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Biomedical subjects

L Tong

Publications and source records attributed to L Tong.

At least 19 recordsLinked to original sources
PubMed2006

Taurine protects against ischemia-reperfusion injury in rabbit livers.

Ischemia-reperfusion injury is of major clinical relevance during liver transplantation. In the present study, the therapeutic efficacy of taurine to protect against ischemia-reperfusion injury was investigated in rabbit livers. We demonstrated that intravenous injection of taurine attenuated liver dysfunction as evidenced by reductions in serum alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. The recovery of morphological and ultrastructural changes in the liver was also promoted by taurine. The mechanism of the protective effect of taurine seems at least to rely on antioxidation, since the lipoperoxides contents in liver tissues were significantly reduced among taurine-treated rabbits. These results suggest that taurine is a potent useful reagent to protect the rabbit liver from ischemia-reperfusion injury.

Animals↗
PubMed2006

Glucose and diabetes: effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton.

Phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) regulates heat shock protein 25 (HSP25), stabilizing fibrillar actin (FA) and preventing cleavage to G-actin (GA). Cultured podocytes (Pods) were exposed to glucose (5.5-50 mM)+/-p38MAPK inhibitor SB202190 (SB) or control SB202474 to assess the effects on FA/GA and Pod structure. The relationship of p38MAPK with in vivo Pod structure and albuminuria (Ualb) was assessed in rats with streptozotocin (SZ)-induced diabetes (DM) for 1 week, 1 month, and 4 months. High glucose induced concentration-dependent increases in pp38MAPK and phosphorylated HSP25 (pHSP25) maintained actin cytoskeleton. Inhibition by SB diminished pp38MAPK and pHSP25, decreased FA/GA, and altered FA and GA immunohistochemical appearance. In SZ-DM, glomerular pp38MAPK and biphosphorylated HSP25 were increased after 1 week, declining at 1 month, and at or below C values at 4 months. Glomerular FA/GA in DM was normal at 1 week, declining at 1 month, and low at 4 months. Ualb/creatinine was similar in DM vs C at 1 week, and increased at 1 and 4 months. Morphometry demonstrated progressively diminishing slit pore density in DM over time, denoting evolving effacement. There were strong correlations between slit membrane density and both glomerular biphosphorylated HSP25 and ln Ualb/cr ratio. The data suggest that increased pp38MAPK and pHSP25 comprise an acute adaptation to glycemic stress. Later depletion of DM may contribute to Pod structural alterations and Ualb.

Actins↗
PubMed2005

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery.

Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms. Mice deficient in ACC2 have continuous fatty acid oxidation and reduced body fat and body weight, validating this enzyme as a target for drug development against obesity, diabetes and other symptoms of the metabolic syndrome. ACC is a biotin-dependent enzyme and catalyzes the carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of the enzyme can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors. The current intense research on these enzymes could lead to the development of novel therapies against metabolic syndrome and other diseases.

Acetyl-CoA Carboxylase↗
PubMed2005

Survival beyond 10 years following heart transplantation: The Cleveland Clinic Foundation experience.

BACKGROUND: Long-term survival after heart transplantation is a desirable although challenging goal. METHODS: We analyzed clinical outcomes in the cohort of 170 patients who have undergone heart transplantation at The Cleveland Clinic Foundation and survived >10 years. RESULTS: We found 10-year and 15-year survival rates of 54% and 41%, respectively, in these patients, but there was also a high incidence of complications, such as hypertension, renal dysfunction, transplant vasculopathy, and malignancy. CONCLUSIONS: Long-term survival following cardiac transplantation is possible although complications are frequent. Beyond 10 years, malignancy is a major cause of death.

Adult↗
PubMed2004

Therapeutic drug monitoring of tacrolimus in early stage after heart transplantation.

