Biomedical subjects

Kenneth A Harris

Publications and source records attributed to Kenneth A Harris.

At least 19 recordsLinked to original sources

PubMed2006

A 5-year evaluation of a methadone medical maintenance program.

Methadone medical maintenance (MMM) is a model for the treatment of opioid dependence in which a monthly supply of methadone is distributed in an office setting, in contrast to more highly regulated settings where daily observed dosing is the norm. We assessed patient characteristics and treatment outcomes of an MMM program initiated in the Bronx, New York, in 1999 by conducting a retrospective chart review. Participant characteristics were compared with those of patients enrolled in affiliated conventional methadone maintenance treatment programs. Patients had diverse ethnicities, occupations, educational backgrounds, and income levels. Urine toxicology testing detected illicit opiate and cocaine use in 0.8% and 0.4% of aggregate samples, respectively. The retention rate was 98%, which compares favorably with the four other MMM programs that have been reported in the medical literature. This study demonstrates that selected patients from a socioeconomically disadvantaged population remained clinically stable and engaged in treatment in a far less intensive setting than traditional methadone maintenance.

Adult↗

PubMed2006

Gender differences in relative dilatation of abdominal aortic aneurysms.

It has been postulated that gender differences in abdominal aortic aneurysm (AAA) rupture risk are due to variation in proportional dilatation. This study's purpose was to examine differences in relative dilatation of AAAs as related to rupture risk and repair thresholds. During a recent 20-month period (August 2003-March 2005), all patients receiving elective endovascular repair of an AAA underwent computer-generated computed tomographic measurements, including suprarenal aortic diameter (D1) and maximum aneurysm diameter (D3). As a measure of proportional dilatation, a D3/D1 ratio was calculated for each patient and compared between genders. Values for males and females were plotted separately (D3 vs. D3/D1), and the resulting linear regression equations allowed for the comparison of proportional dilatation of aneurysms between genders. In 129 patients (108 males, 21 females), mean D3 did not differ between genders (62 +/- 9.0 vs 63.4 +/- 10.8 mm, p = 0.89), while relative dilatation (D3/D1) was significantly greater in females compared to males (2.82 +/- 0.52 vs. 2.55 +/- 0.42, p = 0.02). Linear regression analysis allowed for comparison of D3 as a function of D3/D1 and correlated a 55 mm AAA in males with one of 52 mm in females. These differences became greater with increasing AAA diameters (e.g., 60 and 70 mm AAAs in a male were proportionally similar to 56 and 62 mm AAAs in a female). AAAs of equal diameter represent a greater proportional dilatation in females than in males. This supports the recommendation for a smaller aneurysm diameter (52 mm) threshold for repair in females rather than the commonly used 55 mm threshold in males. Also, these data suggest that the gender difference in rupture risk widens exponentially as aneurysm diameter, and thereby proportional dilatation, increases above this repair threshold.

Angioplasty↗

PubMed2006

Examination of the trend in Canada toward geographic centralization of aneurysm surgery during the endovascular era.

Unlike in the United States, endovascular aneurysm repair (EVAR) has not been widely disseminated in Canada but has remained limited to large-volume vascular surgery units. Since the development of the endovascular program at our hospital, we have experienced a growth in our aneurysm practice and the area of referral. The purpose of this study was to compare the geographic referral area of our aneurysm practice between 1997 (prior to the introduction of EVAR) and 2003 (EVAR and open surgery). Our prospective database was reviewed to identify patients who underwent elective open aneurysm repair in 1997 and 2003 and those who underwent EVAR in 2003. Each patient's county of residence was identified, allowing for grouping of patients into one of four geographic regions (I-IV) increasingly more distant from our hospital. Proportions were compared with the chi(2) test. In 1997, 105 patients underwent open abdominal aortic aneurysm repair, with the majority of patients originating from the two regions in closest proximity to our hospital (I, 34%; II, 46%; III, 18%; IV, 2%). This contrasts with the 2003 EVAR group (n = 63), which had a higher proportion of patients referred from greater distances (I, 13%; II, 27%; III, 27%; IV, 33%) (p < 0.001). The 2003 open group (n = 165) did not differ statistically with respect to region of origin (I, 18%; II, 41%; III, 21%; IV, 19%) compared to their 2003 EVAR counterparts (p = 0.075) but did have a higher proportion of patients from the more distant regions compared to the 1997 open group (p < 0.001). During the last 5 years, we have experienced a doubling of our elective aneurysm case volumes as well as a trend for patients to be referred from greater distances for both EVAR and open repair. This suggests a trend in Canada toward increased centralization of aneurysm care in centers providing both endovascular and open surgical alternatives.

