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Biomedical subjects

C Chu

Publications and source records attributed to C Chu.

At least 55 records · Page 3Linked to original sources
PubMed1996

Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene.

Signal transducers and activators of transcription (Stats) are activated by tyrosine phosphorylation in response to cytokines, and are thought to mediate many of their functional responses. Stat6 is activated in response to interleukin (IL)-4 and may contribute to various functions including mitogenesis, T-helper cell differentiation and immunoglobulin isotype switching. To evaluate the role of Stat6, we generated Stat6-null mice (Stat6 -/-) by gene disruption in embryonic stem cells. The mice were viable, indicating the lack of a non-redundant function in normal development. Although naive lymphoid cell development was normal, Stat6 -/- mice were deficient in IL-4-mediated functions including Th2 helper T-cell differentiation, expression of cell surface markers, and immunoglobulin class switching to IgE. In contrast, IL-4-mediated proliferation was only partly affected.

Animals↗
PubMed1996

Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle.

Caveolin, a 21-24-kDa integral membrane protein, is a principal component of caveolar membranes in vivo. Caveolin interacts directly with heterotrimeric G-proteins and can functionally regulate their activity. Recently, a second caveolin gene has been identified and termed caveolin-2. Here, we report the molecular cloning and expression of a third member of the caveolin gene gamily, caveolin-3. Caveolin-3 is most closely related to caveolin-1 based on protein sequence homology; caveolin-1 and caveolin-3 are approximately 65% identical and approximately 85% similar. A single stretch of eight amino acids (FED-VIAEP) is identical in caveolin-1, -2, and -3. This conserved region may represent a "caveolin signature sequence" that is characteristic of members of the caveolin gene family. Caveolin-3 mRNA is expressed predominantly in muscle tissue-types (skeletal muscle, diaphragm, and heart) and is selectively induced during the differentiation of skeletal C2C12 myoblasts in culture. In many respects, caveolin-3 is similar to caveolin-1: (i) caveolin-3 migrates in velocity gradients as a high molecular mass complex; (ii) caveolin-3 colocalizes with caveolin-1 by immunofluorescence microscopy and cell fractionation studies; and (iii) a caveolin-3-derived polypeptide functionally suppresses the basal GTPase activity of purified heterotrimeric G-proteins. Identification of a muscle-specific member of the caveolin gene family may have implications for understanding the role of caveolin in different muscle cell types (smooth, cardiac, and skeletal) as previous morphological studies have demonstrated that caveolae are abundant in these cells. Our results also suggest that other as yet unknown caveolin family members are likely to exist and may be expressed in a regulated or tissue-specific fashion.

Amino Acid Sequence↗
PubMed1996

Oral clonidine reduces postoperative PCA morphine requirements.

PURPOSE: The purpose of this study was to evaluate the effect of perioperative oral clonidine on postoperative analgesia and PCA morphine requirements in adult patients after major orthopaedic knee surgery. METHODS: In this prospective, double blind, placebo-controlled study 44 patients undergoing either total knee replacement or hemiarthroplasty of the knee were randomly assigned to receive oral placebo or clonidine (5 micrograms . kg-1) 1.5 hr before surgery, and at 12 hr, and 24 hr after the initial dose. Five patients were subsequently withdrawn from study. No other preoperative drugs were given. Preoperative sedation score was recorded. A standardized general anaesthetic was administered to all patients. Postoperative blood pressure, heart rate, PCA morphine use, visual analogue score (VAS) for pain, sedation, nausea, and pruritus were recorded for 36 hr postoperatively. RESULTS: The cumulative PCA morphine used was 37% lower after clonidine 57.3 +/- 26.8 mg (mean +/- SD) compared with placebo 91 +/- 31.6 mg (P = 0.031). There was no difference in pain or sedation scores postoperatively but patients who received clonidine were more sedated preoperatively (P < 0.001) and had a lower mean arterial blood pressure throughout the period of study by 10 to 26 mmHg (P < 0.0001). Clonidine reduced the incidence of postoperative nausea (25% vs 74%) (P < 0.01) and vomiting compared with placebo (10% vs 53%) (P < 0.01) and required less antiemetic (dimenhydrinate 37.5 +/- 20.9 mg vs 82.1 +/- 49.4 mg) but not statistically significant (P = 0.065). CONCLUSIONS: Oral clonidine is a useful component to postoperative balanced analgesia as it decreases PCA morphine requirements and decreases the incidence of nausea and vomiting.

