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Biomedical subjects

K C Kent

Publications and source records attributed to K C Kent.

At least 37 records · Page 2Linked to original sources
PubMed2000

The effect of growth factors, cytokines, and extracellular matrix proteins on fibronectin production in human vascular smooth muscle cells.

PURPOSE: Although 60% to 80% of the mature intimal hyperplastic plaque is composed of extracellular matrix (ECM) proteins, little is known about the factors that stimulate smooth muscle cells (SMCs) to produce these proteins. A major component of the ECM protein is fibronectin. Thus we studied fibronectin production and its response to various growth factors, cytokines, and other ECM proteins that are released at the time of vascular injury. METHODS: Quiescent cultured human SMCs were stimulated for varying intervals with increasing concentrations of agonist. Fibronectin in the cell medium was assayed by immunoblotting with a fibronectin-specific antibody. RESULTS: After 72 hours of stimulation, transforming growth factor-beta (10 ng/mL) had the most profound effect on fibronectin production (9.6- +/- 2.1-fold; P <.05), followed by epidermal growth factor (100 ng/mL; 5.0- +/- 0.1-fold; P <.05, for both). Surprisingly, the platelet-derived growth factors (AA, AB, and BB) and fibroblast growth factor did not stimulate fibronectin production. Among the matrix proteins studied, only collagen type I (20 microg/mL) stimulated fibronectin production (1.9- +/- 0.1-fold; P <.05), whereas collagen type IV and laminin had no effect. The contractile protein angiotensin II (100 ng/mL) was a weak stimulant of fibronectin (1.6- +/- 0.2-fold; P <.05). Time course studies of fibronectin production up to 72 hours revealed kinetics that varied with each agonist. Transforming growth factor-beta stimulated significant early production of fibronectin, whereas fibronectin production in response to epidermal growth factor and collagen type I was initially modest but increased with time. The effect of angiotensin II did not become evident until 72 hours. CONCLUSION: Cytokines, growth factors, and matrix proteins have varying quantitative effects on ECM protein production by human vascular SMCs. Knowledge of the factors that influence ECM protein production may allow for the design of specific inhibitors that can prevent intimal hyperplasia.

Cells, Cultured↗
PubMed1999

The role of mitogen-activated protein kinase and protein kinase C in fibronectin production in human vascular smooth muscle cells.

BACKGROUND: After evaluating various growth factors, cytokines, and extracellular matrix (ECM) proteins, we found that the most potent agonists of smooth muscle cell (SMC) fibronectin (Fn) production were transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF). To determine the possible signaling pathways involved in the production of this matrix protein, we investigated the role of the intracellular proteins, protein kinase C (PKC) and mitogen-activated protein kinase (MAP-K), in TGF-beta- and EGF-induced human vascular SMC Fn production. MATERIALS AND METHODS: After stimulation of human SMCs with TGF-beta (10 ng/ml) and EGF (100 ng/ml), Fn in the cell medium was assayed by immunoblotting using a specific antibody. PKC was activated by brief stimulation of SMC with phorbol 12,13-dibutyrate (PDBu) and inhibited by downregulation with PDBu or the inhibitor, GF109203X. MAP-K was inhibited with PD098059. RESULTS: PKC activation increased basal and synergistically enhanced TGF-beta- and EGF-induced Fn production. However, inhibition of PKC by downregulation and GF109203X did not diminish Fn production by TGF-beta and EGF. Surprisingly, these two methods of inhibition slightly increased basal and agonist-induced Fn production. The MAP-K kinase inhibitor, PD098059, produced an almost complete inhibition of EGF and a partial inhibition of TGF-beta-induced Fn production. CONCLUSIONS: Activation of PKC stimulates Fn production; however, neither TGF-beta nor EGF produce Fn through a PKC-dependent pathway. EGF and TGF-beta both stimulate Fn production at least in part through the intracellular signaling protein MAP-K. Understanding the signaling pathways involved in extracellular matrix protein production will allow the design of specific inhibitors of intimal hyperplasia.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Is thrombolysis of lower extremity acute arterial occlusion cost-effective?

