Biomedical subjects

J D Hughes

Publications and source records attributed to J D Hughes.

At least 19 recordsLinked to original sources

PubMed1999

Noradrenergic modulation of cognitive flexibility in problem solving.

Stress causes impaired performance on tests of creativity. Drugs that block beta-adrenergic receptors improve test performance in patients with test anxiety. Furthermore, catecholamine precursors (L-DOPA) reduce the flexibility of semantic networks. Our study investigated the effect of noradrenergic system modulation on cognitive flexibility in problem solving. Eighteen normal subjects undertook three problem solving tasks (number series, shape manipulation and anagrams) 45 min after propranolol, placebo and ephedrine. On the task that appeared to rely most heavily on cognitive flexibility (anagrams), subjects who were most able to solve these problems demonstrated significantly shorter solution times (logarithmic scores) after propranolol than after ephedrine. This suggested that the noradrenergic system exerts a modulatory effect on cognitive flexibility in problem solving.

Adolescent↗

PubMed1999

Supersonic molecular beam-hyperthermal surface ionisation coupled with time-of-flight mass spectrometry applied to trace level detection of polynuclear aromatic hydrocarbons in drinking water for reduced sample preparation and analysis time.

Analysis of sub-ppb levels of polynuclear aromatic hydrocarbons (PAHs) in drinking water by high performance liquid chromatography (HPLC) fluorescence detection typically requires large water samples and lengthy extraction procedures. The detection itself, although selective, does not give compound identity confirmation. Benchtop gas chromatography/mass spectrometry (GC/MS) systems operating in the more sensitive selected ion monitoring (SIM) acquisition mode discard spectral information and, when operating in scanning mode, are less sensitive and scan too slowly. The selectivity of hyperthermal surface ionisation (HSI), the high column flow rate capacity of the supersonic molecular beam (SMB) GC/MS interface, and the high acquisition rate of time-of-flight (TOF) mass analysis, are combined here to facilitate a rapid, specific and sensitive technique for the analysis of trace levels of PAHs in water. This work reports the advantages gained by using the GC/HSI-TOF system over the HPLC fluorescence method, and discusses in some detail the nature of the instrumentation used.

Chromatography, High Pressure Liquid↗

PubMed1999

The correlation of early flow disturbances with the development of infrainguinal graft stenosis: a 10-year study of 341 autogenous vein grafts.

PURPOSE: Although duplex surveillance of infrainguinal bypass grafts is widely accepted, the optimal frequency and intensity of graft surveillance remains controversial. Earlier reports have suggested that grafts can be stratified into high-risk and low-risk groups based on the presence or absence of early graft flow disturbances. The purpose of this study was to provide long-term data in determining whether early graft flow disturbances detected by means of duplex scanning can predict the development of intrinsic vein graft stenosis. METHODS: We reviewed a series of patients undergoing prospective duplex graft surveillance after autogenous infrainguinal bypass grafting procedures from 1987 to 1997. Patients included in the study underwent at least one duplex scan within 3 months of graft implantation and were observed for a minimum of 6 months. Grafts were categorized as abnormal when a focal flow disturbance with a peak systolic velocity greater than 150 cm/s was identified within 3 months of graft implantation. RESULTS: Of 341 vein grafts in 296 patients who met inclusion criteria, 89 grafts (26%) required revision for intrinsic stenosis; the mean follow-up period was 35 months (range, 6 months to 10 years). Early flow disturbances were detected in 84 (25%) grafts. Grafts with early flow disturbances were more likely to ultimately require revision (43% vs 21%; P =. 0001) and required initial revision earlier (8 months vs 16 months; P =.019). Eighty-two percent of initial graft revisions occurred in the first 2 postoperative years; 69% occurred in the first year. However, an annual 2% to 4% incidence of late-appearing graft stenosis persisted during long-term follow-up. An additional 24 patients (7% of grafts) required an inflow or outflow reconstruction. CONCLUSION: Grafts with early postoperative flow disturbances detected by means of duplex scanning have nearly three times the incidence of graft-threatening stenosis and an earlier requirement for revision, when compared with normal grafts. This suggests that the biology and etiology of these lesions may differ. These data support not only aggressive efforts to detect early graft lesions to stratify grafts at highest risk, but also continued lifelong graft surveillance to detect late-appearing lesions, inflow and outflow disease progression, and maximize graft patency.

