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Biomedical subjects

R W Thompson

Publications and source records attributed to R W Thompson.

At least 19 recordsLinked to original sources
PubMed2000

Accelerated replicative senescence of medial smooth muscle cells derived from abdominal aortic aneurysms compared to the adjacent inferior mesenteric artery.

BACKGROUND: Abdominal aortic aneurysms (AAAs) are associated with aging and atherosclerosis. AAAs arise through a degenerative process characterized in part by depletion of medial smooth muscle cells (SMC), suggesting that generalized aging and SMC senescence represent potential mechanisms contributing to aneurysmal degeneration. It is not yet known whether SMC from AAA tissue exhibit a difference in proliferative capacity compared to SMC from nonaneurysmal vessels or to what extent such differences might be due to aging alone or other patient-specific factors. MATERIALS AND METHODS: Aneurysm wall tissues were obtained from 15 patients undergoing AAA repair. In each case, a segment of the adjacent (nonaneurysmal) inferior mesenteric artery (IMA) from the same patient was used as a control. Paired AAA- and IMA-derived SMC strains were obtained by explant techniques and their proliferative capacities were compared during serial passage in culture. RESULTS: Sustainable SMC cultures were established from all IMA explants but from only 9 of 15 AAAs (P < 0.05). The interval required to achieve primary explant growth was longer for AAAs than IMAs (16.4 +/- 2 vs 6.4 +/- 1 days; P < 0.001), but it was unrelated to patient age, gender, or aneurysm size. AAA-derived SMC appeared larger and rounder than the corresponding IMA-derived SMC, even after repeated passage in culture, and their maximal proliferation was reduced by 44.2 +/- 8% (n = 5 pairs, P < 0.05). Serum-stimulated [(3)H]thymidine uptake in AAA-derived SMC was also reduced by 54.9 +/- 7% (n = 5 pairs, P < 0.01), but flow cytometry revealed no differences in SMC viability, apoptosis, or necrosis. While IMA-derived SMC continued to proliferate beyond passage 20 during serial subculture, all AAA-derived SMC developed replicative senescence by passage 12. CONCLUSIONS: AAA-derived SMC exhibit a distinct morphologic appearance in culture, a diminished proliferative capacity compared to SMC from the adjacent IMA, and a limited in vitro life span. These differences reflect an intrinsic alteration in SMC growth capacity independent of age alone. Tissue-specific processes leading to accelerated replicative senescence may therefore contribute to the selective medial SMC depletion observed in AAAs.

Aged↗
PubMed2000

Heart rate variability, trait anxiety, and perceived stress among physically fit men and women.

BACKGROUND: It is unclear from prior reports whether the relationships between self-ratings of anxiety or emotional stress and parasympathetic nervous system components of heart rate variability are independent of personality and cardiorespiratory fitness. We examined those relationships in a clinical setting prior to a standardized exercise test. METHODS AND RESULTS: Heart rate variability (HRV) was measured during 5 min of supine rest among 92 healthy men (N=52) and women (N=40) who had above-average cardiorespiratory fitness as indicated by peak oxygen uptake measured during grade-incremented treadmill exercise. HRV datasets were decomposed into low-frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.15-0.5 Hz) components using spectral analysis. Self-ratings of trait anxiety and perceived emotional stress during the past week were also assessed. CONCLUSIONS: There was an inverse relationship between perceived emotional stress during the past week and the normalized HF component of HRV (P=0.038). This indicates a lower cardiac vagal component of HRV among men and women who perceived more stress. That relationship was independent of age, gender, trait anxiety, and cardiorespiratory fitness. It was also independent of heart rate; mean arterial blood pressure; and respiration rate, factors which can influence HRV and might be elevated among people reporting anxiety and perceived stress. We conclude that vagal modulation of heart period appears to be sensitive to the recent experience of persistent emotional stress, regardless of a person's level of physical fitness and disposition toward experiencing anxiety.

Adult↗
PubMed2000

Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms.

