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M W Chang

Publications and source records attributed to M W Chang.

At least 37 records · Page 2Linked to original sources
PubMed1996

Gene therapy for vascular proliferative disorders.

Despite major advances in interventional techniques in recent years, restenosis remains an important late complication of percutaneous revascularization procedures. Vascular smooth muscle cell proliferation after arterial injury plays an important role in the pathogenesis of restenosis. Major progress has been made recently in elucidating the cellular and molecular mechanisms underlying this proliferative response. This in turn has led to the development of novel, gene-based approaches for the treatment and prevention of restenosis as well as other vascular proliferative disorders. Included among these are somatic gene therapy the ability to introduce and express recombinant genes in non-germ-line cells of a recipient organism in vivo. This article reviews specific genetic approaches that have recently been developed for the treatment of vascular proliferative disorders such as restenosis, focusing on the use of adenovirus-mediated arterial gene transfer strategies designed to suppress the vascular smooth muscle cell proliferative response associated with these diseases.

Adenoviridae↗
PubMed1995

Cytostatic gene therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene product.

Vascular smooth muscle cell (SMC) proliferation in response to injury is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis after balloon angioplasty. The retinoblastoma gene product (Rb) is present in the unphosphorylated and active form in quiescent primary arterial SMCs, but is rapidly inactivated by phosphorylation in response to growth factor stimulation in vitro. A replication-defective adenovirus encoding a nonphosphorylatable, constitutively active form of Rb was constructed. Infection of cultured primary rat aortic SMCs with this virus inhibited growth factor-stimulated cell proliferation in vitro. Localized arterial infection with the virus at the time of balloon angioplasty significantly reduced SMC proliferation and neointima formation in both the rat carotid and porcine femoral artery models of restenosis. These results demonstrate the role of Rb in regulating vascular SMC proliferation and suggest a gene therapy approach for vascular proliferative disorders associated with arterial injury.

Adenoviridae↗
PubMed1995

Decreased balance performance in cowboy boots compared with tennis shoes.

OBJECTIVE: This study was conducted to examine the relative balance performance of cowboy boots versus tennis shoes when the subject was challenged with different accelerations. The end point was the highest acceleration at which the subject could maintain full foot contact with the platform for each footwear type, ie, break acceleration. DESIGN: Crossover trial. SETTING: General community. PARTICIPANTS: Twenty-seven healthy women, 18 to 40 years old, with shoe sizes between 6 and 9, were selected in a convenience sample after their response to posted ads in a university medical center. INTERVENTION: Each subject was tested 3 times in the forward direction per acceleration on a Motionspec balance platform. A successful series was defined as keeping feet flat for 2 of 3 tests/level. MAIN OUTCOME MEASURE: The planned major outcome was the difference between the highest accelerations at which the subject was successful for each type of footwear. RESULTS: Subjects were found to have a highest sustainable acceleration in boots 10.66 +/- 6.20cm/s2 less than the highest acceleration in shoes. A period effect was found that improved the results of the second footwear tested by 7.2 +/- 6.20cm/s2. CONCLUSIONS: Cowboy boots have a decreased balance performance compared with tennis shoes. Further study should examine the specific features in the boot that contribute to this imbalance and examine the kinematic adaptations of the body to cowboy boots.

Adolescent↗
PubMed1995

Initialization of warfarin dosages using computer modeling.

OBJECTIVE: Software incorporating warfarin pharmacokinetics and pharmacodynamics, as well as a Bayesian regression method, was evaluated for accuracy in predicting steady-state dosages of warfarin during initialization of anticoagulation therapy. DESIGN: A cohort study was used to compare computer predictions with physician-determined doses during a retrospective chart review of 42 patients. PATIENTS: Forty-two patient charts were selected for monitoring anticoagulation initialization therapy. Of the 42 patients reviewed, 22 were excluded on the following bases: uncontrolled congestive heart failure; ongoing treatment with medications that interfered with warfarin metabolism or displaced warfarin from protein binding sites; recent treatment with fresh frozen plasma or vitamin K; or any bleeding disorders, sepsis, malabsorption or significant changes in liver and/or renal function. MAIN OUTCOME MEASURES: Using physician-determined International Normalized Ratios (INRs) as target levels for the software, the number of INR feedbacks needed to stabilize blood drug levels during initialization were compared between physicians and computer forecasting. Population parameters and sequentially measured INRs were used for evaluation. RESULTS: Current oral anticoagulation protocols require significantly more measured INRs than computer forecasting to achieve steady-state dosages (9.5 v 4.4, respectively, p < 0.01). Physicians showed a statistically significant pattern of underdosing patients (4.3 v 1.7 subtherapeutic INRs, respectively, p < 0.01). Computer predictions tended to overdose patients but did not significantly increase the number of supratherapeutic INRs. This study showed that five INR inputs consistently gave accurate steady-state dosage predictions, and in many ways computer modeling was more effective than clinician-determined steady-state dosing in warfarin initialization. CONCLUSIONS: Computer modeling provides a reliable means of predicting initialization dosages for warfarin anticoagulation therapy with five INR inputs and therefore has merit in the clinical setting if used with sound clinical judgment.