Aged↗

PubMed1999

Systematic determination of genetic network architecture.

Technologies to measure whole-genome mRNA abundances and methods to organize and display such data are emerging as valuable tools for systems-level exploration of transcriptional regulatory networks. For instance, it has been shown that mRNA data from 118 genes, measured at several time points in the developing hindbrain of mice, can be hierarchically clustered into various patterns (or 'waves') whose members tend to participate in common processes. We have previously shown that hierarchical clustering can group together genes whose cis-regulatory elements are bound by the same proteins in vivo. Hierarchical clustering has also been used to organize genes into hierarchical dendograms on the basis of their expression across multiple growth conditions. The application of Fourier analysis to synchronized yeast mRNA expression data has identified cell-cycle periodic genes, many of which have expected cis-regulatory elements. Here we apply a systematic set of statistical algorithms, based on whole-genome mRNA data, partitional clustering and motif discovery, to identify transcriptional regulatory sub-networks in yeast-without any a priori knowledge of their structure or any assumptions about their dynamics. This approach uncovered new regulons (sets of co-regulated genes) and their putative cis-regulatory elements. We used statistical characterization of known regulons and motifs to derive criteria by which we infer the biological significance of newly discovered regulons and motifs. Our approach holds promise for the rapid elucidation of genetic network architecture in sequenced organisms in which little biology is known.

Animals↗

PubMed1999

Electrocardiographic and genetic evaluation of giant jungle fowl, broilers, and their reciprocal crosses following unilateral bronchus occlusion.

Electrocardiography is useful as a noninvasive technique for detecting right ventricular hypertrophy in birds developing pulmonary hypertension (PH) and pulmonary hypertension syndrome (PHS, ascites). The objective of this study was to identify every aspect of the Lead II ECG wave form (amplitude or duration) that can be correlated with right ventricular hypertrophy [increased right:total ventricular weight ratios (RV:TV)] indicative of PH across a broad genetic background. Sham operations were conducted, or PH was induced by occluding one extrapulmonary primary bronchus in 14-d-old chicks produced from matings of broilers (B x B), Giant Jungle Fowl (J x J), and their reciprocal crosses (B x J and J x B). Standard three-lead electrocardiograms (ECG) were recorded on Days 28 and 42, and final necropsies were conducted to evaluate the incidence of ascites, confirm sex, and obtain ventricular weights for calculating RV:TV. Ascites did not develop in the J x J, and one each of the B x J and J x B chicks developed ascites; consequently, only data from birds that did not develop ascites were compared. Heart rate was recorded, and the following amplitudes and durations were measured or calculated for three consecutive wave cycles of the Lead II ECG: base of R to the peak of R (RbR), peak of R to base of S (RS), base of S to peak of R' (SR'), S, peak of R' to base of R' (R'R'b), and base of S to peak of T (ST). Differences between the ECG of sham and bronchus clamp groups were more prominent in B x B and B x J than in J x B, and bronchus occlusion did not affect the ECG, growth, or RV:TV ratios of J x J. In contrast, sex influences were more prominent in J x J and J x B than in B x J and B x B. These observations suggest a paternal pattern of inheritance for Lead II ECG wave forms, with crosses sired by broilers (B x B, B x J) exhibiting susceptibility to PH and few ECG differences related to sex, whereas crosses sired by Giant Jungle Fowl U x J, J x B) exhibited resistance to PH and numerous ECG differences related to sex.

Animals↗

PubMed1999

Electrocardiographic evaluation of broilers following unilateral occlusion of an extrapulmonary primary bronchus.