Aortic Aneurysm, Abdominal↗

PubMed2006

Comparison of renal function after endovascular aneurysm repair with different transrenally fixated endografts.

OBJECTIVE: Transrenal fixation of abdominal aortic endografts may provide a more secure proximal attachment with few deleterious effects with respect to renal function. This study's purpose was to determine whether different metals used in two commercially available endografts (Cook Zenith and Medtronic Talent) result in different effects on renal function when placed across renal ostia. METHODS: A total of 140 consecutive patients, between August 2003 and April 2005, who underwent elective endovascular repair of an aortic aneurysm with a nitinol or stainless steel-based endograft with transrenal fixation were reviewed with a mean follow-up period of 5.5 months (range, 1-22 months). The main outcome variable was the percentage change in creatinine clearance (CrCl), which was determined before surgery and at the most recent follow-up. Multiple regression analysis was performed to analyze the contribution of various factors to any deterioration in renal function. RESULTS: The 140 patients were predominantly male (86%), with a mean age of 75 years (range, 56-92) and a mean aneurysm diameter of 62 mm (range, 42-110 mm). The mean intraoperative contrast use was 67 mL (range, 45-160 mL), and after surgery these patients received a mean of 3 surveillance computed tomographic scans (range, 1-7). Nineteen cases (13.6%) required deliberate accessory renal artery coverage. CrCl did not change significantly after surgery; the mean change in CrCl at the end of follow-up was a 2.5% decrease. There was no difference in the reduction in CrCl between endograft types. Only 14.3% of patients experienced a greater than 20% decrease in CrCl. Multiple regression analysis failed to show a relationship between change in renal function and age, sex, aneurysm diameter, infrarenal neck dimensions, endograft type, coverage of accessory renal arteries, intraoperative contrast volume, preoperative CrCl, and postoperative computed tomographic scans. Length of follow-up was an independent predictor (P = .04). CONCLUSIONS: Transrenal endograft fixation results in little deterioration in renal function during intermediate follow-up. The few patients who do experience a decline in renal function do so independently of any features related to the initial endovascular repair, and there is no difference in renal deterioration between endografts with nitinol and stainless steel transrenal bare metal stents.

Aged↗

PubMed2006

Perioperative use of the hands-free technique: a semistructured interview study.

OCCUPATIONALLY CONTRACTED bloodborne infections are preventable, but the use of many protective measures remains limited. THERE IS GROWING EVIDENCE that the use of the hands-free technique (HFT) to pass sharp items during surgical procedures is effective in protecting against sharps injury and bloody contamination. RESEARCHERS CONDUCTED in-depth telephone interviews to explore 20 health care providers' knowledge and use of the HFT. MOST OF THE INTERVIEWEES did not regularly use the HFT, and some were resistant to its use.

Attitude of Health Personnel↗

PubMed2006

Role of heme oxygenase in the protection afforded skeletal muscle during ischemic tolerance.