Adult↗
PubMed1995

Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty.

Vascular smooth muscle cell (VSMC) proliferation after arterial injury is important in the pathogenesis of a number of vascular proliferative disorders, including atherosclerosis and restenosis after balloon angioplasty. Thus, a better understanding of the molecular mechanisms underlying VSMC proliferation in response to arterial injury would have important therapeutic implications for patients with atherosclerotic vascular disease. The p21 protein is a negative regulator of mammalian cell cycle progression that functions both by inhibiting cyclin dependent kinases (CDKs) required for the initiation of S phase, and by binding to and inhibiting the DNA polymerase delta co-factor, proliferating cell nuclear antigen (PCNA). In this report, we show that adenovirus-mediated over-expression of human p21 inhibits growth factor-stimulated VSMC proliferation in vitro by efficiently arresting VSMCs in the G1 phase of the cell cycle. This p21-associated cell cycle arrest is associated both with significant inhibition of the phosphorylation of the retinoblastoma gene product (Rb) and with the formation of complexes between p21 and PCNA in VSMCs. In addition, we demonstrate that localized arterial infection with a p21-encoding adenovirus at the time of balloon angioplasty significantly reduced neointimal hyperplasia in the rat carotid artery model of restenosis. Taken together, these studies demonstrate the important role of p21 in regulating Rb phosphorylation and cell cycle progression in VSMC, and suggest a novel cytostatic gene therapy approach for restenosis and related vascular proliferative disorders.

Adenoviridae↗
PubMed1995

Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery.

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation following arterial injury plays a critical role in a variety of vascular proliferative disorders, including atherosclerosis and restenosis after balloon angioplasty. In this study, we tested the hypothesis that localized arterial infection at the time of balloon angioplasty with an adenovirus (ADV-tk) encoding the herpes simplex virus thymidine kinase gene (HSV-tk), followed by systemic ganciclovir administration, can inhibit VSMC proliferation and neointima formation in a well-characterized model of arterial injury and restenosis. MATERIALS AND METHODS: The left carotid arteries of 31 male Sprague-Dawley rats were subjected to balloon angioplasty and immediately infected with 2 x 10(9) pfu of either ADV-tk or a control adenovirus that does not encode a recombinant protein (ADV-delta E1). Twenty-four hours after injury, animals from each experimental group were randomized to receive a course of systemic ganciclovir (ADV-tk/+GC, ADV delta E1/+GC) or saline (ADV-tk/-GC, ADV-delta E1/-GC). VSMC DNA synthesis was measured by 5'-bromodeoxuridine (BrdU) incorporation 2-4 days after balloon injury. The extent of restenosis, expressed as the neointima to media (I/M) area ratio was determined by digital planimetry 20 days after balloon injury in each of the four treatment groups. Immunohistochemistry using a mAb to von Willebrand factor (vWF) was used to determine the effects of ADV-tk infection and ganciclovir treatment on re-endothelialization of the carotid arteries 20 days following balloon angioplasty. RESULTS: Forty-one percent of the medial VSMCs in the ADV-tk/-GC arteries were labeled with BrdU 4 days after balloon injury. In contrast, ADV-tk infected animals that were treated with systemic ganciclovir (ADV-tk/+GC) displayed a 40% reduction in BrdU-staining medial VSMCs (p < 0.03). I/M area ratios of the three control groups were 1.17 +/- 0.18 (ADV-tk/-GC, n = 5), 1.15 +/- 0.10 (ADV-delta E1/+GC, n = 6), and 0.91 +/- 0.08 (ADV-delta E1/-GC, n = 6). These differences were not statistically significant (p > 0.05). In contrast, the ADV-tk/+GC animals (n = 6) displayed an I/M area ratio of 0.49 +/- 0.13 which was significantly lower than that seen in each of the three control groups (p < 0.02). None of the treated animals showed evidence of significant organ toxicity at autopsy. A regenerated endothelium was observed in the ADV-tk/+GC animals 20 days after balloon injury. CONCLUSIONS: Localized arterial infection with ADV-tk at the time of balloon angioplasty followed by systemic ganciclovir therapy reduces VSMC proliferation and neointimal expansion in the rat carotid artery injury model. Moreover, combined treatment with ADV-tk and systemic ganciclovir does not result in systemic toxicity and appears to selectively eliminate proliferating VSMCs, while preserving the capacity of the injured arterial segments to re-endothelialize within 3 weeks of injury. Taken together, these results support the feasibility of using this gene therapy approach for the treatment of human vascular proliferative disorders.

