precursor for arabinose addition to lipophosphoglycan (LPG) of Leishmania major, using a parasite membrane fraction as the source of arabinosyltransferase. The procedures described provide a useful means for obtaining radiolabeled GDP-D-arabinopyranoside to study synthesis of D-arabinopyranoside-containing glycoconjugates.
Animals↗
Frequent loss of heterozygosity in the region of the D7S523 locus in advanced ovarian cancer.
Loss of heterozygosity (LOH) of the long arm of chromosome 7 occurs frequently in many types of primary cancers. We analyzed 22 primary ovarian cancers for LOH of chromosome arm 7q using a set of 16 microsatellite markers in order to determine the location of a putative tumor suppressor gene (TSG). Eleven samples (50%) showed LOH at least at one locus on chromosome arm 7q. We identified the smallest commonly deleted region to be at 7q31.1, which includes D7S523. LOH of chromosome arm 7q was more frequent in advanced stages (III-IV) (7/9, 78%) than in early stages (I-II) (4/13.31%) of ovarian cancer (P < 0.05). These data suggest that alteration of a TSG at 7q31.1 gene plays an important role in advanced ovarian cancer.
Chromosome Deletion↗
Differential uptake and killing potential of Campylobacter jejuni by human peripheral monocytes/macrophages.
The ability of Campylobacter jejuni to survive in monocytes after phagocytic uptake was tested in a new in vitro model using adherent macrophages derived from human peripheral monocytes. The cells were stimulated with cytokines before use to ensure full phagocytic and killing activity. The kinetics of uptake and killing of bacteria was followed for 72 h with 16 strains, including stool and blood isolates and laboratory adapted strains. Significant bacterial strain differences were not observed, but the viability of phagocytosed bacteria was dependent on the individual donating the macrophages. The majority of blood donors carried macrophages that killed phagocytosed Campylobacter within 24 or 48 h. There was no correlation between the source of isolation of the strains and relative intracellular survival. Bacterial mutants of superoxide dismutase, catalase or polyphosphate kinase were all as sensitive to macrophage killing as their isogenic wild-type strain. In contrast, about 10% of the voluntary blood donors carried monocytes which were incapable of killing phagocytosed bacteria. Such macrophages displayed normal uptake, but killing was insufficient and bacterial growth was observed with all strains and mutants tested. We conclude that (1) since in most cases activated human macrophages kill C. jejuni efficiently after phagocytosis, intra-phagocytic survival is not a common phenomenon during Campylobacter infection; and (2) those individuals carrying macrophages that are unable to destroy phagocytosed bacteria are at risk to develop a bacteremia during Campylobacter infection.
Bacteremia↗
Association of an oculomotor delayed response task and the Wisconsin Card Sort Test in schizophrenic patients.
The relationship between a widely-used neuropsychological test of frontal lobe function, the Wisconsin Card Sort Test, and spatial working memory, as assessed by the oculomotor delayed response task, was examined in schizophrenic patients. Schizophrenic patients were impaired compared with bipolar and normal control subjects on both tasks and their working memory performance was significantly correlated with their WCST measures. The spatial working memory and the WCST deficits in schizophrenia may reflect disrupted circuitry mediated by the dorsolateral prefrontal system.
Adult↗
Simultaneous determination of the elimination profiles of the individual enantiomers of racemic isoproterenol using capillary electrophoresis and microdialysis sampling.
Microdialysis sampling and capillary electrophoresis with electrochemical detection (CE-EC) were used in combination to simultaneously define the elimination profile of each enantiomer of isoproterenol (ISP) administered as a racemic mixture to Sprague-Dawley rats. Resolution of the enantiomers of ISP was accomplished using a running buffer containing methyl-O-beta-cyclodextrin as a chiral recognition reagent. The CE-EC system provided a concentration limit of detection of 0.63 ng ml-1, allowing monitoring of the elimination of ISP for up to six half-lives. Microdialysis sampling was capable of continuously monitoring the concentration of ISP with 60 s resolution. The concentration versus time data for the elimination of (+) and (-) ISP were fit to a biphasic first order elimination model yielding average apparent distribution half-lives of 0.52 +/- 0.07 min and 0.55 +/- 0.08 min and average apparent elimination half-lives of 9.8 +/- 2.2 and 8.8 +/- 2.0 min for (-) and (+) ISP, respectively (n = 3 rats). No statistically significant difference in the average half-lives was found. However, because each enantiomer was simultaneously determined in each animal a paired two-sample t-Test could also be done. This statistical analysis demonstrated that a difference in the elimination half-lives of the enantiomers of ISP does exist.