Administration, Oral↗
PubMed1996

Imaging of orbital floor fractures.

The aim of this study was to compare the efficacy of plain films and computed tomography (CT) in defining inferior orbital fractures and any muscle involvement. Forty-four patients with final diagnosis of orbital floor fractures in the period 1990-94 were retrospectively studied. Computed tomography was performed in 28 patients, 20 being direct coronal acquisitions and eight being fine axial acquisitions with coronal reconstructions. Water's view radiographs were performed in 34 patients. Fourteen fractures on plain films were associated with soft tissue opacities to suggest inferior rectus (IR) muscle involvement, but only two required surgical elevation of the orbital floor. The remaining patients were successfully treated conservatively. Three patients had IR entrapment on direct coronal CT, all requiring surgical elevation of the orbital floor. Seven patients had IR muscle displacement on direct coronal CT and all had conservative management. In four patients with axial acquisition and coronal reconstructions, the CT images were of inadequate quality to determine the presence or absence of a fracture. One patient who had no IR muscle involvement identified on reconstructed coronal CT required surgical elevation of the orbital floor on clinical grounds. We conclude that: (i) soft tissue opacities on plain films are not an accurate indicator of clinically significant IR involvement; (ii) axial CT is not efficacious in detection of fractures or IR involvement; and (iii) direct coronal CT is the most efficacious imaging modality.

Adolescent↗
PubMed1996

Safety and immunogenicity of investigational Shigella conjugate vaccines in Israeli volunteers.

The safety and immunogenicity of investigational conjugates, composed of the O-specific polysaccharides of Shigella sonnei and Shigella flexneri type 2a covalently bound to Pseudomonas aeruginosa recombinant exoprotein A (rEPA), were evaluated in 192 Israeli soldiers. None had significant local reactions or fever. Fourteen days after injection, 90% of S. sonnei-rEPA recipients and 73 to 77% of S. flexneri-rEPA recipients had a fourfold or greater increase in serum immunoglobulin G (IgG) and IgA anti-lipopolysaccharide (anti-LPS) levels; at 2 years, these remained higher than at prevaccination (P < 0.01). There was a fourfold or greater increase in IgM anti-LPS in 20% of vaccinees at 2 weeks, but levels returned to prevaccination values at 6 to 12 months. IgG was the highest and most sustained class of LPS antibodies. Reinjection at day 42 did not boost antibody levels. Eighteen of 23 (78%) who received S. sonnei-rEPA and 13 of 19 (68%) who received S. flexneri-rEPA. had significant IgA-secreting cell responses. Significant IgG antibody-secreting cell responses were detected in 19 of 23 (83%) and 11 of 19 (58%) volunteers following vaccination with S. sonnei-rEPA and S. flexneri 2a-rEPA, respectively. On the basis of these data, further evaluation of the Shigella conjugates for protective efficacy in field trials in Israel was started.

Adolescent↗
PubMed1995

Peroxisomes contain delta 3,5,delta 2,4-dienoyl-CoA isomerase and thus possess all enzymes required for the beta-oxidation of unsaturated fatty acids by a novel reductase-dependent pathway.

The presence of delta 3,5,delta 2,4-dienoyl-CoA isomerase in peroxisomes was demonstrated by determining the subcellular distribution of this enzyme in rat liver. The peroxisomal and mitochondrial forms of the isomerase exhibit similar chain length specificities and they are homologous as indicated by the recognition of the peroxisomal 66-kDa enzyme by an antiserum raised against the mitochondrial 32-kDa isomerase. This report demonstrates that peroxisomes contain all enzymes required for the beta oxidation of unsaturated fatty acids with odd-numbered double bonds by a novel pathway in which double bonds are reductively removed by the NADPH-dependent 2,4-dienoyl-CoA reductase.

Animals↗
PubMed1995

Mitochondrial beta-oxidation of 2-methyl fatty acids in rat liver.