Adenoviridae↗
PubMed1994

Footwear and falls: a case involving new cowboy boots.

We present a case in which footwear contributed to a fall that resulted in a severe closed head injury. The woman in this case was wearing new cowboy-style boots with 1.5-inch heels that placed her ankles at a position of 25 degrees plantar flexion. Each boot heel tapered at a 50 degrees angle at its posterior edge. A steel shank protruded 2.5 in posterior to the metatarsal head, serving as the anterior contact surface in lieu of normal metatarsal contact. The design of the boot plus the fact that she was carrying groceries, reduced her ability to regain her balance after she slipped, and she fell backward, hitting the floor with full force on the occiput. Initial computed tomography scan showed large subdural and epidural hematomas and hemorrhagic contracoup contusions. The patient developed clinical signs and symptoms of secondary brainstem injury, which was later substantiated by magnetic resonance imaging scan.

Accidental Falls↗
PubMed1994

Myogenic knee contracture from acute pelvic venous thrombosis.

A unique case of knee extension contracture resulting from acute pelvic venous thrombosis is presented. Magnetic resonance imaging/angiography and electrodiagnosis aided in understanding the pathogenesis and hence in designing the treatment. Neuropathies contributed to the severity of the problem. Physical treatment to ease the edema improved knee joint range of motion but did not fully restore knee flexion.

Acute Disease↗
PubMed1994

Active compression-decompression CPR improves vital organ perfusion in a dog model of ventricular fibrillation.

OBJECTIVES: This study was designed to assess whether a new method of cardiopulmonary resuscitation (CPR), termed active compression-decompression CPR, or ACD-CPR, improves organ perfusion when compared with standard (S) CPR in a dog model of ventricular fibrillation. BACKGROUND: ACD-CPR has recently been shown to improve hemodynamic and respiratory parameters during cardiac arrest when compared with standard CPR. However, to our knowledge, the effects of ACD-CPR on tissue perfusion have not been investigated. METHODS: Ventricular fibrillation was induced in eight anesthetized, intubated animals. ACD-CPR and standard CPR were each performed twice in alternating order. All interventions were preceded by 1 min of ventricular fibrillation, in which no CPR was performed, and consisted of 6 min of CPR with either technique during which tissue perfusion was measured. Compressions were performed at 80/min with a 50 percent duty cycle and 175 to 200 N downward force applied to the chest wall for both techniques. Epinephrine was administered at the beginning of each 6-min CPR interval. Hemodynamic monitoring of aortic and right atrial pressure was performed continuously and myocardial, cerebral, and renal blood flows were measured using the radiolabeled microsphere technique at baseline and during all interventions. RESULTS: Baseline organ perfusion and hemodynamics were similar for all dogs. Baseline left ventricular, brain, and renal blood flows were 62.0 +/- 5.5, 14.1 +/- 2.1, and 476.3 +/- 55.5 ml/min/100 g, respectively (mean +/- SEM). Compared with standard CPR, ACD-CPR resulted in higher global left ventricular (22.5 +/- 6.2 vs 14.1 +/- 4.0 ml/min/100 g, p < 0.01), cerebral (12.0 +/- 2.4 vs 8.5 +/- 2.3 ml/min/100 g, p < 0.01), and renal cortical (27.8 +/- 5.0 vs 17.5 +/- 5.0 ml/min/100 g, p < 0.05) blood flows. Regional flows to the epicardium, endocardium, and midmyocardium as well as to the frontal, parietal, and occipital lobes of the brain were all significantly improved by ACD-CPR. Aortic systolic (61.7 +/- 4.1 vs 49.5 +/- 3.1 mm Hg, p < 0.01), aortic mean (31.6 +/- 2.8 vs 27.2 +/- 2.2 mm Hg, p = 0.001), and myocardial perfusion pressure (12.9 +/- 3.4 vs 10.4 +/- 3.4 mm Hg, ACD-CPR vs standard CPR, p < 0.01) were all higher during ACD-CPR than during standard CPR. CONCLUSIONS: We conclude that ACD-CPR improves tissue perfusion and systemic hemodynamics compared with standard CPR.