Adrenergic beta-Agonists↗
Homozygous deletions at 9p21 in childhood acute lymphoblastic leukemia detected by microsatellite analysis.
To gain a fuller understanding of the role of deletions of chromosome 9 in the development of childhood acute lymphoblastic leukemia (ALL), we performed detailed deletional mapping of chromosome 9 in 54 primary ALL samples with matched normal DNA using 22 highly polymorphic markers; and this information was combined with our previous data concerning the presence of deletions of CDKN2/INK4A/p16 and CDKN2B/INK4B/p15 in these samples. We have found a very high frequency of loss of heterozygosity (LOH) (31 of 54 cases (57%)) on chromosome arm 9p. As expected, the smallest region of LOH was between D9S1747 and D9S1748 at 9p21, including CDKN2/INK4A/p16, but excluding CDKN2B/INK4B/p15. Homozygous deletions at 9p21 occurred in 23 of 54 (43%) samples (seven of 11 (64%) T-ALL, 16 of 45 (36%) precursor-B ALL). We detected seven cases of homozygous deletions at 9p21 which had not been detected by Southern blot hybridization, showing the power of microsatellite analysis in detecting homozygous deletions. In most cases, homozygous deletions were limited to the region between D9S1747 and CDKN2B/INK4B/p15. We have attempted to determine the mechanism and timing of 9p deletions. Of the 23 samples with homozygous deletions at 9p21, 21 samples had surrounding large LOH. Of the 29 samples with LOH of 9p, homozygous deletion at 9p21 was identified in 22 cases. In addition, six patients have been studied at diagnosis and relapse, all six showed the same 9p21 structure at relapse (normal, three patients; hemizygous deletions, two patients; homozygous deletion, one patient) as their initial presentation. Finally, three patients (homozygous deletion, one patient; hemizygous deletion, two patients) had the IFN-alpha rather than CDKN2/INK4A/p16 deleted. In summary, these data further emphasize the importance of 9p21 loss in the development of childhood ALL.
Carrier Proteins↗
Microsatellite instability and other molecular abnormalities in childhood acute lymphoblastic leukaemia.
Microsatellite instability (MSI) has been considered to represent the defect of DNA mismatch repair systems and has been implicated in the tumourigenesis of several human malignancies. To investigate the possible presence of microsatellite instability in childhood acute lymphoblastic leukaemia (ALL), we examined 48 primary ALL samples. Instability was determined at 85 different microsatellite loci localized to 12 different chromosome arms. Microsatellite instability was detected in five (10%) samples. Interestingly, the instability was found at chromosomal regions associated with frequent alterations. Two samples had instability at the microsatellite marker within the TEL gene on chromosome arm 12p. Two other samples had instability at a microsatellite marker close to CDKN2/p16 on 9p; one of these samples had a homozygous deletion at 9p21. The fifth sample had instability at the microsatellite marker on 6q, which we have found is a frequent region of loss of heterozygosity in childhood ALL. Taken together, instability was rare in childhood ALL, but was localized to the three most frequently deleted chromosome regions in childhood ALL, suggesting that localized microsatellite instability may identify a fragile chromosomal region which could result in alteration of surrounding target genes and lead to leukaemia.
Blotting, Southern↗
Exercise training down-regulates ob gene expression in the genetically obese SHHF/Mcc-fa(cp) rat.
The recently cloned obesity gene (ob) encodes a protein, leptin, which is secreted from adipose tissue and interacts with hypothalamic receptors to decrease appetite, increase energy expenditure, and reduce body lipid stores. The levels of ob mRNA are increased in several models of obesity, consistent with the hypothesis that obese animals may be resistant to the actions of leptin. The present study examined the impact of increased energy expenditure through exercise training on ob mRNA gene expression and body composition in the SHHF/Mc-fa(cp) male rat, a rodent model of obesity, insulin resistance, and type II diabetes. Six week old lean and obese animals were trained 8-12 weeks by treadmill running at 70% peak oxygen uptake, 5 days/wk, for 1.5 hr/day. After endurance training, exercised rats had significantly lower total body fat compared to sedentary rats of the same age, despite maintaining the same body weight. In the obese SHHF/Mcc-fa(cp) rat, the level of ob mRNA expression was markedly increased by four fold in subcutaneous adipose tissue compared to lean controls (p<0.05). In response to exercise training, there was a significant 85 % decrease in ob mRNA in exercised-training lean rats (p < 0.05) compared with non-exercised controls, while in obese-exercised rats, ob gene expression was significantly reduced only by 50% relative to non-exercised obese rats (p < 0.05). These results demonstrate that exercise training reduces fat mass and ob mRNA in lean and obese rats, and supports the hypothesis of a feedback loop between the adipocyte and hypothalamus that attempts to maintain body weight at a constant level by reducing ob gene expression in response to increased energy expenditure.