OBJECTIVE: Ischemic tolerance (IT) is known to improve resistance to ischemia/reperfusion (I/R)-induced injury; however, the mechanisms remain unknown. The authors hypothesized that induction of heme oxygenase (HO), a heat shock protein, would provide anti-inflammatory benefits during IT, thereby preventing leukocyte-derived I/R injury. METHODS: Male Wistar rats were randomly assigned to sham (n = 4), I/R (n = 9), preconditioning (PC)+I/R (n = 7), chromium mesoporphyrin, to inhibit HO (CrMP; n = 4), or PC+I/R+CrMP (n = 6) groups. PC consisted of 5 cycles of I/R, each lasting 10 min, induced by tightening a tourniquet placed above the greater trochantor of the hindlimb. Twenty-four hours later, the hindlimb underwent 2 h of no-flow ischemia followed by intravital microscopy during 90 min reperfusion to assess capillary perfusion (#/mm), tissue injury (ratio of ethidium bromide to bisbenzimide labeled cells/100 microm2), leukocyte rolling (Lr, #/1000 microm2), and adhesion (La, #/1000 microm2) in postcapillary venules of the extensor digitorum longus (EDL) muscle. RESULTS: In the I/R group, Lr was significantly increased (7.1 +/- 0.4) compared to sham (3.1 +/- 0.4). PC+I/R increased Lr (10.8 +/- 0.72), which was further exacerbated by the removal of HO (14.2 +/- 1.3). La (7.8 +/- 2.0) was significantly increased compared to sham (2.4 +/- 0.9), while PC returned La back to sham levels (1.9 +/- 0.7). Removal of HO activity, via CrMP, had no significant effect on La (3.9 +/- 0.7). However, CrMP removed the protection to microvascular perfusion (I/R = 9.4 +/- 1.1, PC = 16.6 +/- 1.8, sham = 20.5 +/- 2.8, PC+CrMP+I/R = 12.3 +/- 2.3) and prevented protection from ischemia-induced tissue injury. CONCLUSION: The data suggest that HO is an important protective mechanism during IT in skeletal muscle, but such protection was by mechanisms other than altered leukocyte-endothelial cell interaction.

Animals↗

PubMed2006

A screening program to identify risk factors for abdominal aortic aneurysms.

BACKGROUND: We aimed to explore the feasibility of a nurse-supervised aneurysm screening program to identify any independent risk factors for abdominal aortic aneurysm (AAA) formation in high-risk patients. METHODS: We conducted a prospective observational study of 90 male patients in a university- affiliated hospital in southern Ontario. The patients were prospectively evaluated and all underwent abdominal ultrasonography, with the main outcome measure being detection of an AAA. RESULTS: AAAs were identified in 18 patients (20%) and had a mean diameter of 3.6 (range 2.8-6.0) cm. A separate analysis was performed to identify risk factors for the presence of an aneurysm. The presence of carotid artery disease proved to be the only statistically significant independent predictor of the presence of AAA (odds ratio 2.23, 95% confidence interval 1.76-2.56). CONCLUSIONS: This study confirms the feasibility of a nurse-supervised AAA screening program, and on the basis of these results we recommend ultrasonographic screening for AAA in patients with a history of carotid artery disease.

Aged↗

PubMed2005

Risk-adjusted analysis of outcomes following elective open abdominal aortic aneurysm repair.

The purpose of this study was to describe a method to analyze outcomes following open abdominal aortic aneurysm (AAA) repair while considering the variability in patients' preoperative risk. Consecutive patients undergoing elective open infrarenal AAA repair during a 4-year period (2000-2003) were reviewed. Thirty-day or in-hospital mortality was the major outcome variable. Preoperative mortality risk was estimated for each patient using a validated scoring system that considers age, renal dysfunction, and coronary artery and cerebrovascular disease. A risk-adjusted cumulative sum method was used to compare observed versus predicted outcomes by assigning a risk-adjusted score, based on log-likelihood ratios, to each patient. These cumulative scores were sequentially plotted with preset control limits to allow for "signaling" when results were substantially different than expected (doubling or halving of odds ratios). Four hundred and sixty-three patients were studied with an overall early mortality rate of 4.5% (n = 21). Patients were allocated to three different preoperative risk groups (low, n = 89; medium, n = 160; high, n = 214) according to a medical comorbidity-based scoring system. Predicted (P) and observed (O) mortality rates for each group were as follows: low, 2.4% (P) and 2.2% (O); medium, 4.1% (P) and 4.4% (O); high, 9.3% (P) and 5.6% (O). The resulting risk-adjusted scores for each patient were plotted sequentially. This plot was flat for the first year and then adopted a negative slope crossing the lower control limit after 266 patients, indicating improved results compared to those expected. This coincided with the adoption of routine intraoperative cell saver use in our practice. This form of analysis allows for the prospective evaluation of results while considering patient-mix variabilities.

