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Biomedical subjects

L Chan

Publications and source records attributed to L Chan.

At least 19 recordsLinked to original sources
PubMed2001

Long-term stable correction of low-density lipoprotein receptor-deficient mice with a helper-dependent adenoviral vector expressing the very low-density lipoprotein receptor.

BACKGROUND: Familial hypercholesterolemia (FH) that results from LDL receptor (LDLR) deficiency affects approximately 1 in 500 persons in the heterozygous state and approximately 1 in 1 million persons in the homozygous state. We tested a novel gene therapy strategy for the treatment of FH in a mouse model. METHODS AND RESULTS: We delivered the VLDL receptor (VLDLR) to the liver of LDLR-deficient mice and compared the effect of a helper-dependent adenoviral vector with all viral coding sequences deleted (HD-Ad-mVLDLR) with a first-generation vector (FG-Ad-mVLDLR), an HD-Ad (HD-Ad-0) that contained no expression cassette, and dialysis buffer (DB). A single intravenous injection of HD-Ad-mVLDLR led to a lowering of plasma cholesterol that lasted >/=6 months. Acute liver toxicity (as measured with liver enzyme elevation) occurred after FG-Ad-mVLDLR but not after HD-Ad-mVLDLR, HD-Ad-0, or DB treatment. At 6 months, VLDLR was detected in the liver with Western blotting and with immunofluorescence staining only in HD-Ad-mVLDLR-treated mice. Aortic atherosclerosis was almost completely prevented in these animals. CONCLUSIONS: HD-Ad-mediated intravenous delivery of VLDLR to hepatocytes is well tolerated. It produces long-term lowering of plasma cholesterol and prevents atherosclerosis development in LDLR-deficient mice. These data provide support for the feasibility and safety of this approach for therapy of human subjects.

Adenoviridae↗
PubMed2001

Tunicamycin induces ubiquitination and degradation of apolipoprotein B in HepG2 cells.

Apolipoprotein (apo) B-100 is an essential component of atherogenic plasma lipoproteins. Previous studies have demonstrated that the production of apoB-100 is regulated largely by intracellular degradation at both the co-translational and post-translational levels and that proteasome-mediated and non-proteasome-mediated pathways are involved in this process. ApoB-100 is a glycoprotein. The present study was undertaken to address the question of whether the inhibition of N-linked glycosylation with tunicamycin would interfere with apoB-100 production. We demonstrated that the treatment of HepG2 cells with tunicamycin decreased the net production of apoB-100 by enhancing co-translational degradation of the protein. This effect of tunicamycin was partly prevented by lactacystin, a specific proteasome inhibitor. Because lactacystin only partly reversed the effects of tunicamycin on apoB biogenesis, tunicamycin seemed also to induce apoB co-translational degradation in HepG2 cells by one or more non-proteasomal pathways. Furthermore, tunicamycin increased apoB ubiquitination approx. 4-fold. The proportion of the newly synthesized apoB-100 that was secreted and incorporated into the nascent lipoprotein particles was unaffected by tunicamycin. Thus the tunicamycin-mediated inhibition of N-linked glycosylation interferes with the production of apoB-100 that is mediated by both proteasomal and non-proteasomal pathways.

Acetylcysteine↗
PubMed2001

Clinically significant blunt cardiac trauma: role of serum troponin levels combined with electrocardiographic findings.

BACKGROUND: The true importance of blunt cardiac trauma (BCT) is related to the cardiac complications arising from it. Diagnostic tests that can predict accurately if such complications will develop or not may allow early and aggressive monitoring or early discharge. We investigated the role of two simple and convenient tests, serum cardiac troponin I (cTnI) and electrocardiogram (ECG), when used to identify patients at risk of cardiac complications after BCT. METHODS: Over a 10-month period, 115 patients with evidence of significant blunt thoracic trauma were prospectively followed to identify the presence of clinically significant BCT (Sig-BCT), defined as cardiogenic shock, arrhythmias requiring treatment, or structural cardiac abnormalities directly related to the cardiac trauma. An ECG was obtained at admission and at 8 hours. Cardiac troponin I was measured at admission, at 4 hours, and at 8 hours. Transthoracic echocardiography was performed when clinically indicated. The sensitivity, specificity, and positive and negative predictive values of ECG and cTnI to identify Sig-BCT were calculated. Clinical risk factors for Sig-BCT were examined by univariate and multivariate analysis. RESULTS: Nineteen patients (16.5%) were diagnosed with Sig-BCT and, in 18 of them, symptoms presented within 24 hours of admission. Abnormal electrocardiographic findings were detected in 58 patients (50%) and elevated cTnI levels in 27 (23.5%). Electrocardiography and cTnI had positive predictive values of 28% and 48% and negative predictive values of 95% and 93%, respectively. However, when both tests were abnormal (positive) or normal (negative), the positive and negative predictive values increased to 62% and 100%, respectively. Other independent risk factors for Sig-BCT were head injury, spinal injury, history of preexisting cardiac disease, and a chest Abbreviated Injury Score greater than 2. CONCLUSION: The combination of ECG and cTnI identifies reliably the presence or absence of Sig-BCT. Patients with an abnormal ECG and cTnI need close monitoring for at least 24 hours. Patients with a normal admission ECG and cTnI can be safely discharged in the absence of other injuries.