PURPOSE: Matrix metalloproteinases (MMPs) are considered to play a central role in the pathogenesis of abdominal aortic aneurysms (AAAs). Doxycycline (Dox) has direct MMP-inhibiting properties in vitro, and it effectively suppresses the development of elastase-induced AAAs in rodents. The purpose of this study was to determine if treatment with Dox suppresses MMPs within human aneurysm tissue and to elucidate the molecular mechanisms underlying this effect. METHODS: Aneurysm tissues were obtained from 15 patients with an AAA, eight of whom had been treated with Dox before surgery (100 mg orally twice a day for 7 days). Protein extracts were examined by means of gelatin zymography and immunoblot analysis, and RNA was examined by means of reverse transcription-polymerase chain reaction (RT-PCR). The effects of Dox on MMP production were further examined in human THP-1 mononuclear phagocytes in vitro. RESULTS: No detectable difference was found between groups by using substrate zymography as a means of assessing total MMP activity, but Dox treatment was associated with a slight (24.4%) reduction in the activated fraction of 72-kDa gelatinase (MMP-2; P <.05). In contrast, a 2.5-fold reduction in the amount of extractable 92-kDa gelatinase (MMP-9) protein in Dox-treated patients was revealed by means of immunoblot analysis (P <.05). Also, a 5.5-fold (81.9%) reduction in MMP-9 messenger RNA (mRNA) in Dox-treated patients was demonstrated by means of quantitative competitive RT-PCR (mean +/- SE, mol MMP-9/mol beta-actin: 1.3 +/- 0.5 vs 7.2 +/- 3.1; P <.04). There was no significant difference between groups in the relative expression of MMP-2 protein or mRNA. In cultured THP-1 monocytes stimulated with phorbol ester, the expression of MMP-9 protein and mRNA were both decreased after exposure to relevant concentrations of Dox in vitro. CONCLUSION: In addition to its recognized effects as a direct MMP antagonist, Dox may influence connective tissue degradation within human aneurysm tissue by reducing monocyte/macrophage expression of MMP-9 mRNA and by suppressing the post-translational processing (activation) of proMMP-2. Through this complementary combination of mechanisms, treatment with Dox may be a particularly effective strategy for achieving MMP inhibition in patients with an AAA.

Aged↗
PubMed2000

Functional importance of connective tissue repair during the development of experimental abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysms (AAAs) involve an unfavorable balance between the destruction and the repair of connective tissue proteins. The purpose of this study was to assess the functional importance of connective tissue repair during experimental aneurysmal degeneration. METHODS: Male Wistar rats (n = 70) underwent transient intraluminal perfusion of the abdominal aorta with porcine pancreatic elastase. In Study I, the aortic diameter was measured before elastase perfusion and at days 0, 2, 7, and 14 (n = 6 rats at each interval). Aortic wall concentrations of desmosine (Des) and hydroxyproline (OHP) were measured at each interval, and the expression of tropoelastin (TE), alpha1(I) procollagen (PC), and lysyl oxidase genes was evaluated by reverse transcription-polymerase chain reaction. In Study II, 22 rats were treated with beta-aminopropionitrile (BAPN) to block connective tissue repair. In Study III (n = 30), rats were treated with doxycycline, a matrix metalloproteinase inhibitor, beginning 7 days after elastase perfusion. RESULTS: AAAs consistently developed between 7 and 14 days after elastase perfusion. Aortic wall Des concentration decreased markedly during aneurysm development, reaching 3% of normal by day 14 (377 +/- 22 pmol of Des/sample on day 0 vs 9 +/- 1 pmol of Des/sample on day 14; P <.05). Aortic wall OHP decreased to only 68% of normal at the same interval (121 +/- 10 nmol of OHP/sample on day 0 vs 82 +/- 14 nmol of OHP/sample on day 14; P <.05). TE and PC expression was undetectable in healthy aorta, but they both increased by day 7 (P <.05); while TE expression decreased again by day 14, PC continued to rise. Lysyl oxidase expression progressively decreased at all intervals after elastase perfusion. Treatment with beta-aminoproprionitrile resulted in acute aortic dissection in 81% of the rats (50% mortality). These early deaths occurred between days 3 and 6, coinciding with aortic infiltration by proteinase-secreting inflammatory cells. Delayed treatment with doxycycline suppressed the progression of aneurysmal dilatation between days 7 and 21 (P <.05 vs untreated controls). CONCLUSIONS: The development of elastase-induced AAAs is accompanied by an active process of connective tissue repair. While this reparative process is necessary to stabilize the developing aneurysm wall, it is insufficient to prevent aneurysm progression. In contrast, reducing the proteolytic destruction of connective tissue proteins promotes stabilization of the aneurysmal aorta.

Aminopropionitrile↗
PubMed2000

Comparison of three methods for measuring the time spent in physical activity.

PURPOSE: Three methods for measuring time spent in daily physical activity (PA) were compared during a 21-d period among 83 adults (38 men and 45 women). METHODS: Each day, participants wore a Computer Science and Applications, Inc. (CSA) monitor and completed a 1-page, 48-item PA log that reflected time spent in household, occupational, transportation, sport, conditioning, and leisure activities. Once a week, participants also completed a telephone survey to identify the number of minutes spent each week in nonoccupational walking and in moderate intensity and hard/very hard-intensity PA. Data were analyzed using descriptive statistics and Spearman rank-order correlations. Three equations developed to compute CSA cut points for moderate and hard/very hard PA were also compared with the PA logs and PA survey. RESULTS: There was modest to good agreement for the time spent in different PA intensity categories between the three CSA cut point methods (r = 0.43-0.94, P < 0.001). Correlations between the CSA and PA logs ranged from r = 0.22 to r = 0.36, depending on the comparisons. Correlations between the survey items and PA logs were r = 0.26-0.54 (P < 0.01) for moderate and walking activities and r < 0.09 (P > 0.05) for hard/very hard activities. Correlations between the survey items and the CSA min per day varied according to the method used to compute the CSA intensity cut points. CONCLUSIONS: The results were consistent with findings from other PA validation studies that show motion sensors, PA logs, and surveys reflect PA; however, these methods do not always provide similar estimates of the time spent in resting/light, moderate, or hard/very hard PA.