BACKGROUND: The TOPAS (thrombolysis or peripheral artery surgery) trial randomized 544 patients with acute lower extremity ischemia to either surgery or thrombolysis. Although statistically equivalent 1-year morbidities and mortalities were demonstrated, the comparative cost-effectiveness of these two interventions has not been explored. MATERIALS AND METHODS: We constructed a Markov decision-analytic model to determine the cost-effectiveness of thrombolysis relative to surgery for a hypothetical cohort of patients with acute lower extremity arterial occlusion. Our measure of outcome was the cost-effectiveness ratio (CER), defined as the incremental lifetime cost per quality-adjusted life year gained. Estimates of 1-year outcomes were based on the TOPAS trial: mortality (lysis, 20%; surgery, 17%), amputation (lysis, 15%; surgery, 13%), the number of additional interventions required following the initial procedure (lysis, 544; surgery, 439). Procedural costs were estimated from the cost accounting system at the New York Presbyterian Hospital as well as from the literature. RESULTS: Operative intervention for acute lower extremity arterial occlusion extended life and was less costly compared to thrombolysis. The projected life expectancy for patients who underwent initial surgery was 5.04 years versus 4.75 years for initial thrombolysis. The lifetime costs were $57,429 for surgery versus $dollar;76,326 for thrombolysis. In performing sensitivity analyses, a threshold CER of $60,000 was considered what society would pay for accepted medical interventions. Thrombolysis became cost-effective if the 1-year mortality rate for lysis was lowered from 20 to 10.7%, if the amputation rate for lysis diminished from 15 to 3.9%, or if the 1-year cost of lysis could be reduced to a level below $13,000. CONCLUSIONS: Initial surgery provides the most efficient and economical utilization of resources for acute lower extremity arterial occlusion. The high cost of thrombolysis is related to the expense of the lytic agents, the need for subsequent interventions in patients treated with initial lysis, and the long-term costs of amputation in patients who fail lytic therapy.

Amputation, Surgical↗
PubMed1999

Is carotid endarterectomy cost-effective in symptomatic patients with moderate (50% to 69%) stenosis?

OBJECTIVE: Recently published data from the North American Carotid Endarterectomy Trial revealed a benefit for carotid endarterectomy (CEA) in symptomatic patients with moderate (50% to 69%) carotid stenosis. This benefit was significant but small (absolute stroke risk reduction at 5 years, 6.5%; 22.2% vs 15.7%), and thus, the authors of this study were tentative in the recommendation of operation for these patients. To better elucidate whether CEA in symptomatic patients with moderate carotid stenosis is a proper allocation of societal resources, we examined the cost-effectiveness of this intervention. METHODS: A decision-analytic Markov process model was constructed to determine the cost-effectiveness of CEA versus medical treatment for a hypothetical cohort of 66-year-old patients with moderate carotid stenosis. This model allowed the comparison of not only the immediate hospitalization but also the lifetime costs and benefits of these two strategies. Our measure of outcome was the cost-effectiveness ratio (CER), defined as the incremental lifetime cost per quality-adjusted life year saved. We assumed an operative stroke and death rate of 6.6% and a declining risk of ipsilateral stroke after the ischemic event with medical treatment (first year, 9.3%; second year, 4%; subsequent years, 3%). The hospitalization cost of CEA ($6,420) and the annual costs of major stroke ($26,880), minor stroke ($798), and aspirin therapy ($63) were estimated from a hospital cost accounting system and the literature. RESULTS: CEA for moderate carotid stenosis increased the survival rate by 0.13 quality-adjusted life years as compared with medical treatment at an additional lifetime cost of $580. Thus, CEA was cost-effective with a CER of $4,462. Society is usually willing to pay for interventions with CERs of less than $60,000 (eg, CERs for coronary artery bypass grafting at $9,100 and for dialysis at $53,000). CEA was not cost-effective if the perioperative risk was greater than 11.3%, if the ipsilateral stroke rate associated with medical treatment at 1 year was reduced to 4.3%, if the age of the patient exceeded 83 years, or if the cost of CEA exceeded $13,200. CONCLUSION: CEA in patients with symptomatic moderate carotid stenosis of 50% to 69% is cost-effective. Perioperative risk of stroke or death, medical and surgical stroke risk, cost of CEA, and age are important determinants of the cost-effectiveness of this intervention.

Aged↗
PubMed1999

The cost-effectiveness of endovascular repair versus open surgical repair of abdominal aortic aneurysms: A decision analysis model.