The mitochondrial beta-oxidation of 2-methyl fatty acids was studied with coupled rat liver mitochondria and purified enzymes. Measurements of mitochondrial respiration supported by 2-methyl fatty acids, straight chain fatty acids, or their coenzyme A (CoA) thioesters revealed that free short-chain and medium-chain 2-methyl fatty acids are oxidized nearly or as efficiently as are their straight chain analogs. Long-chain 2-methyl hexadecanoyl-CoA is also oxidized, although more slowly than its unbranched counterpart. However, medium-chain 2-methyldecanoyl-CoA, in contrast to its unbranched analog, is not oxidized at all. Of all acyl-CoA dehydrogenases only long-chain acyl-CoA dehydrogenase acts on medium-chain and long-chain 2-methylacyl-CoA thioesters. The resultant 2-methyl-2-enoyl-CoA thioesters are substrates of the mitochondrial trifunctional beta-oxidation complex which catalyzes the sequential hydration, dehydrogenation, and thiolytic cleavage of 2-methyl-substituted substrates to yield chain-shortened acyl-CoA thioesters and propionyl-CoA. The matrix enzymes L-3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase, in contrast to enoyl-CoA hydratase, are inactive with medium-chain and long-chain 2-methyl-substituted chain substrates. The specificity of the beta-oxidation enzymes toward 2-methyl-branched substrates forms the basis for assays of long-chain acyl-CoA dehydrogenase and the trifunctional beta-oxidation complex in the presence of their mitochondrial isozymes. It is concluded that rat liver mitochondria can oxidize 2-methyl fatty acids, but does so most effectively with medium-chain and short-chain ones that can enter mitochondria directly in a carnitine-independent manner.

Acyl Coenzyme A↗
PubMed1995

Pathophysiologic aspects of end-stage heart failure.

Heart failure is not a distinct disease, but rather a complex clinical syndrome that can result from virtually any form of heart disease. The so-called "end stages" of heart failure do not respect etiologic boundaries. Patients are characterized clinically by extreme cardiomegaly, breathlessness, and fluid retention. Despite recent advances in the pharmacologic management of congestive heart failure, it remains a highly lethal and disabling disorder. Only through an improved understanding of the basic biology of the early stages of the syndrome can heart failure be prevented or at least forestalled. There is now intense interest in understanding the mechanisms operative in early left ventricular remodeling, which has the potential to culminate in end-stage heart failure. The study of animal models has been particularly useful in this regard, as have clinical studies performed in the early stages of acute myocardial infarction. The remodeling process is characterized by myocyte loss and segmental scarring, interstitial fibrosis, myocardial slippage, and myocyte hypertrophy. Although the mechanisms responsible for these topographic changes are as yet unclear, the net result is progressive enlargement of the heart, culminating in severe left ventricular dysfunction. A long-held view that cardiomegaly is a necessary adaptive process that maintains stroke volume in the presence of a falling ejection fraction has been challenged, although undoubtedly the early responses to myocardial injury in the form of myocyte hypertrophy and maintenance of wall stress are useful adaptations. However, as the left ventricle continues to dilate and hypertrophy over time, a form of overadjustment occurs that perhaps is an important contributory factor toward end-stage failure.

Cardiomegaly↗
PubMed1995

Adjuvant activity of QS-21 for experimental E. coli 018 polysaccharide vaccines.

Three types of experimental vaccines containing O-side-chain polysaccharide from the enterotoxigenic strain Escherichia coli 018 were evaluated. The immunogenicity of free O-polysaccharide (PS), a polysaccharide-diphtheria toxoid conjugate (PS-conj), and detoxified lipopolysaccharide (dLPS) was tested in female ICR mice, either alone or in combination with QS-21, a purified saponin adjuvant derived from the bark of the tree Quillaja saponaria Molina. Both the number of individual mice responding and the titres of O-polysaccharide specific antibodies in pools of sera were increased by the addition of QS-21. The immune response to both O-specific polysaccharide and carrier was primarily IgM and IgG1. The addition of QS-21 not only increased the level of IgG1, but also had a significant adjuvant effect on antigen-specific IgG2a, IgG2b and IgG3.

Adjuvants, Immunologic↗
PubMed1995

Post-infarction myocardial remodelling: why does it happen?

