Biomedical subjects
A W Chan
Publications and source records attributed to A W Chan.
The enigma of recent onset dilated cardiomyopathy: what cause, what consequence, what control?
Acute onset dilated cardiomyopathy is a very common presentation encountered by cardiologists in clinical practice, but little is known about the etiology, pathophysiology, definitive diagnosis and management of this syndrome. The vast majority of cases are considered as idiopathic cardiomyopathy, or primary or secondary myocarditis, although rarely definitive diagnoses are obtained after extensive diagnostic procedures. Two scenarios are presented as a basis for a discussion of this challenging syndrome.
Transient obstruction of the mitral valve by a massive thrombus complicating percutaneous valvuloplasty.
Percutaneous transseptal mitral valvuloplasty was attempted in a patient with severe rheumatic mitral stenosis. Introduction of the balloon into the left atrium resulted in thrombotic occlusion of the mitral valve. Circulatory arrest ensued. The thrombus was disrupted during cardiopulmonary resuscitation. Thrombolysis was administered and the patient recovered uneventfully.
Oral health status, oral microflora, and non-surgical periodontal treatment of renal transplant patients receiving cyclosporin A and FK506.
OBJECTIVES: To determine the oral health status, oral microflora and the effect of non-surgical periodontal treatment on gingival overgrowth of renal allograft recipients receiving either cyclosporin A (CsA) or FK506 (Tacrolimus) as an immunosuppressant. MATERIALS AND METHODS: A total of 47 patients receiving CsA (mean age 43.1 years) and 10 receiving FK506 (mean age 40.1 years) were included in the study. Stone casts were taken for measurement of gingival overgrowth. An oral rinse technique was used to investigate the prevalence of yeasts, and aerobic and facultatively anaerobic Gram-negative rods (AGNR). RESULTS: The CsA and FK506 patients exhibited a Gingival Overgrowth Index (GOI) of 45.2%, and 25.1%, respectively (p < 0.05). The CsA patients had a GOI of 15.2% after one year of non-surgical periodontal treatment. The difference between pre- and postoperative gingival overgrowth indices was significant (p < 0.0001). Candida albicans and Klebsiella pneumoniae were the most notable yeast and AGRN found. CONCLUSIONS: Renal transplant patients, being immunocompromised, constitute a high-risk group for gingival overgrowth. However, the FK506 regime appeared to ameliorate this effect, compared with CsA. Non-surgical periodontal treatment was effective in reducing established gingival overgrowth in both CsA and FK506 patients (p < 0.05). Adequate pre- and post-transplant oral health care is recommended, for these patients, irrespective of the drug regime.
Recent alcohol intake as estimated by the Health Habits and History Questionnaire, the Harvard Semiquantitative Food Frequency Questionnaire, and a more detailed alcohol intake questionnaire.
Epidemiologic studies often rely on food frequency questionnaires (FFQs) to collect information on alcoholic beverage intake. However, estimation of alcohol intake using FFQs may be of some concern because of limited questions concerning alcohol intake. The authors compared estimates of alcohol intake during the 12-24 months prior to interview obtained from the Health Habits and History Questionnaire and the Harvard Semiquantitative Food Frequency Questionnaire with those from a more extensive alcohol questionnaire, the Drinking Pattern Questionnaire, among 133 healthy subjects (75 men, 58 women) aged 35-73 years, residents of western New York State. Data were collected in 1995 during two separate interviewer-administered computer-assisted interviews conducted approximately 2 weeks apart. For each questionnaire, average daily ounces (1 oz = 30 ml) of alcohol intake from alcoholic beverages were calculated as the product of the reported beverage-specific drink size (ounces) and the average daily frequency of intake multiplied by a factor representing the percentage of alcohol provided by each beverage. Estimates of total alcohol and liquor intake, but not of beer and wine intake, tended to be higher for the Drinking Pattern Questionnaire compared with the FFQs. Spearman's correlation coefficients ranged from 0.69 to 0.84. These results suggest that although the Drinking Pattern Questionnaire produced higher estimates than either FFQ, both FFQs provide a reasonable ranking of participants' alcohol intake.