Electrocardiography↗
PubMed2001

Penetrating esophageal injuries: multicenter study of the American Association for the Surgery of Trauma.

OBJECTIVE: The purpose of this study was to define the period of time after which delays in management incurred by investigations cause increased morbidity and mortality. The outcome study is intended to correlate time with death from esophageal causes, overall complications, esophageal related complications, and surgical intensive care unit length of stay. METHODS: This was a retrospective multicenter study involving 34 trauma centers in the United States, under the auspices of the American Association for the Surgery of Trauma Multi-institutional Trials Committee over a span of 10.5 years. Patients surviving to reach the operating room (OR) were divided into two groups: those that underwent diagnostic studies to identify their injuries (preoperative evaluation group) and those that went immediately to the OR (no preoperative evaluation group). Statistical methods included Fisher's exact test, Student's T test, and logistic regression analysis. RESULTS: The study involved 405 patients: 355 male patients (86.5%) and 50 female patients (13.5%). The mean Revised Trauma Score was 6.3, the mean Injury Severity Score was 28, and the mean time interval to the OR was 6.5 hours. There were associated injuries in 356 patients (88%), and an overall complication rate of 53.5%. Overall mortality was 78 of 405 (19%). Three hundred forty-six patients survived to reach the OR: 171 in the preoperative evaluation group and 175 in the no preoperative evaluation group. No statistically significant differences were noted in the two groups in the following parameters: number of patients, age, Injury Severity Score, admission blood pressure, anatomic location of injury (cervical or thoracic), surgical management (primary repair, resection and anastomosis, resection and diversion, flaps), number of associated injuries, and mortality. Average length of time to the OR was 13 hours in the preoperative evaluation group versus 1 hour in the no preoperative evaluation group (p < 0.001). Overall complications occurred in 134 in the preoperative evaluation group versus 87 in the no preoperative evaluation group (p < 0.001), and 74 (41%) esophageal related complications occurred in the preoperative evaluation group versus 32 (19%) in the no preoperative evaluation group (p = 0.003). Mean surgical intensive care unit length of stay was 11 days in the preoperative evaluation group versus 7 days in the no preoperative evaluation group (p = 0.012). Logistic regression analysis identified as independent risk factors for the development of esophageal related complications included time delays in preoperative evaluation (odds ratio, 3.13), American Association for the Surgery of Trauma Organ Injury Scale grade >2 (odds ratio, 2.62), and resection and diversion (odds ratio, 4.47). CONCLUSION: Esophageal injuries carry a high morbidity and mortality. Increased esophageal related morbidity occurs with the diagnostic workup and its inherent delay in operative repair of these injuries. For centers practicing selective management of penetrating neck injuries and transmediastinal gunshot wounds, rapid diagnosis and definitive repair should be made a high priority.

Adolescent↗
PubMed2001

Oral tolerance to protein antigens.

Oral tolerance is an active non-response to antigens delivered via the oral route. Mechanisms governing tolerance induction have been well characterized in mouse. Similar studies in man are lacking, although there is evidence that tolerance can be induced. In disease states, tolerance is altered and this may account for the presence of mucosal inflammation. In food hypersensitivity there is evidence that allergens may be handled differently and this may play a role in disease expression.

Administration, Oral↗
PubMed2001

Emergency medicine terminology in the United Kingdom--time to follow the trend?

