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R W Thompson

Publications and source records attributed to R W Thompson.

At least 19 recordsLinked to original sources
PubMed1999

Expression of collagenase-3 (MMP-13) in human abdominal aortic aneurysms and vascular smooth muscle cells in culture.

Collagen degradation is important in the pathogenesis of abdominal aortic aneurysms (AAA) but the enzymes responsible are undefined. Collagenase-3 is a recently described matrix metalloproteinase (MMP-13) with limited tissue distribution and a highly regulated pattern of expression. Using reverse transcription-polymerase chain reaction and Southern blots, amplification products corresponding to MMP-13 were uniformly detected in samples of AAA and atherosclerotic aorta (ATH), but not in normal aortic controls. By densitometric analysis of blots normalized to beta-actin, the expression of MMP-13 was 1.8-fold higher in AAA compared to ATH (P < 0.05). Immunoreactive MMP-13 was localized to medial smooth muscle cells (SMC) in AAA tissue and to human vascular SMC in culture, which also expressed MMP-13 mRNA. These findings indicate for the first time that SMC production of MMP-13 may contribute to the pathophysiologic progression of AAA.

Alternative Splicing↗
PubMed1999

MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial.

Abdominal aortic aneurysms (AAAs) represent a chronic degenerative condition associated with a life-threatening risk of rupture. The evolution of AAAs is thought to involve the progressive degradation of aortic wall elastin and collagen, and increased local production of several matrix metallo-proteinases (MMPs) has been implicated in this process. We have previously shown that tetracycline derivatives and other MMP inhibitors suppress aneurysm development in experimental animal models of AAA. Doxycycline also reduces the expression of MMP-2 and MMP-9 by human vascular wall cell types and by AAA tissue explants in vitro. To determine whether this strategy might have a role in the clinical management of small AAA, we examined the effect of doxycycline on aortic wall MMP expression in vivo. Patients were treated with doxycycline (100 mg p.o. bid) for 7 days prior to elective AAA repair, and aneurysm tissues were obtained at the time of surgery (n = 5). Tissues obtained from an equal number of untreated patients with AAA were used for comparison. By reverse transcription-polymerase chain reaction and Southern blot analysis, MMP-2 and MMP-9 were both found to be abundantly expressed in the aneurysm wall. Preoperative treatment with doxycycline was associated with a 3-fold reduction in aortic wall expression of MMP-2 and a 4-fold reduction in MMP-9 (p < 0.05 compared to untreated AAA). These preliminary results suggest that even short-term treatment with doxycycline can suppress MMP expression within human AAA tissues. Given its pleiotropic effects as an MMP inhibitor, doxycycline may be particularly effective in suppressing aortic wall connective tissue degradation. While it remains to be determined whether MMP inhibition will have a clinically significant impact on aneurysm expansion, it is expected that this question can be resolved by a properly designed prospective randomized clinical trial.

Anti-Bacterial Agents↗
PubMed1999

Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908).

BACKGROUND: Abdominal aortic aneurysms (AAAs) are associated with chronic inflammation, disruption of medial elastin, and increased local production of elastolytic matrix metalloproteinases (MMPs). The purpose of this study was to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect the development of experimental AAAs. METHODS: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (DeltaAD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were examined by light microscopy. RESULTS: AAAs developed in all vehicle-treated rats, with a mean AD (+/- SE) that increased from 1.60 +/- 0.03 mm before perfusion to 5.98 +/- 1.02 mm on day 14 (DeltaAD = 276.4 +/- 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/- 0.05 mm to 3.59 +/- 0.34 mm (DeltaAD = 128.1 +/- 18.7%; P <.05, vs vehicle). The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 +/- 6.8%. Aortic wall desmosine fell by 85.4% in the vehicle-treated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sample; P <.05) but only by 65.6% in the animals treated with RS 312908 (416.2 +/- 120.5 pmol/sample). In contrast, hydroxyproline was not significantly affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation. CONCLUSIONS: Systemic MMP inhibition suppresses aneurysmal dilatation in the elastase-induced rodent model of AAA. Consistent with its direct inhibitory effect on various MMPs, RS 132908 promotes the preservation of aortic elastin and appears to enhance a profibrotic response within the aortic wall. Hydroxamate-based MMP antagonists may therefore be useful in the development of pharmacologic approaches to the suppression of AAAs.

Animals↗
PubMed1999

Source of elastin-degrading enzymes in mycotic aortic aneurysms: bacteria or host inflammatory response?