Activities of Daily Living↗
PubMed2000

The utility of the Digi-walker step counter to assess daily physical activity patterns.

PURPOSE: The Digi-Walker step counter is a promising and cost-effective tool to measure physical activity under free-living conditions. Two specific studies were conducted to evaluate the number of steps required to meet current physical activity guidelines. METHODS: Thirty-one adults (17 men, 14 women) served as participants. In study 1, we determined the number of steps to complete a mile under two different conditions and three paces. In study 2, we conducted a field trial to examine the relationship between daily step counts and other indices of physical activity. Participants in this study wore a Digi-Walker for 2 consecutive weeks and completed the 7-d physical activity recall (PAR) after each week. RESULTS: In study 1, there were no differences in step counts by site, but steps were inversely related to pace, with values ranging from 1330 to 1996. Individual step counts at a specific pace were negatively correlated with height, weight, leg length, and stride length and were positively correlated with body fatness. In study 2, participants had average daily step counts of 11,603 when structured vigorous activity was included and 8265 when only light and moderate activity were measured. Modest correlations were found between step counts and estimated energy expenditure. Similar correlations were observed when step counts were related to minutes of activity per day and minutes of sitting per day. CONCLUSIONS: Pedometers provide a useful indicator of daily step counts but variability in activity patterns make it difficult to establish step count guidelines that correspond with other public health guidelines.

Activities of Daily Living↗
PubMed2000

A comparative evaluation of three accelerometry-based physical activity monitors.

PURPOSE: Accelerometry-based activity monitors offer promise for the assessment of free-living physical activity. They provide an objective record of frequency, intensity, and duration of physical activity with minimal burden on participants. The purpose of this study was to evaluate the absolute and relative validity of three contemporary activity monitors (Computer Science and Applications, Inc. [CSA], Tritrac, and Biotrainer) under both laboratory and field conditions. METHODS: Fifty-two participants completed two 30-min choreographed routines designed to simulate a variety of lifestyle physical activities. Three different treadmill paces were completed in both routines to evaluate reliability and validity under laboratory conditions. Six different lifestyle activities were also examined to evaluate the validity of the monitors under field conditions. During each routine, the activity levels of participants were monitored with the three activity monitors as well as by indirect calorimetry systems. RESULTS: The correlations between the monitors and measured VO2 were higher for treadmill activity (mean r = 0.86) compared with lifestyle activity (mean r = 0.55). Correlations among the different monitors were high for both treadmill (r = 0.86) and lifestyle activities (r = 0.70), suggesting that the monitors provide similar information under both conditions. Under laboratory conditions, the CSA yielded accurate predictions of energy expenditure (EE), whereas the Tritrac and Biotrainer tended to overestimate the EE (101-136% of measured value). The Tritrac, however, was found to have less error in individual estimates of EE. Under field conditions, all of the monitors underestimated EE (range: 42-67% of measured value). CONCLUSION: The observed differences among the monitors were attributed primarily to differences in the accuracy of the calibration equations rather than to the monitors themselves. Further research is needed to better understand how to use these devices for field-based assessments of physical activity.

Activities of Daily Living↗
PubMed2000

Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms.

Abdominal aortic aneurysms represent a life-threatening condition characterized by chronic inflammation, destructive remodeling of the extracellular matrix, and increased local expression of matrix metalloproteinases (MMPs). Both 92-kD gelatinase (MMP-9) and macrophage elastase (MMP-12) have been implicated in this disease, but it is not known if either is necessary in aneurysmal degeneration. We show here that transient elastase perfusion of the mouse aorta results in delayed aneurysm development that is temporally associated with transmural mononuclear inflammation, increased local production of several elastolytic MMPs, and progressive destruction of the elastic lamellae. Elastase-induced aneurysmal degeneration was suppressed by treatment with a nonselective MMP inhibitor (doxycycline) and by targeted gene disruption of MMP-9, but not by isolated deficiency of MMP-12. Bone marrow transplantation from wild-type mice prevented the aneurysm-resistant phenotype in MMP-9-deficient animals, and wild-type mice acquired aneurysm resistance after transplantation from MMP-9-deficient donors. These results demonstrate that inflammatory cell expression of MMP-9 plays a critical role in an experimental model of aortic aneurysm disease, suggesting that therapeutic strategies targeting MMP-9 may limit the growth of small abdominal aortic aneurysms.

Animals↗
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↗