This study was conducted to provide a comprehensive evaluation of both the amplitudes and durations of the Lead II electrocardiogram (ECG) in nonascitic and ascitic broilers. At 14 d of age, male and female broiler chicks were sham-operated (SHAM, n = 27), or pulmonary hypertension was initiated by occluding one extrapulmonary primary bronchus (BRONCHUS CLAMP, n = 57). Lead II ECG and BW were recorded on Days 28 (ECG1) and 42 (ECG2), necropsies were conducted on all birds dying after Day 28, and final necropsies were conducted on Day 49. Data collected at necropsy included the presence (ASCITIC) or absence (NONASCITIC) of ascites, sex, and ventricular weights for calculating the right:total ventricular weight ratio (RV:TV), which serves as a reliable index of pulmonary hypertension. In each bird, three consecutive ECG1 and ECG2 wave cycles were quantified for both amplitude and duration of the following wave segments: Rb-R, R-S, S-R', R'-R'b, and S-T. The S wave amplitude was calculated by subtracting R-S from Rb-R and heart rate (HR) was measured from the peak of one T wave to the peak of the next. In the majority of comparisons, ASCITIC and BRONCHUS CLAMP broilers had larger S, R'-R'b, and S-T amplitudes, longer R-S, R'-R'b, and S-T durations, and a slower HR than NONASCITIC and SHAM broilers, regardless of sex. The differences in ECG wave forms and durations between ASCITIC and NONASCITIC broilers were greater on Day 42 (ECG2) than on Day 28 (ECG1), but when both ECG were used to develop a regression equation to estimate RV:TV, the R2 was 0.79. The most important Lead II ECG parameters associated with the development of ascites were an increasingly negative S wave amplitude and greater amplitudes and durations for R'-R'b and S-T as well as a decrease in the HR.

Airway Obstruction↗

PubMed1999

Developmental stuttering and Parkinson's disease: the effects of levodopa treatment.

The effects of dopamine on developmental stuttering was studied in a 44 year old man with developmental stuttering and Parkinson's disease during three levodopa "on" periods and three "off" periods. When compared with the "off" periods, during the "on"' periods he demonstrated an increase of speech dysfluencies. These findings lend support to the dopamine hypothesis of developmental stuttering.

Adult↗

PubMed1998

A regional pedal ischemia scoring system for decision analysis in patients with heel ulceration.

PURPOSE: The objective of this study was to evaluate patients undergoing operative debridement for heel ulceration and to categorize pedal perfusion and its influence on therapeutic alternatives. METHODS: Patients with heel ulceration were stratified by arteriography and graded I (patent posterior tibial, PT), II (occluded PT/reconstituted from peroneal), III (PT reconstituted from dorsal pedal), IV (no PT reconstitution but visible heel tributaries), and V (avascular heel). RESULTS: From May 1992 through January 1997, 23 patients underwent operative treatment for 25 heel ulcers. The heel ischemia score stratified patients into two groups: 1, revascularization/debridement (71% grades I to III, 29% grade IV, 0% grade V); and 2, free tissue transfer with or without revascularization (100% grades IV, V). Cumulative functional limb salvage was 91% (BP), 60% (BP + TT), and 81% (TT) at 24 months (P = 0.15 log rank). CONCLUSION: The heel ischemia score may direct treatment of heel ulceration by identifying patients who will need vascularized tissue transfer early in their treatment regimen.

Angiography↗

PubMed1998

Vein patching reduces neointimal thickening associated with prosthetic graft implantation.