Elastolytic matrix metalloproteinases play a central role in the development of chronic atherosclerotic aortic aneurysms, but mycotic aortic aneurysms are a distinct and unusual form of aneurysm disease caused by bacterial infection. Mycotic aortic aneurysms follow a more rapid and unpredictable course than chronic aneurysm disease and they exhibit a predilection for the suprarenal aorta, further implying unique pathophysiologic mechanisms. The purpose of this study was to examine the nature and source of elastin-degrading enzymes in mycotic aortic aneurysm. Bacterial isolates and aortic tissues were obtained from four consecutive patients undergoing surgical repair of suprarenal mycotic aortic aneurysm. Using an in vitro 3H-labeled elastin degradation assay, elastin-degrading enzyme activity was only observed in the bacteria-conditioned medium from an isolate of Pseudomonas aeruginosa. Elastin-degrading enzyme activity in the aortic tissue homogenate of this patient was abolished by the serine protease inhibitor, phenylmethylsulfonyl fluoride, but it was not suppressed by the metalloproteinase inhibitor, ethylenediamine tetraacetic acid (EDTA). In contrast, elastin-degrading enzyme activity in the bacterial-conditioned medium was decreased by about half by both phenylmethylsulfonyl fluoride and EDTA. Elastin substrate zymography revealed two phenylmethylsulfonyl fluoride-inhibitable elastin-degrading enzyme activities in the aortic tissue homogenate that corresponded to human neutrophil elastase (approximately 30 kDa) and its stable complex with alpha 1-proteinase inhibitor (approximately 80 kDa), but no activity attributable to Pseudomonas elastase, a 33-kDa metal-dependent enzyme. Human neutrophil elastase was readily detected throughout mycotic aortic aneurysm tissues by immunohistochemistry, but elastolytic metalloproteinases were only occasionally observed. The results of this study suggest that the elastin-degrading enzyme produced in mycotic aortic aneurysm are largely serine proteases of host neutrophil origin, rather than elastases produced by the infecting microorganisms or the macrophage-derived metalloproteinases typically observed in atherosclerotic aneurysm disease. Further studies will be needed to extend these findings to a larger number of patients with mycotic aortic aneurysm and those caused by additional microorganisms.

Aged↗
PubMed1998

Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.

Elastolytic matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAA), a disorder characterized by chronic aortic wall inflammation and destruction of medial elastin. The purpose of this study was to determine if human macrophage elastase (HME; MMP-12) might participate in this disease. By reverse transcription-polymerase chain reaction, HME mRNA was consistently demonstrated in AAA and atherosclerotic occlusive disease (AOD) tissues (six of six), but in only one of six normal aortas. Immunoreactive proteins corresponding to proHME and two products of extracellular processing were present in seven of seven AAA tissue extracts. Total HME recovered from AAA tissue was sevenfold greater than normal aorta (P < 0.001), and the extracted enzyme exhibited activity in vitro. Production of HME was demonstrated in the media of AAA tissues by in situ hybridization and immunohistochemistry, but HME was not detected within the media of normal or AOD specimens. Importantly, immunoreactive HME was specifically localized to residual elastin fragments within the media of AAA tissue, particularly areas adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two- to fivefold greater than other elastases found in AAA tissue. Therefore, HME is prominently expressed by aneurysm-infiltrating macrophages within the degenerating aortic media of AAA, where it is also bound to residual elastic fiber fragments. Because elastin represents a critical component of aortic wall structure and a matrix substrate for metalloelastases, HME may have a direct and singular role in the pathogenesis of aortic aneurysms.

Aortic Aneurysm, Abdominal↗
PubMed1998

A low-cost, multi-channel, EMG signal processing amplifier.

There is a growing need in studies of movement control to expand the number of muscles from which EMG activity is recorded during performance of motor tasks. Optimal viewing and analysis of this EMG activity requires signal processing which provides adjustable gain and baseline offset as wells as selectable AC coupling, rectification and filtering. This paper presents a low-cost circuit that combines two channels of EMG signal processing capability in one module.

Animals↗
PubMed1998

Surgical treatment of patients with symptomatic vertebrobasilar insufficiency.