INTRODUCTION: Little is known about the pharmacokinetic (PK) profiles of tacrolimus (Tac) within the first week after heart transplantation (HT) in adults. Our objective was to investigate the PK profiles of Tac in early after HT. METHODS: Twenty-three adult HT patients received Tac as primary immunosuppression. Tac was administered orally at a starting dosage of 0.10 mg/kg/d. The Tac dosages were adjusted to a target range of 10 to 20 ng/mL during the first 1 month after HT. The PK profiles were analyzed immediately after the first dose (PK1; n = 14), at day 3 (PK2; n = 10), and at day 7 (PK3; n = 8) to assess the relationships between PK parameters and acute rejection rates. RESULTS: The correlation between Tac trough levels and Tac-AUCs were r = .95 PK1; r = .82, PK2; and r = .88, PK3. When AUC(0-12h) was controlled in the range from 150 to 300 ng x h/mL (10 to 20 ng/mL trough levels), 17 of 18 patients (94.4%) did not show evidence of significant rejection (72.2% grade 0, 16.7% 1A, and 5.5% grade 1B). One patient displayed a grade 2 biopsy score (5.5%). Mean AUC(0-12h) values of Tac were significantly lower among patients who experienced acute rejection than those who remained rejection-free (89 vs 217 ng x h/mL, P = .023). CONCLUSION: The initial trough levels are good indicators of systemic exposure. To reduce the risk of rejection and renal toxicity, the trough levels should be controlled in range from 10 to 20 ng/mL in early stage after HT.

Adolescent↗
PubMed2004

The relation between birth size and the results of refractive error and biometry measurements in children.

AIM: To examine the association of birth parameters with biometry and refraction in Singapore Chinese schoolchildren. METHODS: Chinese children aged 7-9 years (n = 1413) from three schools in Singapore were recruited. Birth parameter information on birth weight, head circumference, length at birth, and gestational age were obtained from standard hospital records. Cycloplegic autorefraction, keratometry and biometry measures (axial length, vitreous chamber depth, lens thickness, and anterior chamber depth) were obtained. RESULTS: Across the normal birthweight range (2.0-4.9 kg), children with birth weights > or =4.0 kg had longer axial lengths (adjusted mean 23.65 mm versus 23.16 mm), compared with children with birth weights <2.5 kg, after controlling for age, sex, school, height, parental myopia, and gestational age. For every 1 cm increment in head circumference at birth, the axial length was longer by 0.05 mm. For every 1 cm increment in birth length, the axial length was longer by 0.02 mm in multivariate analysis. Additional week increases in gestational age till 46 weeks resulted in axial lengths that were longer by 0.04 mm, controlling for age, sex, school, parental myopia, and height. Children with larger birth weights, head circumferences, birth lengths, or gestational ages had deeper vitreous chambers and larger corneal curvature radii; however, there were no significant associations with refraction. CONCLUSIONS: Children who were born heavier, had larger head sizes or lengths at birth, or who were born more mature had longer axial lengths, and deeper vitreous chambers; but there were no differences in refraction at ages 7-9 years, possibly because of the observed compensatory flattening of the cornea.

Anterior Chamber↗
PubMed2003

Photodynamic therapy with photofrin in combination with Buthionine Sulfoximine (BSO) of human glioma in the nude rat.

High concentrations of cellular glutathione (GSH) within tumour cells may reduce the ability of photodynamic therapy (PDT) to selectively destroy tumour, consequently, a means of improving the therapeutic ratio of PDT in brain tumour is necessary. Therefore, we hypothesize that PDT in combination with Buthionine Sulfoximine (BSO), an agent which lowers cellular glutathione, can significantly enhance destruction of U87 and U251n tumour cells. PDT was performed using Photofrin as a photosensitiser in combination with BSO administration on male Fisher rats with intracerebral U87 and on non-tumour rats (administered at different optical doses in combination with Photofrin). In vitro experimentation utilising colony forming, cell cytotoxicity, and matrigel artificial basement membrane invasion assays showed significant enhancement of tumour kill and significant reduction of migration in tumour cells treated with BSO in combination with Photofrin PDT in comparison with individual therapies for both U87 and U251n cell lines. In vivo combination PDT-BSO treatment of U87 tumour rats exhibited significantly more tumour necrosis than individual treatments. In conclusion, our data suggests BSO enhances Photofrin PDT treatment of human glioma.

Animals↗
PubMed2002

Photodynamic therapy with photofrin reduces invasiveness of malignant human glioma cells.

In this study we investigated the influence of Photofrin-based photodynamic therapy (PDT) on the migration of two human glioma cell lines in vitro. U87 and U25ln tumour cells were treated with Photofrin at various doses and subjected to a fixed optical (632 nm) dose of 100 mJ/cm(2). Photofrin cytotoxicity was determined using MTT and colony forming assays. Using a matrigel artificial basement membrane migration assay, we demonstrated that low doses of subcytotoxic PDT treatment, such as PDT with 2.5 micro g/ml Photofrin on U87 cells and 1 micro g/ml on U25ln cells, significantly ( p<0.001) inhibited in vitro migration of both cell lines. Furthermore, in a qualitative spheroid confrontation assay, subcytotoxic PDT of co-cultures between tumour spheroids and brain aggregates resulted in an absence of progressive tumour invasion and destruction of the brain aggregate. In conclusion, our data indicate that low-dose subcytotoxic PDT with Photofrin significantly inhibits invasiveness of U87 and U25ln cells.