PURPOSE: Modified anastomotic techniques utilizing autogenous vein-cuffs or patches have been devised with the hope of improving prosthetic graft patency. The mechanisms of the presumed improvement in patched anastomoses have never been elucidated and remain speculative. We characterized the healing response of the Taylor vein patch in prosthetic arteriovenous fistulae in a canine model of intimal hyperplasia. METHODS: Six adult dogs underwent placement of bilateral (6 patched, 6 control) 4-mm diameter expanded polytetrafluoroethylene loop femoral artery-vein fistulae. Serial duplex ultrasound examinations confirmed graft patency until explant at 6 weeks. Differential light microscopy with computerized image analysis was performed on serial 5-microm sections. Intimal thickness through the venous anastomosis and outflow veins of Taylor patch and control (nonpatched) grafts were compared. Cell type-specific immunocytochemical antibody stains for smooth muscle cells (alpha SMC actin) and endothelial cells (von Willebrand factor) were performed. RESULTS: Eleven of 12 grafts remained patent for 6 weeks, 1 control graft thrombosed. Mean duplex-derived peak systolic velocities of patched (96 cm/sec) and control (108 cm/sec) grafts were similar. Microscopy revealed more intimal pannus anastomotic suture line ingrowth in controls (mean thickness = 178 microm) than Taylor patched grafts (mean 147 microm, p = 0.0002). Significantly less intimal thickening was present in the outflow vein of patched (mean thickness = 90 microm) versus control grafts (mean 195 microm, P <0.0001). The intima maintained a single cell layer of vWF + endothelial cells, while the majority of the cells comprising the lesion expressed alpha SMC actin. CONCLUSION: Perianastomotic pannus is primarily composed of intimal smooth muscle cells. Neointimal thickening is significantly reduced in prosthetic arteriovenous fistulae created with the Taylor vein patch in a canine model. Reduction in perianastomotic intimal thickening may explain the reported clinical improvement in prosthetic bypass graft patency when modified with vein patch techniques.

Anastomosis, Surgical↗

PubMed1998

Treatment of patients with venous thromboembolism and malignant disease: should vena cava filter placement be routine?

PURPOSE: It has been proposed that inferior vena cava filter placement should be the initial treatment of deep venous thrombosis (DVT) or pulmonary embolus (PE) in patients with coexisting malignant disease. We have chosen instead to selectively place filters only in patients with either a contraindication to anticoagulation therapy or a subsequent complication from anticoagulation therapy. The treatment efficacy and mortality rates in patients with concomitant malignant disease and venous thromboembolism using this approach was determined. METHODS: We retrospectively reviewed all patients at our institution with malignant disease in whom venous thromboembolism developed between August 1991 through August 1996 and identified 166 patients with PE (n = 8), DVT (n = 147), and DVT/PE (n = 11). Of these patients, 138 (83.1%) were initially treated with anticoagulation therapy, and 28 (16.9%) had primary filter placement because of contraindications to anticoagulation therapy (10 for intracranial tumors, 11 for recent or upcoming operations, 6 for recent hemorrhage, and 1 for a malignant bloody pericardial effusion). RESULTS: Thirty-two (23%) of the 138 patients who initially underwent anticoagulation therapy subsequently required a filter for the following reasons: bleeding (n = 15, 10.9%); recurrent thromboembolism (n = 6, 4.3%); heparin-induced thrombocytopenia (n = 1, 0.7%); and perceived high risk for bleeding with continued anticoagulation therapy (n = 11, 8%). Both bleeding and recurrent thromboembolism developed in 1 patient. Sixty patients (36%) received filters. No major technical complications occurred from filter placement. Major recurrent thromboembolic complications developed in 10 patients: DVT (n = 6, 10%), PE (n = 2, 3.3%), inferior vena cava thrombosis and phlegmasia cerulea dolens (n = 1, 1.7%), superior vena cava thrombosis (n = 1, 1.7%). Venous gangrene developed in 1 patient with DVT. The 1-year actuarial survival rates for patients treated with filter and anticoagulation therapy were 35% and 38%, respectively (P = NS). CONCLUSION: In summary, our experience suggests that 64% of patients with malignant disease and venous thromboembolism are effectively treated with anticoagulation alone; 17% require primary filter placement for standard indications, and an additional 19% require subsequent filter placement because of complications (primarily bleeding) or failure of anticoagulation therapy. Although technical complications of filter placement are low, serious life-threatening or limb-threatening thromboembolic complications developed in 17% of patients. Survival was poor in all patients, regardless of treatment. These data support a conservative approach of routine anticoagulation therapy with selective filter placement.

Adolescent↗

PubMed1998

Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation.