We report our experience with surgical management of symptomatic vertebrobasilar insufficiency (VBI). Forty revascularizations were carried out in 39 patients over 90 months. Dizziness (52%) and syncope/presyncope (32%) were the most common symptoms. Arteriography was performed in all patients, with subclavian steal seen in 55% of patients. Procedures performed included 22 cases of carotid-subclavian bypass or transposition (55%), seven direct vertebral reconstructions (17.5%), four great vessel reconstructions (10%), four isolated carotid endarterectomies (10%), and three axilloaxillary bypasses (7.5%). One patient died, and the combined morbidity and mortality rate was 15%. Outpatient follow-up was available on 37 of the 38 patients discharged alive. At a mean follow-up of 16.4 months, 34 patients had no VBI complaints. Three of four patients treated with CEA alone had persistent VBI complaints. We conclude that a variety of anatomic lesions can result in VBI symptoms, with subclavian steal being the most common. Procedures which directly correct the anatomic abnormality result in sustained symptom resolution with acceptable complication rates.

Aged↗
PubMed1998

Pharmacologic suppression of experimental abdominal aortic aneurysms: acomparison of doxycycline and four chemically modified tetracyclines.

BACKGROUND: Matrix metalloproteinases (MMPs) likely contribute to the degradation of medial elastin in abdominal aortic aneurysms (AAAs), and tetracycline antibiotics exhibit MMP-inhibiting properties. The purpose of this study was to compare the effects of doxycycline and several non-antibiotic chemically modified tetracyclines (CMTs) in a rat model of elastase-induced AAA. METHODS: Fifty-two male Wistar rats underwent intraluminal perfusion of the abdominal aorta with porcine pancreatic elastase. The rats then were treated for 7 days with subcutaneous injections of saline solution, different doses of doxycycline, or 1 of 4 different CMTs. The aortic diameters were measured with microcalipers, and the fixed tissues were examined by means of light microscopy. Gelatin zymography was used to assess the MMP activity in the aortic tissue extracts. RESULTS: The mean aortic diameter in the control group increased by 126% +/- 14% on day 7 (from 1.57 +/- 0.04 mm to 3.54 +/- 0.27 mm; P <.05), and 5 of 6 animals (83%) had AAAs. Doxycycline appeared to inhibit aortic dilatation in a dose-dependent manner, and AAAs did not develop in any animals. Half-maximal effects were observed at a dose of approximately 6 mg/kg/day, and maximal effects were noted at greater than 30 mg/kg/day. No AAAs were observed in the animals that were treated with CMTs at 15 mg/kg/day. Each of the following CMTs exhibited an efficacy that was similar to that of doxycycline (percent inhibition of aortic dilatation vs control; all P <.05): CMT-3 (47.6%), CMT-4 (38.9%), CMT-7 (47.6%), CMT-8 (54.0%), and doxycycline (51.6%). Tissues from saline solution-treated controls exhibited a transmural inflammatory response and marked destruction of the medial elastic lamellae. Tetracycline derivatives limited the disruption of medial elastin without appearing to alter either the inflammatory response or the rat aortic wall production of metallogelatinases. CONCLUSION: Tetracycline derivatives suppress the development of AAAs after elastase-induced aortic injury in the rat. The aneurysm-suppressing effects of doxycycline appear to be dose-dependent and distinct from its antibiotic activities, and they coincide with the structural preservation of medial elastin fibers. Further studies are needed to explore the potential of MMP-inhibiting tetracyclines as a novel pharmacologic strategy for the suppression of aortic aneurysms.

Animals↗
PubMed1998

Surgical management of subclavian-vein effort thrombosis as a result of thoracic outlet compression.

BACKGROUND: There is considerable variability and controversy in the current management of subclavian-vein effort thrombosis. The purpose of this study was to determine the long-term effectiveness and the functional outcome of our preferred treatment strategy of early thrombolysis/recanalization and prompt extensive supraclavicular decompression. PATIENTS AND METHODS: Thirty-three patients who ranged in age from 15 to 60 years underwent operative decompression of 34 primary subclavian-vein thromboses, one of which was bilateral. There were 21 patients with acute thrombosis 7 of whom had had prior unsuccessful balloon venoplasty, 1 with stent placement and 8 patients with chronic/recurrent thrombosis 5 of whom had had 9 unsuccessful prior operations for attempted decompression. Four patients had high-grade symptomatic stenosis and positional occlusion. A supraclavicular approach was used in 32 cases and, in 23 cases, was complemented by an infraclavicular (n = 21) or transaxillary (n = 2) incision. Complete subclavian-vein decompression was achieved by first-rib resection (n = 31), scalenectomy (n = 33), and circumferential venolysis (n = 34). RESULTS: Follow-up was obtained in 30 patients at a mean of 31 months. Twenty of the 21 patients with acute thrombosis had a complete resolution of symptoms with a return to full activity; the other patient was lost to follow-up. Four of the 8 patients with chronic thrombosis reported a mild relief of symptoms but still had limitations of activities of daily living. All of the patients with high-grade symptomatic stenosis with positional occlusion had a complete relief of symptoms and a return to full activity. CONCLUSION: The optimal management of acute effort thrombosis of the subclavian vein includes anticoagulation therapy, thrombolysis/recanalization, confirmatory positional venography, and early supraclavicular decompression of the subclavian vein. In the patients with chronic subclavian-vein thrombosis and positional venographic evidence of compression of first-rib bypass graft collaterals, the initial anticoagulation therapy should be followed by the surgical decompression of the collaterals. The supraclavicular approach alone or with an infraclavicular incision provides optimal exposure for scalenectomy, total first-rib resection, and circumferential venolysis.