Animals↗
PubMed2002

Accuracy of family history of cancer as reported by men with prostate cancer.

OBJECTIVES: To report on the accuracy of probands providing information on specific cancer types in their families and the ability of investigators to document these reports. Accurate information on the health status of family members is critical when studying familial patterns of diseases. However, collecting these data require significant resources. METHODS: We identified 143 patients with prostate cancer from the University of Texas M. D. Anderson Cancer Center who had reported at least 1 first-degree relative with cancer. There were 263 first-degree relatives identified, for whom we confirmed diagnoses using medical records, death certificates, and verbal confirmation. The data are reported in summary statistics and compared with chi-square analysis. RESULTS: We documented 78% of the reports, with an accuracy rate of 81.6%. We found that accuracy was highly related to the site reported. Accuracy and documentation levels were not related to the age or income of the proband. The education level was significantly associated with the ability to document cancer, but not with the accuracy of the report. The accuracy and documentation differed by the relationship of the first-degree relative to the proband. CONCLUSIONS: Proband reporting of cancer in first-degree relatives varies widely by site, with common metastatic sites the most inaccurate. No reliable demographic factors were found that would reasonably predict the ability to document the accuracy of the report. We found a significant proportion of proband-reported prostate cancer was, in reality, benign prostatic hyperplasia. We propose a strategy of targeting male relatives and reports of cancer in common metastatic sites for aggressive follow-up.

Death Certificates↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2001

Determination of the mechanism of human malic enzyme with natural and alternate dinucleotides by isotope effects.

Human malic enzyme was studied by steady state kinetics, deuterium isotope effects, and 13C isotope effects with both the physiological dinucleotide cofactor and several alternate cofactors. The log V vs pH profile with NAD revealed two pK(a) values too close to be separately determined, but with an average value of 7.33. The log V/K vs pH profile with NAD revealed two pK(a) values at 7.4 and 5.6. Deuterium and 13C isotope effects indicate that the mechanism of human malic enzyme is stepwise with both NAD and epsilonNAD, but that hyperconjugation in the transition state for hydride transfer is detectable only with the former. With thioNAD and APAD, the isotope effects do not clearly indicate whether the mechanism is stepwise or concerted. The intrinsic 13C isotope effect for decarboxylation was calculated to be 1.0485 by measurement of the partition ratio of oxaloacetate in the presence of NADH and human malic enzyme (decarboxylation to pyruvate/reduction to malate = 2.33). The isotope effect and partitioning data suggest that the energy barrier for decarboxylation of oxaloacetate is not as high relative to the barrier for reduction of oxaloacetate as with the chicken liver enzyme.

Carbon Isotopes↗
PubMed2001

How to take advantage of non-crystallographic symmetry in molecular replacement: 'locked' rotation and translation functions.

Many protein molecules form assemblies that obey point-group symmetry. These assemblies are often situated at general positions in the unit cell such that the point-group symmetry of the assembly becomes non-crystallographic symmetry (NCS) in the crystal. The presence of NCS places significant constraints on structure determination by the molecular-replacement method. The locked rotation and translation functions have been developed to take advantage of the presence of NCS in this structure determination, which generally requires four steps. (i) The locked self-rotation function is used to determine the orientation of the NCS assembly in the crystal, relative to a pre-defined 'standard' orientation of this NCS point group. (ii) The locked cross-rotation function is used to determine the orientation of one monomer of the assembly in the standard orientation. This calculation requires only the structure of the monomer as the search model. (iii) The locked translation function is used to determine the position of this monomer relative to the center of the assembly. Information obtained from steps (ii) and (iii) will produce a model of the entire assembly centered at the origin of the coordinate system. (iv) An ordinary translation function is used to determine the center of the assembly in the crystal unit cell, using as the search model the structure of the entire assembly produced in step (iii). The locked rotation and translation functions simplify the structure-determination process in the presence of NCS. Instead of searching for each monomer separately, the locked calculations search for a single rotation or translation. Moreover, the locked functions reduce the noise level in the calculation, owing to the averaging over the NCS elements, and increase the signals as all monomers of the assembly are taken into account at the same time.