Combinatorial chemistry reveals a new motif that binds the platelet fibrinogen receptor, gpIIbIIIa.
Among cell adhesion molecules, the classic Arg-Gly-Asp (RGD) motif is the best studied. We used combinatorial chemical and affinity immunochemical methods to find a novel motif of unnatural peptide ligands for the fibrinogen receptor of platelets, gpIIbIIIa (alphaIIbbeta3). The new d-amino acid motif, p(f/y)l, is unique among the ligands that bind the RGD pocket: It lacks the carboxylic acid group that is believed to coordinate with calcium in the MIDAS motif of the receptor. With an IC50 of 14 microM for the most potent compound, these linear p(f/y)l peptides had affinities similar to those of linear peptides containing RGD, and reversed sequences failed to compete with binding up to 1 mM. As the new motif was so different, molecular modeling was employed to suggest a model for molecular recognition. A reversed binding mechanism common for d-amino acid mimics of natural l-amino acid peptides offers an attractive hypothesis that suggests three points of contact similar to those made by the RGD-mimicking monoclonal antibody, OPG2. Interestingly, the model proposes that pi-electrons in the new motif may substitute for the carboxylate group present in all other RGD-types of ligands. Although modeling linear peptides is subjective, the pi-bonding model provides intriguing possibilities for medicinal chemistry after appropriate confirmatory studies.
Timing of DNA integration, transgenic mosaicism, and pronuclear microinjection.
Selection of transgenic embryos prior to embryo transfer is a means to increase the efficiency of transgenic livestock production. Among transgenic reporters, cytoplasmic expression of green fluorescent protein (GFP) has features that make it ideal for transgenic embryo selection. The primary objective of this study was to assess cytoplasmic expression of a specially designed GFP reporter as a tool for transgenic bovine embryo selection. A second objective was to evaluate this reporter for studying transgenic mosaicism related to timing of integration of pronuclear microinjected DNA. Transgenic embryos produced by pronuclear injection showed a discrete pattern of GFP expression with clusters at 25, 50, and 100% of blastomeres expressing GFP. This pattern of mosaicism is interpreted to indicate that the integration of microinjected DNA occurred, not only at the pronuclear stage, but also in the subsequent cell divisions. Among the GFP-positive transgenic embryos, only in 21% did all the blastomeres show the green fluorescence. Using the fraction of positive blastomeres within an embryo, the timing of integration of microinjected DNA was estimated. The frequency of nonmosaic embryos expressing GFP is consistent with published germline transmission success rates of transgenic cattle derived from pronuclear microinjected embryos. These results indicate the possible application of GFP as a marker of transgenic embryos and graphically illustrate underlying complexities in DNA integration in embryos subjected to pronuclear microinjection.
Balloon entrapment during side-branch angioplasty through a stent.
Entrapment of the distal tip of a balloon catheter occurred during attempted passage between the struts of a stent into a side branch. Traction on the balloon resulted in fracture of the catheter shaft requiring extraction with percutaneous retrieval forceps.
Alcohol dehydrogenase 3 genotype modification of the association of alcohol consumption with breast cancer risk.