Aged↗

PubMed2005

Midterm follow-up of inflammatory abdominal aortic aneurysms following endovascular repair.

The role of endovascular therapy in the management of inflammatory aneurysms of the infrarenal abdominal aorta has been controversial. Review of our endovascular database identified six patients who have undergone treatment for preoperatively diagnosed inflammatory abdominal aortic aneurysms. Outcomes measured were primary success of the procedure, variation in computed tomographic (CT) scan-defined perianeurysmal fibrosis, change in aneurysm size, development of endoleak, requirement of reintervention, aneurysm rupture, and progression or resolution of symptoms. At a median follow-up of 20 months (range 4-56 months), endovascular repair has been successful in all six patients. All patients demonstrated CT reduction of perianeurysmal fibrosis, with a median of 47% absolute reduction (range 33-69%, p = 0.014). All patients had aneurysm sac shrinkage, with a mean of 41% (range 6-86%, p = 0.04). There were no aneurysm ruptures or persistent endoleaks. Of the three patients who presented with abdominal or back pain, all are now symptom-free. One patient required reintervention for limb thrombosis of a bifurcated graft after 2 years. In conclusion, endovascular treatment of an inflammatory abdominal aortic aneurysm is safe and effective and the treatment of choice in anatomically suitable patients.

Aged↗

PubMed2005

Risk-adjusted analysis of early mortality after ruptured abdominal aortic aneurysm repair.

PURPOSE: Ruptured abdominal aortic aneurysms (RAAAs) continue to result in early mortality in up to 50% of patients. Additionally, it remains difficult to compare outcomes given the variability in patient comorbidities and presentation. The purpose of this study was to describe an instrument that permits the prospective analysis of outcomes after RAAA repair while adjusting for the variability in preoperative risk. METHODS: Consecutive patients undergoing attempted open RAAA repair over a 5-year period (1999 to 2003) at our center were reviewed. Thirty-day or in-hospital mortality was the main outcome variable. Preoperative mortality risk was estimated for each patient by using a validated modification of the POSSUM scoring system (V-POSSUM). A risk-adjusted cumulative sum method (RA-CUSUM) was used to compare observed versus predicted outcomes by assigning a risk-adjusted score, based on log-likelihood ratios, to each patient. These scores were sequentially plotted with preset control limits to allow for "signaling" when results were substantially different from expected (doubling or halving of odds ratios). RESULTS: A total of 136 patients were reviewed, with an early mortality rate of 45.6%. V-POSSUM scores were accurate in predicting mortality for the entire cohort, with an observed-to-predicted mortality ratio of 0.92 (P = .80). Each patient's risk-adjusted score was plotted sequentially. In one segment of the resulting plot, the graph adopted a negative slope and crossed the lower control limit, indicating improved results compared with predicted. CONCLUSIONS: V-POSSUM scores in this series accurately predicted early mortality after RAAA surgery. The RA-CUSUM method allows for the prospective evaluation of outcomes, while taking into account patient variability. In the current study, this resulted in the identification of a series of patients who had improved outcomes compared with predicted.

Adult↗

PubMed2005

National audit of the recent utilization of endovascular abdominal aortic aneurysm repair in Canada: 2003 to 2004.