Whole-genome mRNA quantitation can be used to identify the genes that are most responsive to environmental or genotypic change. By searching for mutually similar DNA elements among the upstream non-coding DNA sequences of these genes, we can identify candidate regulatory motifs and corresponding candidate sets of coregulated genes. We have tested this strategy by applying it to three extensively studied regulatory systems in the yeast Saccharomyces cerevisiae: galactose response, heat shock, and mating type. Galactose-response data yielded the known binding site of Gal4, and six of nine genes known to be induced by galactose. Heat shock data yielded the cell-cycle activation motif, which is known to mediate cell-cycle dependent activation, and a set of genes coding for all four nucleosomal proteins. Mating type alpha and a data yielded all of the four relevant DNA motifs and most of the known a- and alpha-specific genes.

Cloning, Molecular↗

PubMed1998

Flow-dependent pulmonary vasodilation during acute unilateral pulmonary artery occlusion in Jungle Fowl.

Giant Jungle Fowl previously were shown to be highly resistant to the onset of pulmonary hypertension syndrome (PHS, ascites) under conditions that induce a substantial incidence of PHS in broiler chickens. In the present study, lightly anesthetized, clinically healthy 12- to 13-wk-old male Giant Jungle Fowl maintained a lower respiratory rate, a similar hematocrit, and superior arterial blood gas values when compared with 6-wk-old male broilers. Giant Jungle Fowl weighed less than broilers (1,860 +/- 19 vs 2,788 +/- 63 g, respectively) and had equivalent absolute values for pulmonary arterial pressure, cardiac output, and pulmonary vascular resistance. Acute unilateral pulmonary artery occlusion in Giant Jungle Fowl doubled the pulmonary vascular resistance and forced the right ventricle to propel a sustained 60% increase in blood flow through the vasculature of the unoccluded lung. A transient increase in pulmonary arterial pressure initially was required to overcome the vascular resistance of the unoccluded lung; however, flow-dependent vasodilation gradually reduced the pulmonary vascular resistance and permitted pulmonary arterial pressure to return toward control levels. Unilateral pulmonary artery occlusion also triggered an immediate reduction in the partial pressure of oxygen in arterial blood, and the gradual return of pulmonary arterial pressure toward control levels did not eliminate this ventilation-perfusion mismatch, which has been attributed to blood flowing too rapidly through the unoccluded lung to permit diffusive gas equilibration. The inherent capacity for flow-dependent pulmonary vasodilation may reduce the susceptibility of Giant Jungle Fowl to PHS by reducing the increment in pulmonary arterial pressure required to propel an elevated blood flow through the lungs.

Animals↗

PubMed1997

Boundary layer infusion of nitric oxide reduces early smooth muscle cell proliferation in the endarterectomized canine artery.

To evaluate the direct effect of nitric oxide (NO) on vascular smooth muscle cell (SMC) proliferation in vivo, we used an expanded polytetrafluoroethylene (ePTFE)-based local infusion device to deliver an NO donor, proline/NO (PROLI/NO), to the luminal boundary layer of endarterectomized artery and the distal anastomosis of the graft in a canine model. Once delivered to the blood, PROLI/NO releases NO by a mechanism involving pH-dependent decomposition. Six dogs underwent bilateral femoral artery endarterectomies. ePTFE infusion devices, blindly primed with PROLI/NO to one artery or proline to the contralateral vessel, were anastomosed proximal to the injured segments so that each animal served as its own control. PROLI/NO or proline was continuously delivered for 7 days from an osmotic reservoir, through the wall of the graft infusion device. Euthanasia was carried out at 7 days, and the processed specimens were blindly analyzed for SMC proliferation at both graft anastomoses and endarterectomized segments by a bromodeoxyuridine index assay. All dogs survived with no clinical side effects. In comparing the treated and control vessels, NO released from PROLI/NO significantly reduced SMC proliferation by 43% (13.24 +/- 1.24% versus 23.24 +/- 1.01%, P = 0.004) at the distal anastomoses and by 68% (10.58 +/- 1.63% versus 25.17 +/- 3.39%, P = 0.007) at endarterectomized segments. However, there was no significant difference in blood flow measurements between treated and control arteries (56.25 +/- 6.50 ml/min versus 46.50 +/- 3.20 ml/min, P = 0.094). These data demonstrate that local boundary layer infusion of NO released from PROLI/NO significantly reduces SMC proliferation in injured arteries with no effect on regional blood flow. This study suggests a new strategy to inhibit early SMC proliferation in injured arteries and probably to control intimal hyperplastic lesion formation in the manipulated vessels.