Myocardial remodelling is currently the subject of intense investigative interest. The question "Why does it happen?' is not clearly answerable by today's methods; however, the work of many basic scientists and clinicians has allowed an improved understanding of the process. Multiple mechanisms are probably operative in the cardiac remodelling process, including cell drop-out, myocyte slippage, collagen replacement and growth, and myocyte hypertrophy. The concept of heart failure as primarily a structural problem rather than the result of a specific biochemical "defect' is advanced. There is now direct evidence that cardiac myocytes are enlarged in both experimental and clinical left ventricular remodelling. Possible signal processing cascades are potential pathways to myocyte remodelling. Although not proven, the enlarged and elongated cardiac myocyte may be at a structural disadvantage, thus contributing functionally to the clinical syndrome of heart failure. Reversal of established cardiomegaly--regression of myocardial remodelling--is an unusual but occasional event in patients with cardiomyopathy that can be observed experimentally.

Cardiomegaly↗
PubMed1995

Compensatory and maladaptive responses to cardiac dysfunction.

The field of congestive heart failure continues to be vigorously investigated at both the basic science level and in the clinic. As we move from the "hemodynamic" to the "neurohormonal" model of heart failure, more emphasis is being placed on interruption of neurohormone activity as a therapeutic strategy. A number of important clinical trials have been reported in the past year that underscore the potential of using drugs to inhibit neuroendocrine activity. The ultimate neuroendocrine inhibitors are perhaps the beta-adrenergic blocking drugs. They have yet to be adequately studied in a statistically powerful, randomized, placebo-controlled multicenter trial. Such a trial is about to begin in North America. In the meantime, numerous studies continue to confirm manifestations of neurohormone imbalance in clinical heart failure. Reduced heart rate variation has been under intensive investigation. A great variety of animal models of heart failure are also currently being studied. Perhaps more important advances have been made in the treatment of patients with heart failure than in any other field in internal medicine in recent years. However, improved patient survival tends to further increase the overall cost of patient care. Perhaps we are simply shifting the patient population, extending survival by 9 to 18 months. More advanced heart failure is more expensive to care for. It is only through understanding the basic biology and pathophysiology of heart failure that fresh new ideas will emerge leading to earlier therapy and, ultimately, prevention of this important disorder.

Animals↗
PubMed1994

Estimation of peroxisomal beta-oxidation in rat heart by a direct assay of acyl-CoA oxidase.

The contribution of peroxisomes to palmitate beta-oxidation in rat heart was estimated by either inhibiting mitochondrial beta-oxidation or measuring the activity of acyl-CoA oxidase. When respiratory inhibitors such as KCN or antimycin plus rotenone, or inhibitors of mitochondrial fatty acid uptake such as 2-tetradecylglycidic acid or 2-bromopalmitate, were used, degrees of inhibitions ranging from 24% to 87% were observed for palmitate beta-oxidation by a rat heart homogenate. Although the oxidation of palmitoyl-L-carnitine by coupled rat heart mitochondria was almost completely (94%) inhibited by KCN, the inhibition by antimycin plus rotenone was incomplete (77%) and was stimulated by L-carnitine. A direct assay of acyl-CoA oxidase, based on the spectrophotometric measurement at 300 nm of 2,4-decadienoyl-CoA formation from 4-trans-decenoyl-CoA, was evaluated with the aim of obtaining reliable values for the activity of this enzyme, which is presumed to catalyse the rate-limiting step of peroxisomal beta-oxidation. Activities determined by use of this assay were much higher than activities obtained by a coupled assay [Small, Burdett and Connock (1985) Biochem. J. 227, 205-210] commonly used to measure the activity of acyl-CoA oxidase. However, both methods yielded the same relative activities with different tissue homogenates. Based on an estimated palmitoyl-CoA oxidase activity of 0.3 nmol/min per mg of protein, the contribution of peroxisomes to palmitate beta-oxidation in a rat heart homogenate would optimally be 4%, and most likely is several-fold lower.

Acyl-CoA Oxidase↗
PubMed1994

Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis.

X-chromosome-inactivation assays can be used to assess clonality. We used such an assay at the human androgen-receptor gene locus in three female patients with histologically proven Langerhans cell histiocytosis. All patients were heterozygous for this locus. Cells bearing the Langerhans cell phenotype were purified from involved tissue after fluorescence-activated cell sorting with monoclonal antibodies against the CD1a complex. After HhaI digestion of DNA, these CD1a positive cells demonstrated a non-random X-chromosome-inactivation pattern, whereas CD1a negative cells in the same tissue showed a random pattern. Our data suggest that Langerhans cell histiocytosis represents a clonal proliferation of cells bearing the Langerhans cell phenotype.