OBJECTIVE: To determine the frequency of use of the terms "accident and emergency" and "emergency medicine" and their derivatives in original articles in the Journal of Accident and Emergency Medicine. METHODS: Hand search of all articles in the Journal of Accident and Emergency Medicine from September 1995 to July 2000, categorising the first use of terminology in each original article to describe the specialty, its departments, or their staff into either accident and emergency or emergency medicine groups. RESULTS: There is a clear trend towards increasing use of the terms emergency medicine, emergency physician and emergency department, with decreasing use of the terms accident and emergency medicine, accident and emergency department and accident and emergency doctor, although the latter group still constitutes the majority. CONCLUSION: The use of emergency medicine to describe the specialty in the United Kingdom is increasing, although this may reflect the Journal's growing international standing. This trend should be taken into account in the debate over the specialty's name in this country.

Accidents↗
PubMed2001

The role of gynecologists in providing primary care to elderly women.

BACKGROUND: Federal legislation has recently been proposed to designate obstetrician-gynecologists (OBGs) as primary care physicians. The Institute of Medicine identifies care unrestricted by problem or organ system as an essential characteristic of primary care. We examined the degree to which OBGs in the state of Washington offer this aspect of primary care to their elderly patients by investigating the type and amount of nongynecologic care they provide. METHODS: Using 1994 Part B Medicare claims data for Washington residents, we identified visits made by women aged 65 years and older to OBGs (N=10,522) and 9 other types of specialists. Diagnoses were classified as in or out of the domain of care traditionally provided by each specialty. Visit volumes, proportion of out of domain visits, and the frequency of diagnoses were reported. RESULTS: Of the patient visits to obstetrician-gynecologists, 12.2% had nongynecologic diagnoses. The median percentage of nongynecologic visits for individual OBGs was 6.7%. Patients who saw OBGs received 15.4% of their overall health care from an OBG; patients who saw family physicians received 42.9% of their total health care from a family physician. CONCLUSIONS: In 1994, a small amount of the care that Washington OBGs provided to their elderly patients was for nongynecologic conditions. Studies are needed to evaluate how the practices of OBGs have changed since the 1996 implementation of a primary care requirement in obstetrics-gynecology residencies, and if adopted, how legislation designating OBGs as primary care physicians affects the health care received by elderly women.

Age Factors↗
PubMed2001

Hepatitis C virus infection and morphologic study in B lymphocytes of patient with hepatitis C.

OBJECTIVE: To study hepatitis C virus (HCV) infection in B lymphocytes of patients with hepatitis C and to establish a B cell line with HCV infection and observe the hepatitis C virus like particles. METHODS: A B lymphoblastoid cell line was established by Epstein-Barr virus induced transformation directly from peripheral blood mononuclear cells of a patient with hepatitis C. The HCV antigen and HCV RNA were detected by immunohistochemical technique. Reverse transcription-polymerase chain reaction(RT-PCR) and in situ hybridization and HCV particle were detected by electron microscopy. RESULTS: Positive HCV RNA was found in supernatants of B cell line. HCV Ag and HCV RNA were also showed positive. Electron microscopy observed HCV spherical virus like particles with a diameter of approximately 65 nm and 110 nm and the "bud mutation" of HCV in the cytoplasmic vesicles of B lymphocytes. CONCLUSIONS: HCV could infect B lymphocytes and replicate in the cell line. HCV particles are formed by "bud mutation" of HCV in the cytoplasmic vesicles of B-lymphocytes.

B-Lymphocytes↗
PubMed2000

Hammerhead ribozyme as a therapeutic agent for hyperlipidemia: production of truncated apolipoprotein B and hypolipidemic effects in a dyslipidemia murine model.

In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. To reduce the levels of apoB mRNA, we used adenovirus-mediated vector to target hammerhead ribozyme at GUA(6679) downward arrow of apoB mRNA (designated AvRB15) in the liver of a dyslipidemic mouse model that is deficient in apoB mRNA editing enzyme and overexpresses human apoB100. In this study, we delivered approximately 4 x 10(11) virus particles of AvRB15 (active ribozyme) or AvRB15-mutant (inactive ribozyme) to the animals. Using Southern blot analysis, we readily detected RB15 DNA in the mouse liver as long as day 35 after injection. This result was correlated with the RNA expression of RB15 by RNase protection assay. Using reverse ligation-mediated polymerase chain reaction, the 3' cleavage product of apoB mRNA was detected, and the exact cleavage site was confirmed by sequencing. Importantly, the levels of human and mouse apoB mRNA decreased approximately 80% after AvRB15 transduction. There was a marked decrease in plasma cholesterol, triglyceride, and human apoB of 42, 51, and 62%, respectively, when compared with the inactive ribozyme-treated group. Moreover, ribozyme cleavage of apoB mRNA generated a truncated protein of the expected size (apoB48.1), which was associated with lipoprotein particles in the very low density, low density, and high density lipoprotein fractions. Taken together, these results indicate that apoB mRNA-specific hammerhead ribozyme can be used as a potential therapeutic agent to modulate apoB gene expression and to treat hyperlipidemia.