PURPOSE: Endovascular repair (EVR) is a less-invasive method for the treatment of abdominal aortic aneurysms (AAAs) as compared with open surgical repair (OSR). The potential benefits of EVR include increased patient acceptance, less resource utilization, and cost savings. This study was designed to determine whether the EVR of AAAs is a cost-effective alternative to OSR. METHODS: A cost-effectiveness analysis was performed using a Markov decision analysis model to compute long-term survival rates in quality-adjusted life years and lifetime costs for a hypothetical cohort of patients who underwent either OSR or EVR. Probability estimates of the different outcomes of the two alternative strategies were made on the basis of a review of the literature. The average costs of (1) the immediate hospitalization ($16,016 for OSR, $20,083 for EVR), (2) the complications that resulted from each procedure, (3) the subsequent interventions, and (4) the surveillance protocol were determined on the basis of average resource utilization as reported in the literature and from our hospital's cost accounting system. Our measure of outcome was the cost-effectiveness ratio. RESULTS: For our base-case analysis (70-year-old men with 5-cm AAAs), EVR was cost-effective with a cost-effectiveness ratio of $22,826-society usually is willing to pay for interventions with cost-effectiveness ratios of less than $60,000 (eg, cost-effectiveness ratios for coronary artery bypass grafting and dialysis are $9500 and $54,400, respectively). This conclusion did not vary significantly with increases in procedural costs for EVR (ie, if the cost of the endograft increased from $8000 to $12,000, EVR remained cost-effective with a cost-effectiveness ratio of $32,881). The cost-effectiveness of EVR was critically dependent on EVR producing a large reduction in the combined mortality and long-term morbidity rate (stroke, dialysis-dependent renal failure, major amputation, myocardial infarction) as compared with OSR (ie, a reduction in the combined mortality and long-term morbidity rate of OSR from 9.1% to 4.7% made EVR no longer cost-effective). CONCLUSION: Despite the high cost of new technology and the need for close postoperative surveillance, EVR is a cost-effective alternative for the repair of AAAs. However, the cost-effectiveness of this new technology is critically dependent on its potential to reduce morbidity and mortality rates as compared with OSR. EVR may not be cost-effective in medical centers where OSR can be performed with low risk.

Aged↗
PubMed1998

Smooth muscle cell migration and proliferation are mediated by distinct phases of activation of the intracellular messenger mitogen-activated protein kinase.

PURPOSE: Mitogen-activated protein kinase (MAPK) is a ubiquitous signaling protein that has been associated with cellular proliferation; however, its role in cellular migration has not been established. In this study, we investigate the role of MAPK in platelet-derived growth factor (PDGF)-induced migration and proliferation of human vascular smooth muscle cells (SMCs). METHODS: SMC migration was measured using a microchemotaxis assay (4 hours), and proliferation was assessed using 3H-thymidine uptake and cell counts. PD098059 was used as a specific noncompetitive inhibitor of MAPK activation. RESULTS: Coincubation of SMCs with PD098059 resulted in significant inhibition of PDGF-BB (5 ng/ml)-induced SMC chemotaxis and proliferation. The IC50 for both processes was approximately 10 mumol/L with complete inhibition at 50 mumol/L. Stimulation of SMCs with PDGF produced an early peak in MAPK activity followed by a plateau of activity that persisted for 24 hours. We hypothesized that variations in the temporal activation of MAPK might explain the action of this enzyme on these two disparate cellular events. By adding PD098059 at intervals after stimulation of SMCs with PDGF, we demonstrated an association between MAPK activity within the first 15 minutes and SMC migration, whereas MAPK activity between 1 and 4 hours was associated with SMC proliferation. CONCLUSIONS: MAPK activity is essential for both SMC migration and proliferation, and distinct phases of enzyme activation are required to stimulate these two discrete cellular events. Inhibition of this signaling protein may prove to be a useful method for preventing intimal hyperplasia.

Becaplermin↗
PubMed1998

The impact of Clostridium difficile on a surgical service: a prospective study of 374 patients.

OBJECTIVE: To evaluate the epidemiology of Clostridium difficile colitis (CDC) in a subset of patients admitted specifically to a surgical service. SUMMARY BACKGROUND DATA: CDC is an increasingly prevalent nosocomial infection that can prolong hospitalization and adversely affect patient outcome. Although this disease has been investigated extensively in patients admitted to medical services, the incidence and risk factors for the development of this disease in patients admitted to a surgical service have not been studied. METHODS: Over a 5-month period, 374 patients admitted to the general, vascular, thoracic, and urologic surgery services were monitored for the development of symptomatic CDC (defined as >3 bowel movements per 24 hours and a positive cytotoxin assay or culture). RESULTS: Twenty-one patients developed CDC (incidence, 5.6%). Factors that independently predisposed to infection included admission from a skilled care facility, use of the antibiotic cefoxitin, and an operative procedure for bowel obstruction. Other factors associated with CDC included colectomy, treatment with any antibiotic, nasogastric tube suction, advanced age, and prior antibiotic treatment. Abdominal pain and fever were also more common in patients with CDC. Morbidity included prolonged hospitalization in all patients and urgent colectomy in one. CONCLUSIONS: CDC frequently affects surgical patients, producing morbidity ranging from mild diarrhea to life-threatening illness. A variety of factors, many of which are associated with intestinal stasis, predispose to the development of CDC.

Adolescent↗
PubMed1998

Is routine duplex ultrasound surveillance after carotid endarterectomy cost-effective?