Anastomosis, Surgical↗

PubMed1997

Time-course study of intimal hyperplasia in the endarterectomized canine artery.

In an effort to characterize intimal hyperplastic lesions, we have undertaken a time-course study in a canine endarterectomy model of intimal hyperplasia. Twenty dogs underwent surgical endarterectomies of the carotid arteries. A total of 23 of 27 (85%) injured arteries were patent, which consisted of 6, 8, 5, and 4 arteries found to be patent at 1, 2, 5, and 11 weeks, respectively. Measurable intimal thickening developed at 1 week (0.08 +/- 0.01 mm) and at 2 weeks (0.13 +/- 0.02 mm), maximized at 5 weeks (0.29 +/- 0.03 mm), and subsided at 11 weeks (0.21 +/- 0.01 mm) after injury. Endothelial cells covering intimal hyperplastic tissues were seen only at 11 weeks. The intimal cell proliferation rate reached a maximum of 24% at 1 week, decreased dramatically at 2 weeks, and remained at low levels but higher than baseline levels at 5 and 11 weeks. Extracellular matrix (ECM) content accounted for 29% of total intimal volume at 1 week after endarterectomy and increased to 37, 40, and 47% at 2, 5, and 11 weeks, respectively. These data demonstrate that maximum intimal cell proliferation occurs at 1 week and maximum intimal hyperplasia at 5 weeks after arterial injury. Intimal ECM content increased with time after injury throughout the duration of this study. The uniform and consistent intimal lesion that was established in this large animal model is clinically relevant and can be used to study cellular and molecular mechanisms of restenosis and to evaluate therapeutic interventions.

Animals↗

PubMed1997

Endoscopic venous valve transplantation with a valve-stent device.

In this report we describe the outcome of a 6-week study of the valve-stent device in a goat model. Six female goats underwent endoscopic subcutaneous harvest of a valve-containing segment of external jugular vein. This segment was sutured inside a 10-mm Wallstent (Schneider Inc., USA), and the device was compressed and loaded into a 12 Fr. introducer sheath and deployed through a venotomy into the contralateral external jugular vein. The animals were anticoagulated for 1 week and euthanized at 6 weeks. Flow studies, manual strip test, and angioscopic evaluation were performed prior to sacrifice. All six valve-stents were patent at harvest by Doppler flow studies, and five of six were competent as demonstrated by the manual strip test. At angioscopic evaluation, the valves were open. Gross and histologic examination revealed intact valve leaflets in five specimens. This technique is a minimally invasive approach to valve harvest and transplantation with a valve-stent device. We have demonstrated that valve-stent can remain patent and competent for up to 6 weeks. This technique may have potential application in venous valvular incompetence.

Animals↗

PubMed1997

Identification of predictors for lower extremity vein graft stenosis.

BACKGROUND: The cause of intrinsic vein graft stenosis, which develops in at least 20% of infrainguinal autogenous bypass grafts during the intermediate follow-up interval, is unknown. We performed standard duplex surveillance of all lower extremity bypass grafts and evaluated the potential of comorbid patient risk factors that might predict development of vein graft flow disturbance or high-grade graft stenosis. METHODS: Patients with at least 6 months of postoperative duplex surveillance were identified through our vascular registry. The association of clinical and hemodynamic profiles of graft performance were compared with specific patient risk factors, including demographics, cigarette smoking, antihypertensive medical therapy, type and quality of conduit, degree of ischemia, bypass run-off, and presence of infection, using stepwise logistic regression analysis. RESULTS: Ninety-three patients (55 male, 38 female; mean age 69) underwent 100 infrainguinal bypasses. Twenty-six high-grade graft stenoses (>70%) were identified in 26 patients during follow-up (mean 21 months) by graft-flow peak systolic velocity (PSV) >300 cm/sec on more than one duplex examination, and were electively revised. Graft flow disturbances (180 cm/sec >PSV <300 cm/sec) were identified in an additional 13 grafts (6 regressed, 7 observed). The need for graft revision was associated with an early graft flow disturbance (P = 0.02), or drop in ankle-brachial index >0.15 (P = 0.03), and the use of an alternative conduit in 13 of 100 grafts (P = 0.04). Only smoking was associated with the development of a duplex detected graft flow disturbance during follow up (P = 0.03). CONCLUSION: Grafts with early flow disturbances warrant close duplex surveillance to identify graft-threatening stenosis. Risk factors that may predict future lower extremity bypass graft stenosis are smoking and the use of alternative bypass conduits.