Adipose Tissue↗
Verapamil accelerates the transition to heart failure in obese, hypertensive, female SHHF/Mcc-fa(cp) rats.
We sought to characterize the effects of the nonselective Ca2+ channel antagonist, verapamil, and the vascular-selective Ca2+ channel antagonist, felodipine, on obese, hypertensive, heart failure-prone, female SHHF/Mcc-fa(cp) rats. Rats were treated for < or = 2 months with verapamil (57 mg/kg/day) or felodipine (24 mg/kg/day). Blood pressures were determined at monthly intervals by the tail-cuff method. Heart weights and myosin isoforms were measured at the end of treatment. Direct cardiac effects of verapamil and felodipine were examined in electrically field stimulated, fura-2/AM-loaded cardiomyocytes. Both Ca2+ channel antagonists reduced systolic blood pressures. Verapamil, but not felodipine, increased heart weights and decreased expression of the myosin V1 isoform. In older animals, 75% of those treated with verapamil developed end-stage congestive heart failure. Age-matched control and felodipine-treated rats remained healthy. In isolated cardiomyocytes, 10(-9) M verapamil significantly reduced Ca2+ transient amplitudes but 10(-9) M felodipine did not. Both Ca2+ channel antagonists reduced blood pressures in obese, hypertensive, female SHHF rats. Verapamil, but not felodipine, produced heart failure in a large number of these animals. Differences between the in vivo effects of the two Ca2+ channel antagonists may be related to the differing effects on sarcolemmal Ca2+ influx.
Animals↗
Benign and malignant esophageal strictures: treatment with a polyurethane-covered retrievable expandable metallic stent.
PURPOSE: To evaluate the clinical effectiveness of a polyurethane-covered, retrievable, self-expandable metallic stent and hook catheter in the treatment of esophageal strictures. MATERIALS AND METHODS: Stents were constructed of 0.4-mm stainless steel wire in a cylindric zig-zag configuration of six to nine bends. Four to eight stents were connected in tandem by dipping in a polyurethane solution. A nylon loop was hooked inside to each bend of the proximal portion of the stent and strung with a thread. Under fluoroscopic guidance, 22 stents were placed in 16 patients with a malignant stricture and five patients with a benign stricture. The stent was removed with a hook catheter 2 months after placement in patients with a benign stricture and when complications occurred in patients with a malignant stricture. All patients had dysphagia with ingestion of soft foods or liquids. RESULTS: Stent placement was technically successful and well tolerated in 20 patients. In one patient, the stent was misplaced but relocated successfully. After stent placement, all patients were able to ingest solid and/or soft foods without dysphagia. After stent removal, strictures showed improvement but recurred in two patients. CONCLUSION: Use of polyurethane-covered, retrievable expandable stents seems to be a feasible and effective method of treatment of benign and malignant esophageal strictures.
Adolescent↗
Age-dependent augmentation of cardiac endothelial NOS in a genetic rat model of heart failure.
Alterations in nitric oxide (NO) biosynthesis in the heart have been implicated in the pathophysiology of heart failure. We compared changes in cardiac nitric oxide synthase (NOS) activity and expression in genetically heart failure-prone (SHHF) rats at 6, 12, and 18 mo of age with those in age-matched spontaneously hypertensive (SHR) and Sprague-Dawley (SD) rats. Systolic blood pressure was significantly higher in SHHF and SHR rats compared with SD rats; however, it declined with age in SHHF rats only. Left ventricular mass increased with age in SHR and SHHF, but not in SD rats. Plasma nitrate and nitrite level was elevated in SHHF and SHR rats at 18 mo only. In left ventricular homogenates from SHHF rats, Ca(2+)-dependent NOS activity increased markedly with age and was accompanied by enhanced expression of endothelial NOS (eNOS). In contrast, SHR rats showed a much smaller increase in Ca(2+)-dependent NOS activity over time without changes in eNOS expression; neither parameter was altered with age in SD rats. Ca(2+)-independent NOS activity was not detected in any heart. This is the first report of a unique alteration in myocardial NOS activity in hypertensive rats genetically prone to heart failure.
Aging↗
Skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase gene expression in congestive heart failure.