Animals↗
PubMed1987

Use of the Escherichia coli gene for asparagine synthetase as a selective marker in a shuttle vector capable of dominant transfection and amplification in animal cells.

A new dominant amplifiable selective system for use in bacterium-animal cell shuttle vectors was developed by the insertion of a 2-kilobase genomic fragment containing the cloned Escherichia coli gene for asparagine synthetase (AS) into the pBR322-simian virus 40 recombinant vector pSV2 so as to place the translational initiator codon for the bacterial AS about 1,000 base pairs downstream from the simian virus 40 early promoter. This new construct, pSV2-AS, retains bacterial sequences for transcriptional and translational initiation and so can express AS in bacteria. The construct can also complement AS- mutants of mammalian cells, giving AS+ transfectants capable of growth in medium lacking asparagine, with relatively high efficiency (about 300 colonies per microgram of DNA per 10(6) cells exposed). The vector can be amplified up to 100-fold in such AS+ transfectants by selection in asparagine-free medium containing increasing concentrations of the AS inhibitor beta-aspartyl hydroxamate. AS+ transfectants were found to be much more resistant to a second AS inhibitor, Albizziin, than were normal AS+ animal cell lines. This difference, which may indicate a strong resistance of the bacterial AS enzyme to Albizziin, was exploited to develop an effective selection for bacterial AS transfectants of a number of wild-type AS+ cell lines of rat, Chinese hamster, mouse, and human origin. LR-73 cells, a Chinese hamster AS+ cell line, were transfected with pSV2-AS with an efficiency of about 1,000 colonies per 0.5 microgram of DNA per 10(6) cells. The integrated construct in these cells was amplified by incubation of the transfectants in increasing concentrations of beta-aspartyl hydroxamate. Advantages and disadvantages of this new dominant, selectable, and amplifiable marker over markers commonly used in shuttle vectors are discussed.

Amino Acids, Diamino↗
PubMed1986

The structure of HSAG-1, a middle repetitive genetic element which elicits a leukemia-related cellular surface antigen.

HSAG-1 is a cloned member of a heterogeneous middle repetitive family of genetic elements which is capable of eliciting a leukemia-related surface antigen detected with a monoclonal antibody after DNA transformation of mouse cells. HSAG-1 was originally isolated from a Chinese hamster-human leukemia hybrid cell gene library both by sib-selection for antigen producing activity and by hybridization with labelled human genomic human DNA. We show here that the human labelled site is at the right hand end of the insert, while the antigen-eliciting portion is included in a 1450 bp fragment at the left hand end of the insert. We also present the complete nucleotide sequence of the 3369 bp insert. The sequence contains 12 elements which bear a significant resemblance to accepted consensus sequences for Alu repetitive elements. The right hand end contains adjacent elements with close sequence similarity to portions of the human and hamster type I and type II Alu consensus sequences. All of the other Alu-related elements have diverged relative to the Alu consensus sequences by additions, long deletions and substitutions. The left hand portion of the insert which has the antigen-producing activity contains four of these diverged elements representing a relatively high proportion (26%) of the nucleotide sequence. The sequence is thus consistent with our previous observations of a repetitive family with biological function.

Animals↗
PubMed1976

Biotin status and lipid metabolism in adult obese hypercholesterolemic inbred rats.

A statistically significant inverse association was generally found between plasma total lipid, cholesterol, or phospholipid and biotin status of 300-day-old male inbred BHE (IN-BHE) rats. Plasma, liver, and carcass lipid of both sexes generally had a significant direct association with liver lactate dehydrogenase activity; an inverse association in males resulted with improved biotin status. Elevated plasma lactate indicative of anaerobic glycolysis was found. It is proposed that an increased reductive environment - a consequence of accumulated NADH - could account for enhanced triglyceride synthesis and that this effect could explain the obesity in the IN-BHE rats. After the injection of 300 mug of biotin, plasma levels of lactate and pyruvate fell in male rats, indicating a stimulatory effect of biotin upon the oxidative pathways in these animals.

Animals↗