Aged↗

PubMed1997

Anti-VLA-4 antibody reduces intimal hyperplasia in the endarterectomized carotid artery in nonhuman primates.

PURPOSE: Recently, very late antigen-4 (VLA-4) has been shown to mediate initial monocyte adhesion and migration to the injured artery. We hypothesized that blocking monocyte adhesion using a specific monoclonal antibody against VLA-4 may reduce intimal hyperplasia. METHODS: Bilateral carotid endarterectomies were performed in eight adult baboons. Among them, five animals received an intravenous bolus injection of anti-VLA-4 antibody (3 mg/kg) during surgery and again after 2 weeks. Three animals underwent bilateral carotid endarterectomies and served as untreated control subjects. Specimens were harvested at 4 weeks and subjected to morphometric analysis, cell proliferation assay, and immunostaining for macrophages. RESULTS: All of the endarterectomized arteries were patent except for one in the treated group. The number of macrophages in the intimal tissues was significantly reduced in the treated arteries compared with that in the control vessels (15.78 +/- 3.05 cells/section versus 33.50 +/- 6.13 cells/section; p < 0.001). The cell proliferation rate was significantly lower (p < 0.001) in the treated vessels (2.88% +/- 1.07%) compared with the control vessels (4.89% +/- 0.77%). The intimal area at the endarterectomized sites of carotid arteries was significantly less (p < 0.05) in the group treated with the anti-VLA-4 antibody (1.10 +/- 0.68 mm2) than in the control group (2.00 +/- 0.52 mm2). CONCLUSION: These data show that blocking monocyte adhesion by use of an anti-VLA-4 antibody significantly reduces the number of intimal macrophages, intimal cell proliferation, and intimal hyperplasia in injured carotid arteries in baboons. This study supports a central role for macrophages in the development of intimal hyperplasia and may suggest a new therapeutic strategy to prevent clinical restenosis.

Animals↗

PubMed1997

Reduced blood flow accelerates intimal hyperplasia in endarterectomized canine arteries.

The purpose of this study was to evaluate a technique that accelerates intimal hyperplasia by reduction of blood flow. Bilateral endarterectomies were performed in both femoral and carotid arteries in six dogs. One week later, all animals underwent banding of an artery distal to the injured region to reduce the blood flow by 50%. The contralateral injured arteries served as controls. At 11 weeks, the specimens were harvested and analyzed. Five of 12 (42%) of the flow-restricted arteries and nine of 12 (75%) of the non-flow-restricted arteries were patent at 11 weeks (P<0.05). Marked stenotic intimal hyperplastic lesions developed in the flow-restricted arteries (69% stenosis) as compared with the non-flow-restricted arteries (37% stenosis). Mean(s.d.) intimal thickness, intimal areas, and intimal/medial area ratio were 0.52(0.19) mm, 3.17(1.11) mm2, and 1.12(0.33)%, respectively, in the flow-restricted arteries. Their counterparts in the non-flow-restricted arteries were 0.21(0.09) mm, 1.70(1.09) mm2, and 0.58(0.14)%, respectively (P<0.05). Extracellular matrix comprised 48% of total intimal volumes in the flow-restricted arteries. Cell proliferation and occluded arteries were also characterized. These data demonstrate that reduction of blood flow significantly accelerated intimal hyperplasia and occlusion rates in endarterectomized arteries. Advanced intimal hyperplastic lesions (>50% stenosis) possess a high extracellular matrix content. This new animal model is a reliable generator of advanced stenotic lesions in a relatively short time period and can be used to study biologic mechanisms of stenosis and evaluate therapeutic interventions.

Animals↗