Congestive heart failure leads to skeletal muscle abnormalities, one of which is a prolongation of sarcoplasmic reticulum Ca2+ flux. The purpose of this study was to determine whether skeletal muscle of spontaneous hypertensive and heart failure rats have alterations in the expression of the sarcoplasmic (or endoplasmic) reticulum Ca(2+)-ATPase (SERCA) gene. Northern analysis revealed that SERCA1, the predominant skeletal muscle isoform, was decreased by 45%, 43%, and 58% in the tibialis anterior, plantaris, and diaphragm muscles, respectively. Ribonuclease protection assay showed that the decrease was due to the adult isoform, SERCA1a, with minor changes in the alternatively spliced neonatal isoform, SERCA1b. There was no change in SERCA1 mRNA levels in gastrocnemius muscles. No change was found in SERCA2a (cardiac/slow skeletal isoform) mRNA or protein levels or in SERCA2b (smooth muscle isoform), dihydropyridine receptor, or alpha-actin mRNA levels in diaphragm muscle. Northern blot and ribonuclease protection assays showed that SERCA2a decreased 61% in the heart while the alternatively spliced isoform, SERCA2b, decreased 27%. Western analysis of the tibialis anterior, diaphragm, and gastrocnemius muscles showed a decrease in SERCA1 protein levels by 46%, 64%, and 42%, respectively, whereas sarcoplasmic reticulum Ca(2+)-ATPase activity, a functional correlate of SERCA expression, was decreased by 38%, 38%, and 40% in the same muscles, SERCA2 protein expression decreased by 36% in the failing heart. Decreases in both mRNA and protein suggest pretranslational control of SERCA1 expression, whereas the lack of decreased SERCA1 mRNA in gastrocnemius muscle suggests translational regulation. The decreased SERCA1 protein expression in all muscles studied probably contributes to contractile abnormalities related to excitation-contraction coupling function in heart failure.
Animals↗
Growth hormone response to the hypothalamic somatostatinergic activity in acromegalic patients.
Oral glucose administration suppresses the TRH-induced TSH response by enhancing the hypothalamic somatostatinergic activity (HSA). We assessed the HSA in 13 acromegalic patients by measuring glucose-induced suppression of TRH-stimulated TSH secretion. The HSA showed wide variation with up to 64% suppression. The mean HSA of the patients (25 +/- 6%) did not differ from that in normal young men (19 +/- 4%) in our previous study. Six patients had normal or low HSA, and the other 7 patients had high HSA. The mean TRH-stimulated TSH levels of the patients with normal or low HSA was significantly lower than that of the patients with high HSA (5.13 +/- 0.10 vs. 11.30 +/- 2.80 mU/L). The HSA did not relate to sex, age, tumor size, basal GH levels, the paradoxical responses to TRH and GnRH, octreotide response, or the gsp oncogene. In the combined glucose-TRH test, glucose pretreatment completely suppressed the paradoxical increase in GH level at 30 min in 4 patients. However, it could suppress the paradoxical GH response by only 6-51% in the other 5 patients who also showed the paradoxical response in TRH test. The tumor diameter of patients with good response to the HSA was significantly larger than that of the patients with poor response (31 +/- 5 vs. 14 +/- 2 mm) as was the tumor grade (3.3 +/- 0.3 vs. 1.7 +/- 0.2). This study supports the idea that a reduction of HSA is not a primary cause of acromegaly, and the HSA seems to increase to suppress the autonomous secretion of GH from the pituitary adenomas. HSA as well as the response of tumors to HSA do not determine tumor growth.
Acromegaly↗
Craniofacial morphology of conotruncal anomaly face syndrome.
OBJECTIVE AND DESIGN: The conotruncal anomaly face syndrome (CTAF) comprises congenital heart disease and dysmorphic face, and is frequently associated with cleft palate or hypernasality. There have been many discussions about the overlap with velocardiofacial syndrome (VCF). The aim of this study was to clarify the craniofacial characteristics of CTAF patients by clinical examination, and photogrammetric and cephalometric analyses, and to clarify the differences compared to published data on VCF. RESULTS: The facial features of CTAF included hypertelorism, small palpebral fissures, upward slanting of palpebral fissures, bloated eye lids, low nasal bridge, small mouth, open mouth at rest, and malformed auricles. Cephalometric features included bialveolar protrusion, small gonial angle, backward rotation of the mandibular ramus, and labial inclination of the maxillary incisors. An acute cranial base angle was also noted. These results differed from those of VCF. There were, however, no obvious pathognomonic findings for the differential diagnosis between CTAF and VCF. CONCLUSIONS: Considering these findings, use of CATCH 22, the inclusive classification of cardiac anomalies, cleft palate, and dysmorphic face may be of value for the clinical understanding in these patients.
Alveolar Process↗
A 5-nucleotide insertion in the antithrombin gene causing a quantitative antithrombin deficiency.
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Alleles↗