Animals↗
PubMed2000

Synthesis and antiviral activities of N-9-oxypurine 1,3-dioxolane and 1,3-oxathiolane nucleosides.

Two series of 1,3-dioxolanes and 1,3-oxathiolane nucleosides containing N-9-oxypurine were synthesized as potential antiviral agents. These compounds were prepared by reacting the sugar moieties with iodo- or bromotrimethylsilane, followed by treatment with a mixture of sodium hydride and the desired N-hydroxy purine base. The preparation of these N-hydroxybases was also described. No significant antiviral activity was observed against HIV, HBV, HSV-1, HSV-2, or HCMV.

Anti-HIV Agents↗
PubMed2000

Treatment of acute myocardial infarction and 30-day mortality among women and men.

BACKGROUND: Previous studies have suggested that women with acute myocardial infarction receive less aggressive therapy than men. We used data from the Cooperative Cardiovascular Project to determine whether women and men who were ideal candidates for therapy after acute myocardial infarction were treated differently. METHODS: Information was abstracted from the charts of 138,956 Medicare beneficiaries (49 percent of them women) who had an acute myocardial infarction in 1994 or 1995. Multivariate analysis was used to assess differences between women and men in the medications administered, the procedures used, the assignment of do-not-resuscitate status, and 30-day mortality. RESULTS: Among ideal candidates for therapy, women in all age groups were less likely to undergo diagnostic catheterization than men. The difference was especially pronounced among older women; for a woman 85 years of age or older, the adjusted relative risk was 0.75 (95 percent confidence interval, 0.68 to 0.83). Women were somewhat less likely than men to receive thrombolytic therapy within 60 minutes (adjusted relative risk, 0.93; 95 percent confidence interval, 0.90 to 0.96) or to receive aspirin within 24 hours after arrival at the hospital (adjusted relative risk, 0.96; 95 percent confidence interval, 0.95 to 0.97), but they were equally likely to receive beta-blockers (adjusted relative risk, 0.99; 95 percent confidence interval, 0.95 to 1.03) and somewhat more likely to receive angiotensin-converting-enzyme inhibitors (adjusted relative risk, 1.05; 95 percent confidence interval, 1.02 to 1.08). Women were more likely than men to have a do-not-resuscitate order in their records (adjusted relative risk, 1.26; 95 percent confidence interval, 1.22 to 1.29). After adjustment, women and men had similar 30-day mortality rates (hazard ratio, 1.02; 95 percent confidence interval, 0.99 to 1.04). CONCLUSIONS: As compared with men, women receive somewhat less aggressive treatment during the early management of acute myocardial infarction. However, many of these differences are small, and there is no apparent effect on early mortality.

Adrenergic beta-Antagonists↗
PubMed2000

Apolipoprotein B, a paradigm for proteins regulated by intracellular degradation, does not undergo intracellular degradation in CaCo2 cells.