OBJECTIVES: Because alcohol dehydrogenase 3 (ADH3) is rate-limiting in alcohol oxidation and is polymorphic, we examined ADH3 genotype in relation to alcohol intake and breast cancer risk. METHODS: We conducted a case-control study among Caucasian women aged 40-85 with incident, pathologically confirmed breast cancer and controls, frequency-matched on age and county. Queries included alcohol intake in the past 20 years. Genomic DNA was genotyped for the exon VIII ADH polymorphism by PCR followed by restriction enzyme digestion. Computation of odds ratios (OR) and 95% confidence intervals (CI) was by unconditional logistic regression. RESULTS: We found increased risk among pre- (OR 2.3, 95%, CI 1.2-4.3) but not postmenopausal women (OR 1.1, 95% CI 0.7-1.7) associated with ADH3(1-1) compared to ADH3(1-2) and ADH3(2-2) genotypes. Risk was increased for premenopausal women with the ADH3(1-1) genotype and alcohol intake above the median (OR 3.6, 95% CI 1.5-8.8) compared to lighter drinkers with the ADH3(2-2) or ADH3(1-2) genotypes. ORs were close to null for premenopausal women in other drinking and genotype groups and for postmenopausal women categorized by genotype and alcohol consumption. CONCLUSION: Among premenopausal women there may be a group more genetically susceptible to an alcohol consumption effect on breast cancer risk.
Transgenic animals: current and alternative strategies.
Transgenic animal technology is one of the most fascinating technologies developed in the last two decades. It allows us to address questions in life sciences that no other methods have achieved. The impact on biomedical and biological research, as well as commercial interests are overwhelming. The questions accompanying this fast growing technology and its diversified applications attract the attention from a variety of entities. Still, one of the most fundamental problems remaining is the search for an efficient and reliable gene delivery system for creating transgenic animals. The traditional method of pronuclear microinjection has displayed great variability in success among species. While an acceptable efficiency in the production of transgenic mice has been attained, the relative low efficiency (<1%) in creating transgenic livestock has become one of the barriers for its application. In the past decades, improvements in producing transgenic livestock have made a slow progression, however, the recent advancement in cloning technology and the ability to create transgenic livestock in a highly efficient manner, have opened the gate to a new era in transgenic technology. Discoveries of new gene delivery systems have created an enthusiastic atmosphere that has made this technology so unique. This review focuses on gene delivery strategies as well as various approaches that may assist the advancement of transgenic efficiency in large animals.
Effect of cocaine on cardiac biochemical functions.
The role of cocaine in cardiac ischemia and subsequent reversible and irreversible pathologic changes is well established. Nevertheless, the mechanisms leading to cardiac injury and irreversible cellular changes remain elusive. Reactive oxygen species (ROSs) are the critical mediators of cellular damage during ischemia-reperfusion. To explore the response of cardiac oxidative stress parameters to intravenous (i.v.) And intraperitoneal (i.p.) cocaine exposure, cardiac total glutathione (GSH, GSSG), malonaldialdehyde (MDA), Mn-superoxide dismutase (Mn-SOD), catalase (CAT), GSH-peroxidase (GSH-px), and GSH s-transferase (GST) were measured, along with biochemical and histologic markers indicative of cardiac injury. Repeated i.p. cocaine exposure produced significant impairment in cardiac integrity, demonstrated by increased circulating lactate (2.4-fold; p < 0.0001), creatine kinase (2.2-fold; p < 0.0001), and creatinine levels (1.7-fold; p < 0.0001). Infiltration of neutrophils into myocardial cavities also was evident. These changes paralleled increases in cardiac MDA (25%; p < 0.04), GSSG (55%; p < 0.001), protein carbonyls (23%; p < 0.05), and Mn-SOD (23%; p < 0.05) levels, indicative of oxidative stress, decreases in GSH (35%; p < 0.01), adenosine triphosphate (ATP; 26%; p < 0.04), GSH-px (28%; p < 0.03), CAT (32%; p < 0.01), and GST (50%; p < 0.001) levels. Intravenous cocaine administration also had similar effects on cardiac oxidative stress measures. In conclusion, our data indicate that cocaine administration compromised the heart's antioxidant defense system.
Comparability of nutrient estimation by three food frequency questionnaires for use in epidemiological studies.