BACKGROUND: Although duplex ultrasound surveillance of patients after carotid endarterectomy (CEA) is routinely performed, the use of this policy has been questioned. We evaluated the cost-effectiveness of this strategy. METHODS: Using a decision-analytic Markov model that depicts the natural history of patients after CEA, we compared a strategy of duplex ultrasound surveillance to a strategy of no surveillance. Probability estimates were derived from the literature and costs were obtained from the hospital's cost accounting system. Sensitivity analyses were performed to test the robustness and stability of our base-case conclusion to variations in the underlying assumptions. RESULTS: Using baseline estimates we determined that duplex ultrasound surveillance after CEA reduced the incidence of stroke; however, this required significant additional expense, which resulted in an incremental cost-effectiveness ratio of $126,950. This ratio could decrease to a more acceptable level (less than $100,000) if a subset of patients could be identified whose rate of progression to greater than 80% stenosis exceeded 6% per year or whose stroke rate associated with uncorrected asymptomatic stenosis exceeded 2.6% per year. Also, the cost-effectiveness ratio was reduced to less than $100,000 if patients were younger than 55 years old at the time of initial CEA or if the cost of CEA could be reduced to less than $7,000. CONCLUSIONS: Duplex ultrasound surveillance after CEA is associated with an unfavorable cost-effectiveness ratio. However, this strategy may be cost-effective in younger patients or in those patients who have a more progressive form of disease.

Aged↗
PubMed1998

Risk factors and their role in the diseases of the arterial wall.

The leading cause of death and disability in developed nations is atherosclerosis. Multiple risk factors, including hyperlipidemia, cigarette smoking, diabetes mellitus, and hypertension, predispose to the development of atherosclerosis. The mechanisms by which these risk factors exacerbate atherosclerosis involve the potentiation of endothelial and smooth muscle cell dysfunction as well as disturbances in coagulation. These mechanisms are discussed in detail in this chapter. Understanding the pathophysiology of how risk factors accelerate the progression of atherosclerosis will aid the clinician in attempts to treat the atherosclerotic patient.

Arteriosclerosis↗
PubMed1997

Enhancement of migration by protein kinase Calpha and inhibition of proliferation and cell cycle progression by protein kinase Cdelta in capillary endothelial cells.

Activation of protein kinase C (PKC) induces angiogenesis, migration, and proliferation of endothelial cells (EC), but can also prevent growth factor-induced EC proliferation. To determine whether these disparate effects are mediated by substrates of individual PKC isoenzymes, PKCalpha and PKCdelta were overexpressed in rat microvascular EC. Basal and stimulated migration were enhanced in PKCalpha EC compared with either PKCdelta or control EC. Serum-induced growth of PKCdelta EC was decreased, while that of PKCalpha cells was similar to control EC. Phorbol ester markedly inhibited PKCdelta EC growth but enhanced growth of PKCalpha and control EC. To determine possible causes for this altered proliferation, the effect of PKCdelta on adhesion, mitogen-activated protein kinase activity, and cell cycle progression was measured. Adherence of PKCdelta EC to vitronectin was significantly enhanced. Serum-induced extracellular signal-regulated kinase-2 activity was increased equally in both PKCalpha and PKCdelta EC above that of control, while extracellular signal-regulated kinase-1 activity was similar in all EC. Cell cycle analysis suggested that PKCdelta EC entered S phase inappropriately and were delayed in passage through S phase. Thus, PKCalpha may mediate some proangiogenic effects of PKC activation; conversely, PKCdelta may direct antiangiogenic aspects of overall PKC activation, including slowing of the cell cycle progression.

Animals↗
PubMed1997

Activation of pp60c-src is necessary for human vascular smooth muscle cell migration.

BACKGROUND: The most widely distributed nonreceptor tyrosine kinase is pp60c-src (src), yet the role of this intracellular signaling protein in cell migration has not been defined. Given that smooth muscle cell (SMC) migration is essential for the development of intimal hyperplasia, we investigated the importance of src in locomotion of human vascular SMC. METHODS: SMC migration was evaluated using a microchemotaxis chamber assay and videomicroscopy. Src kinase activity was determined by measuring phosphorylation of a synthetic derivative of p34cdc2, a specific substrate for src. Blocking antibodies to src were introduced using a cytoplasmic microinjection technique. RESULTS: Stimulation of SMC with platelet-derived growth factor (PDGF)-BB and AB resulted in an increase in src activation, whereas PDGF-AA did not consistently enhance src activity. These findings correlated with the ability of the PDGF isotypes to stimulate SMC chemotaxis; PDGF-BB and AB produced 7.4 +/- 0.3- and 5.3 +/- 0.5-fold increases in SMC chemotaxis, whereas PDGF-AA inhibited chemotaxis. SMC migration in response to PDGF-BB and serum was significantly inhibited by intracellular injection of a blocking antibody. CONCLUSIONS: Our findings reveal an association between agonist-induced src activation and chemotaxis. Moreover, an antibody that inhibits src activation dramatically inhibits migration of individual SMC. We conclude that activation of src is necessary for SMC migration. Because of its importance in SMC migration, either molecular or pharmacologic inhibitors of src may be useful in the control of intimal hyperplasia.

Becaplermin↗