Crystallography↗
PubMed2001

A current 10-year retrospective survey of 199 surgically treated orbital floor fractures in a nonurban tertiary care center.

This study characterizes the surgically treated patient population suffering from orbital floor fractures by use of current data from a large series consisting of 199 cases taken from a nonurban setting. Data were gathered through a retrospective chart review of patients surgically treated for orbital floor fractures at the University of Michigan Health System, collected over a 10-year period. Data regarding patient demographics, signs and symptoms of presentation, cause of injury, nature of injury, associated facial fractures, ocular injury, and associated nonfacial skeleton trauma were collected. In total, there were 199 cases of orbital floor fractures among 189 patients. Male patients outnumbered female patients by a 2:1 ratio and were found to engage in a wider range of behaviors that resulted in orbital floor fractures. Motor vehicle accidents were the leading cause of orbital floor fractures, followed by physical assault and sports-related mechanisms. The ratio of impure to pure orbital floor fracture was 3:1. The most common signs and symptoms associated with orbital floor fractures, in descending order, were periorbital ecchymosis, diplopia, subconjunctival hemorrhage, and enophthalmos. Associated facial fractures were found in 77.2 percent of patients, the most prevalent of which was the zygoma-malar fracture. Serious ocular injury occurred in 19.6 percent of patients, with globe rupture being the most prevalent, accounting for 40.5 percent of those injuries. There was a 38.1 percent occurrence of associated nonfacial skeletal trauma; skull fracture and intracranial injury were the most prevalent manifestations. Associated cervical-spine fractures were rare (0.5 percent). Statistical examination, using odds ratios and chi-squared analysis, demonstrated significant associations that have not previously been reported. Impure and pure orbital floor fractures revealed striking differences in several demographic aspects, including mechanism of injury, signs and symptoms of presentation, spectrum of associated trauma, and the severity of concomitant trauma.

Accidents, Traffic↗
PubMed2001

COMO: a program for combined molecular replacement.

The combined molecular-replacement protocol uses a limited six-dimensional search to solve a structure by the molecular-replacement method, with the sampling of the rotational degrees of freedom guided by the rotation function. This protocol therefore automatically combines the information on the rotational and translational parameters of the search model. The combined molecular-replacement protocol has been implemented in a new computer program, COMO. The calculation of the Patterson correlation translation function has been optimized to improve its speed performance. A packing check is implemented that automatically removes impossible solutions and thereby increases the signal in the calculation. A family of atomic models can be used as the search model; the program will automatically select the model that gives the best result. The command interface is well organized and requires the definition of only a few critical parameters by the user. In addition, a graphical user interface has been constructed for the program. The program has been used to solve several difficult molecular-replacement problems. A case is presented where the program automatically determined the orientation and position of five copies of a search model in a high-symmetry space group.

Computer Simulation↗
PubMed2001

Solution-state NMR investigations of triosephosphate isomerase active site loop motion: ligand release in relation to active site loop dynamics.

Product release is partially rate determining in the isomerization reaction catalyzed by Triosephosphate Isomerase, the conversion of dihydroxyacetone phosphate to D-glyceraldehyde 3-phosphate, probably because an active-site loop movement is necessary to free the product from confinement in the active-site. The timescale of the catalytic loop motion and of ligand release were studied using 19F and 31P solution-state NMR. A 5'-fluorotryptophan was incorporated in the loop N-terminal hinge as a reporter of loop motion timescale. Crystallographic studies confirmed that the structure of the fluorinated enzyme is indistinguishable from the wild-type; the fluorine accepts a hydrogen bond from water and not from a protein residue, with minimal perturbation to the flexible loop stability. Two distinct loop conformations were observed by 19F NMR. Both for unligated (empty) and ligated enzyme samples a single species was detected, but the chemical shifts of these two distinct species differed by 1.2 ppm. For samples in the presence of subsaturating amounts of a substrate analogue, glycerol 3-phosphate, both NMR peaks were present, with broadened lineshapes at 0 degrees C. In contrast, a single NMR peak representing a rapid average of the two species was observed at 30 degrees C. We conclude that the rate of loop motion is less than 1400 s(-1) at 0 degrees C and more than 1400 s(-1) at 30 degrees C. Ligand release was studied under similar sample conditions, using 31P NMR of the phosphate group of the substrate analogue. The rate of ligand release is less than 1000 s(-1) at 0 degrees C and more than 1000 s(-1) at 30 degrees C. Therefore, loop motion and product release are probably concerted and likely to represent a rate limiting step for chemistry.

Binding Sites↗