Studies in different liver-derived cells in culture indicate that apolipoprotein (apo) B-100 production is regulated largely by intracellular degradation and the ubiquitin-proteasome pathway is a major mechanism for the degradation. The proteasomal degradation of apoB-100 was postulated to be an intrinsic property of the protein that occurs even in the presence of optimal amounts of lipids supplied to the cell. We examined apoB-100 and apoB-48 biogenesis in CaCo2, a human colon carcinoma cell line. To our surprise, apoB-100 and apoB-48 were quantitatively secreted by CaCo2 cells; essentially none of the newly synthesized apoB was degraded before secretion in a 2-h period whether the cells were cultured on filter or on plastic. Furthermore, although ubiquitin immunoreactivity was readily detected in the intracellular apoB isolated from HepG2 cells, little or no ubiquitin was detectable in the intracellular apoB from CaCo2 cells. The amounts of free ubiquitin and total and non-apoB ubiquitinated proteins were comparable in HepG2 and CaCo2 cells, indicating that CaCo2 cells have the necessary machinery for tagging ubiquitin chains onto cellular proteins for proteasomal degradation. Incubation in lipoprotein-deficient serum did not induce apoB degradation, but the addition of a microsomal triglyceride transfer protein inhibitor led to apoB degradation in CaCo2 cells. Finally, similar proportions of apoB polypeptide in isolated microsomes from CaCo2 and HepG2 cells were accessible to exogenously added trypsin, indicating that the mere exposure of apoB nascent chains to the cytosolic compartment is insufficient to cause the proteasomal degradation. Therefore, the intracellular degradation of apoB is not an intrinsic property of the protein, and the phenomenon is neither universal nor inevitable. The unconditional use of apoB as a paradigm for intracellular protein degradation is not warranted.

Apolipoprotein B-100↗
PubMed2000

P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice.

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E(-/-) (deficient) mice fed a normal chow diet. All mice were apo E(-/-) and CAM(+/+) or CAM(-/-) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 +/- 0. 65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin null mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

Animals↗
PubMed2000

Two-dimensional electrophoresis map of the human hepatocellular carcinoma cell line, HCC-M, and identification of the separated proteins by mass spectrometry.

Currently, one of the most popular applications of proteomics is in the area of cancer research. In Africa, Southeast Asia, and China, hepatocellular carcinoma is one of the most common cancers, occurring as one of the top five cancers in frequency. This project was initiated with the purpose of separating and identifying the proteins of a human hepatocellular carcinoma cell line, HCC-M. After two-dimensional gel electrophoresis separation, silver staining, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analyses, tryptic peptide masses were searched for matches in the SWISS-PROT and NCBI nonredundant databases. Approximately 400 spots were analyzed using this approach. Among the proteins identified were housekeeping proteins such as alcohol dehydrogenase, alpha-enolase, asparagine synthetase, isocitrate dehydrogenase, and glucose-6-phosphate 1-dehydrogenase. In addition, we also identified proteins with expression patterns that have been postulated to be related to the process of carcinogenesis. These include 14-3-3 protein, annexin, prohibitin, and thioredoxin peroxidase. This study of the HCC-M proteome, coupled with similar proteome analyses of normal liver tissues, tumors, and other hepatocellular carcinoma cell lines, represents the first step towards the establishment of protein databases, which are valuable resources in studies on the differential protein expressions of human hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed2000

Manual wheelchair pushrim biomechanics and axle position.

OBJECTIVE: The biomechanics of wheelchair propulsion have been linked to upper extremity injury. Specifically, prior studies have correlated increased median nerve dysfunction with increasing propulsion frequency and a higher rate of rise of the resultant, or total, pushrim force. Despite this link, there is little research on the effect of wheelchair setup on propulsion biomechanics. The objective of this study was to determine the effect of rear axle position relative to the shoulder on pushrim biomechanics. DESIGN: Case series. SETTING: Biomechanics laboratory. PARTICIPANTS: Forty individuals with paraplegia who use manual wheelchairs for mobility. INTERVENTION: Subjects propelled their own wheelchairs on a dynamometer at two different steady-state speeds and going from a dead stop to maximum speed. Bilateral biomechanical data were obtained using a force- and moment-sensing pushrim and a motion analysis system. MAIN OUTCOME MEASURES: Position of the axle relative to the shoulder at rest both horizontal (XPOS) and vertical (YPOS), and pushrim biomechanical variables including frequency of propulsion, peak and rate of rise of the resultant force, planar moment, and push angle. Partial correlation coefficients between relative axle position and propulsion biomechanics variables were calculated. RESULTS: After controlling for subject characteristics, XPOS was significantly correlated with the frequency of propulsion (p < .01) and the rate of rise of the resultant force (p < .05). In addition, both XPOS and YPOS were significantly correlated with the push angle at multiple speeds (p < .05). CONCLUSION: Specific biomechanical parameters known to correlate with median nerve injuries were found to be related to axle position relative to the shoulder. Providing wheelchair users with adjustable axle position and then fitting the user to the wheelchair can improve propulsion biomechanics and likely reduce the risk of injury.

Adult↗