Replication of results is an important issue in studies of diet and disease, possibly dependent on data collection method. We compared assessments from the Health Habits and History Questionnaire (HHHQ), the Harvard Semiquantitative Food Frequency Questionnaire (HFFQ), and the New York State Cohort Food Frequency Questionnaire (CFFQ) for estimates of daily intakes of energy, protein, carbohydrates, total fat, dietary fiber, cholesterol, vitamins A, C, and E, and carotenoids. Fifty-nine men and 50 women aged 35-73 years completed the HHHQ and HFFQ as interviews and the 44-food CFFQ as a self-administered mailed questionnaire. Comparability was assessed with Spearman correlation coefficients. Quantitation of nutrient intake differed by nutrient, questionnaire, and nutrient calculation method. Ranking on energy and macronutrient intake for the HHHQ and HFFQ ranged from 0.62 to 0.80; ranking for micronutrient intake ranged from 0.56 to 0.80. For the CFFQ with the HHHQ or HFFQ, correlations ranged between 0.29 and 0.62. The CFFQ performs comparably to the HHHQ and HFFQ for some, but not all, nutrients; our results suggest that the HHHQ and HFFQ can be used interchangeably with reasonable confidence in studies of diet and disease.
Adverse events associated with balloon rupture during percutaneous coronary intervention.
BACKGROUND: Balloon rupture is a potential complication of coronary angioplasty. The literature is inconsistent regarding associated adverse consequences. The experience of St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, with balloon rupture is reviewed. PATIENTS AND METHODS: All patients who underwent percutaneous coronary intervention complicated by balloon rupture at St Paul's Hospital from April 1992 to March 1996 were identified from the hospital's database (Seattle Systems, Seattle, Washington). Procedural logs, database records, clinical charts and all cineangiograms were reviewed in detail. RESULTS: A total of 2984 patients had percutaneous coronary revascularization and 110 patients experienced balloon rupture. These occurred in 101 (92%) native coronary arteries and 9 (8%) occurred in saphenous vein grafts. Stents were deployed in 44 (40%) patients; 34 of the stents used were half Johnson & Johnson PS153 stents (Johnson & Johnson Interventinal Systems, Peterborough, Ontario). An event-free postangioplasty course during the index hospitalization was observed in 102 patients (93%); eight patients (7%) had one or more important adverse events postprocedure. These included three deaths (one following a dissection and out-of-catheterization laboratory occlusion, a second following an abrupt occlusion of another target artery and emergency bypass surgery, and another with cardiogenic shock postmyocardial infarction and an unaltered course following angioplasty); one urgent bypass surgery after a left main dissection; and two nonfatal myocardial infarctions (one patient had tamponade and one patient experienced congestive heart failure). Four of the eight events were directly related to the procedure. The rate of death and emergency bypass surgery with balloon rupture did not differ from that of patients without balloon rupture in the authors' centre (1.8% versus 1.4%, not significant). CONCLUSIONS: The majority of patients did not experience any adverse clinical outcomes and demonstrated good angiographic results after balloon rupture. The data did not detect an excess of major adverse events beyond that expected in a diverse general angioplasty population.
Transgenic cattle produced by reverse-transcribed gene transfer in oocytes.
A critical requirement for integration of retroviruses, other than HIV and possibly related lentiviruses, is the breakdown of the nuclear envelope during mitosis. Nuclear envelope breakdown occurs during mitotic M-phase, the envelope reforming immediately after cell division, thereby permitting the translocation of the retroviral preintegration complex into the nucleus and enabling integration to proceed. In the oocyte, during metaphase II (MII) of the second meiosis, the nuclear envelope is also absent and the oocyte remains in MII arrest for a much longer period of time compared with M-phase in a somatic cell. Pseudotyped replication-defective retroviral vector was injected into the perivitelline space of bovine oocytes during MII. We show that reverse-transcribed gene transfer can take place in an oocyte in MII arrest of meiosis, leading to production of offspring, the majority of which are transgenic. We discuss the implications of this mechanism both as a means of production of transgenic livestock and as a model for naturally occurring recursive transgenesis.
Aminopyrine-induced blood dyscrasias.