Antibodies, Monoclonal↗
PubMed1994

Hepatic beta-oxidation of 3-phenylpropionic acid and the stereospecific dehydration of (R)- and (S)-3-hydroxy-3-phenylpropionyl-CoA by different enoyl-CoA hydratases.

The hepatic beta-oxidation of 3-phenylpropionic acid (PPA) was studied by the use of subcellular fractions and purified enzymes with the aim of characterizing intermediates and the subcellular location of this pathway. Respiration measurements with coupled rat liver mitochondria indicate that PPA is efficiently metabolized by mitochondrial beta-oxidation. In contrast, the peroxisomal beta-oxidation of this compound is at best a very slow process, as evidenced by the low activity of peroxisomal acyl-CoA oxidase toward 3-phenylpropionyl-CoA. In mitochondria, 3-phenylpropionyl-CoA is effectively dehydrogenated to cinnamoyl-CoA, which is only slowly converted to benzoylacetyl-CoA due to the unfavorable equilibrium of the hydration of cinnamoyl-CoA to 3-hydroxy-3-phenylpropionyl-CoA. Benzoylacetyl-CoA is a substrate of 3-ketoacyl-CoA thiolase. The dehydration of 3-hydroxy-3-phenylpropionyl-CoA to cinnamoyl-CoA forms the basis for a sensitive and stereospecific assay of enoyl-CoA hydratases. The progress of this reaction, which proceeds to near completion, can be measured spectrophotometrically at 308 nm. Soluble mitochondrial and peroxisomal enoyl-CoA hydratases only act on the (R,L) isomer, whereas the peroxisomal D-3-hydroxyacyl-CoA dehydratase is specific for the (S,D) isomer. Both substrates can be easily prepared from the commercially available enantiomeric acids. It is concluded that PPA, a key compound in Knopp's classical study that led him to formulate the principle of beta-oxidation, is overwhelmingly, if not completely, degraded by mitochondrial beta-oxidation.

Acyl Coenzyme A↗
PubMed1994

Reproductive health research in China: the Ford Foundation initiatives.

Increasing demographic and epidemiological evidence shows that maternal health problems are widespread and are linked to social, cultural, and economic factors, in particular, to women's status in society. Thus, there is an urgent need to expand existing knowledge about these influences on reproductive health and to empower women to gain control over them. To this end, there is a need for a comprehensive, interdisciplinary approach with an emphasis on social science research and training. The Ford Foundation, after an extensive review of its work in population and development, embarked on a new, ten-year, comprehensive reproductive health program for the 1990s. This paper describes one component of that program, a partnership with the All China Women's Federation to sponsor a series of reproductive health research activities. It examines the development and evaluates the positive and negative outcomes of the project, which commenced in 1991, from the perspective of a consultant involved in the process. So far, the project has generated interest in reproductive health in at least twenty-one Chinese provinces and has fostered a real partnership between the sponsoring and the collaborating agency. Based on the immediate outcomes of a research competition designed to identify research projects and investigators, of participant evaluation of the methodology training course, and of the strategies aimed at building capabilities and strengthening institutions in order to ensure future success, I conclude that the Ford Foundation's reproductive health initiative in China is a worthwhile and sustainable project.

China↗
PubMed1994

Resource intensity weighing and case mix grouping: assumptions and implications for health service performance evaluation.

The use of Resource Intensity Weights (RIWs*) for equity funding and utilization management assumes validity of the cost estimates, reliability of the patient categorization scheme, equivalence of the bases for cost comparison, and equity of the subsequent resource distribution. This paper examines these assumptions, and concludes that caution must be taken when using the current RIWs and Case Mix Groups (CMGs*) for resource allocation and performance evaluation purposes. RIW has represented a milestone in the history of Canadian health care product costing and management. It would be prudent for health care professionals at the operational level to provide structured and continuing feedback that can contribute to the validation and refinement of these valuable management tools.

Diagnosis-Related Groups↗