Adolescent↗
PubMed1998

Recombinant cDNA clones for immunodiagnosis of strongyloidiasis.

Because diagnosis of strongyloidiasis by stool examination is unreliable and because of the potential for serious disease in Strongyloides infections, there is need for improved diagnostic aids to facilitate recognition and treatment of this parasitic infection. Serologic testing, when available, requires antigen preparation from infected primates or dogs that can be difficult to maintain. Several recombinant clones from a cDNA library prepared from the infective stage of Strongyloides stercoralis were characterized. Serologic results indicate that the recombinant proteins were equally or more reactive than the larval somatic antigen. No cross-reactivity with recombinant antigen 5a was found with sera from patients with filarial or intestinal nematode infections. Recombinant antigens 5a and 12a detected parasite-specific IgE and IgG4 antibodies in Strongyloides-infected patients. Sequence analysis showed these antigens to be rich in proline and charged amino acids. Lack of homology from database searches suggests that the antigens are unique. These recombinant antigens should be useful in diagnostic and epidemiologic studies of strongyloidiasis.

Amino Acid Sequence↗
PubMed1998

Therapeutic potential of tetracycline derivatives to suppress the growth of abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAA) represent a potentially lethal disorder associated with aging and atherosclerosis. Although current management of AAA is predicted on early detection and elective surgical repair, routine screening for AAA is infrequent, because most AAA are too small to warrant repair when first detected and because there are no therapeutic approaches proven to suppress aneurysm expansion. Basic research on this problem suggests that chronic inflammation and increased local production of elastin-degrading proteinases play prominent roles in the process of aneurysmal degeneration. Members of the matrix metalloproteinases (MMP) family appear to be the most prominent elastases produced in human AAA, suggesting that unique therapeutic targets might exist for aneurysm disease. Studies using a representative animal model for AAA support this view, providing a means for further development of pharmacological approaches to suppress aneurysm expansion. Indeed, recent work indicates that tetracycline derivatives have the potential to interrupt the progressive connective tissue destruction that occurs in AAA, by virtue of their non-antimicrobial properties as MMP inhibitors, and they do so at clinically achievable dose schedules. These findings support the view that MMPs are potentially important pharmacotherapeutic targets in AAA and, moreover, that tetracyclines might be useful in suppressing aneurysm expansion in vivo. Because tetracycline derivatives offer a number of distinct advantages as MMP inhibitors for patients with small AAA, prospective clinical trials of this novel therapeutic strategy can be anticipated in the near future.

Animals↗
PubMed1997

Surgical treatment of thoracic outlet compression syndromes. II. Supraclavicular exploration and vascular reconstruction.

Supraclavicular exploration has become a widely utilized, versatile, and effective approach in the treatment of thoracic outlet compression syndromes. It is applicable to neurogenic, arterial, and venous form of TOS. Although certain aspects of the surgical anatomy are quite familiar to most vascular surgeons, considerable attention must be given to the details of this procedure to avoid inadequate decompression, serious injury, or predictable causes of recurrent compression. Supraclavicular exploration and its variations provide an excellent approach to the entire spectrum of problems encountered in patients with TOS, and in many centers it has superceded the transaxillary approach previously popularized for these disorders. Because supraclavicular exploration for TOS involves a number of unique technical considerations and because it is typically applied to a difficult clinical problem outside the routine experience of most vascular surgeons, it should be undertaken only with appropriate training and interest in the comprehensive management of patients with TOS.

Blood Vessel Prosthesis↗
PubMed1997

Ischemic colitis.

This article contains a current review of ischemic colitis, including its etiology, pathophysiology, diagnostic modalities, and treatment options. A special emphasis is given to ischemic colitis following aortic reconstruction.

Aortic Aneurysm, Abdominal↗