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Test-retest reliability of the cognitive lifetime drinking history.
A new measure of lifetime alcohol consumption, the Cognitive Lifetime Drinking History (CLDH) uses beverage-specific questions on drink sizes and assesses drinking patterns to enhance recall. Two methods of establishing drinking intervals were examined: 1) floating--the respondent's report of when drinking changed, and 2) fixed--defined in terms of decades. Test-retest reliability for lifetime ounces of alcohol consumed and times intoxicated in lifetime estimated at visits 1 week or more apart was assessed in postmyocardial infarction patients (n = 81) and controls (n = 138) who had had at least 12 drinks in a year during their lifetimes. No significant differences in estimates of lifetime ounces of alcohol or times intoxicated were observed. Spearman's r ranged between 0.85 and 0.92 for the floating and fixed versions of the CLDH administered at a single visit and between 0.74 and 0.85 for the floating or fixed administered at both visits. Time between visits did not influence correlations. Intervals reported on the floating CLDH were comparable for postmyocardial infarction patients and controls. It took approximately 5 minutes longer to administer the floating CLDH than the fixed CLDH. Findings support use of the CLDH for case-control studies and suggest that the floating and fixed versions would yield comparable results.
Impairment of mitochondrial respiration and electron transport chain enzymes during cocaine-induced hepatic injury.
Morphological and biochemical changes in mitochondrial have been reported early in the course of cocaine-induced hepatotoxicity. This study was designed to examine the effects of repeated cocaine exposure in vivo on mitochondrial respiration, activities of respiratory chain enzymes, and lipid peroxide measures in liver. Male Sprague-Dawley rats were exposed to cocaine (5 i.p. injections of 25 mg/kg; 3-day period). Blood and liver samples were taken, and hepatic mitochondria were isolated by differential centrifugation. The cocaine-treated rats developed oxidative stress in hepatic mitochondria as evidenced by a significant increase in malonaldialdehyde (MDA; 52%; p < 0.0001) and a decreased glutathione (GSH; 22%; p < 0.0003). Blood aspartate aminotransferase (AST) and glutathione s-transferase (GST) levels in cocaine groups were significantly elevated (2.6 and 3.2 fold, respectively; p < 0.0001 for both). Cocaine caused a decrease in state-3 respiration and respiratory control ratio (RCR) ratio when exposed to site I and II substrates; these changes were parallelled by a decrease in complex I (22%; p < 0.003), succinate cytochrome c reductase (27%; p < 0.004), and complex IV (24%; p < 0.003). In conclusion, functional abnormalities of hepatic mitochondria accompany lipid peroxidation caused by cocaine, supporting the hypothesis that the mitochondria is one of the major intracellular targets of cocaine hepatotoxicity.
Cocaine-induced increase of Mn-SOD in adult rat liver cells.
Cultured adult rat liver cells (non-induced) were exposed to two different concentrations (2 microg/ml and 4 microg/ml) of cocaine-HCI for 1-3 hours. Cocaine-treated rat liver cells showed a significant increase in manganese superoxide dismutase (Mn-SOD) activity with time. Coinciding the rise in Mn-SOD activity was the Mn-SOD mRNA transcript, which also demonstrated a time-dependent elevation in its level (p<0.005). At the end of 1 and 3 hr. of cocaine exposure, the increase in Mn-SOD activity was 23% (p<0.05) and 39% (p<0.005), respectively. In contrast, activities of catalase (CAT) and glutathione peroxidase (GSH-px) were significantly diminished. Induction of Mn-SOD mRNA by cocaine (4 microg/ml) was inhibited by actinomycin D (4 microM), revealing that the up regulation of Mn-SOD involved transcriptional activation. The increase in Mn-SOD was accompanied by a decrease in liver cell integrity, indicated by increased lactate dehydrogenase (LDH) release by rat liver cells. These results suggest that antioxidant enzymes may play a critical role in cocaine-induced liver injury.