OBJECTIVES: Worldwide, increasing proportions of aortic aneurysms are repaired electively via the endovascular route. The purpose of this study was to report the recent utilization of endovascular repair in Canada by reviewing a national administrative database. METHODS: The Canadian Institute for Health Information database (a collection of all acute care hospitalizations) was reviewed to identify patients who received nonemergent repair of an abdominal aortic aneurysm (AAA) between April 1, 2003 and March 31, 2004. During this 1-year period, differentiation between endovascular (EVAR) and open repair was possible using ICD-10-CA procedural codes in eight of ten provinces. Case volumes, patient age, length of hospitalization, and mortality were stratified by method of repair, province, and size and teaching status of hospitals. RESULTS: In this 1-year period, 1996 patients in eight provinces (representing 72% of Canada's population) underwent open repair (n = 1818, 91.1%) or EVAR (n = 178, 8.9%) of a nonruptured AAA. National utilization rates were 8.4 and 0.8 per 100,000 population for open repair and EVAR. These rates were more constant for EVAR (0 to 1.3) then for open repair (4 to 18.3) when analyzed on a provincial basis. Mean patient age did not differ between EVAR and open repair (73.7 vs 71.9 years, P = 0.4) while mean length of stay (5.8 vs 11.9 days, P = 0.03) and in-hospital mortality (0.6% vs 4.6%, P = .025) were significantly lower for EVAR than for open repair. Most EVAR (96%) and more than half of open repairs (56%) were performed in academic teaching centers. CONCLUSIONS: Although EVAR results in significant reductions in length of hospitalization and early mortality, it continues to be underutilized in Canada compared with other national reports involving administrative databases.

Aged↗

PubMed2005

Heme oxygenase modulates small intestine leukocyte adhesion following hindlimb ischemia/reperfusion by regulating the expression of intercellular adhesion molecule-1.

OBJECTIVE: Heme oxygenase is the rate-limiting enzyme in the degradation of heme into carbon monoxide, iron, and bilirubin. Recent evidence suggests that the induction of heme oxygenase-1 is associated with potent anti-inflammatory properties. The objectives of this study were to determine the temporal, regional, and cellular distribution of heme oxygenase-1 within the small intestine and its role in modulating remote intestinal leukocyte recruitment following trauma induced by hindlimb ischemia/reperfusion. DESIGN: Randomized, controlled, prospective animal study. SETTING: Hospital surgical research laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Mice underwent 1 hr of bilateral hindlimb ischemia, followed by 3, 6, 12, or 24 hrs of reperfusion. MEASUREMENTS AND MAIN RESULTS: Heme oxygenase-1 messenger RNA, heme oxygenase-1 protein, and heme oxygenase activity were measured using reverse transcription polymerase chain reaction, Western blot, immunohistochemistry, and spectrophotometric assay, respectively. The jejunum was also exteriorized to quantify the flux of rolling and adherent leukocytes and R-Phycoerythrin conjugated intercellular adhesion molecule-1 monoclonal antibody fluorescence intensity in submucosal postcapillary venules with the use of intravital microscopy. Ischemia/reperfusion led to a significant increase in heme oxygenase-1 messenger RNA in the jejunum and ileum 3 hrs following limb reperfusion, with a subsequent increase in heme oxygenase-1 protein and heme oxygenase activity at 6 hrs. Ischemia/reperfusion also led to a significant 1.4-fold increase in leukocyte rolling, whereas inhibition of heme oxygenase via injection of tin protoporphyrin IX (20 micromol/kg intraperitoneally) resulted in a three-fold increase in leukocyte adhesion, compared with ischemia/reperfusion alone. This increase in adhesion was significantly reduced to baseline in mice treated with intercellular adhesion molecule-1 monoclonal antibody before heme oxygenase inhibition (40 microg/mouse), whereas inhibition of heme oxygenase activity following ischemia/reperfusion also led to a significant increase in R-Phycoerythrin intercellular adhesion molecule-1 monoclonal antibody fluorescence intensity. CONCLUSIONS: Our data suggest that remote trauma induced by hindlimb ischemia/reperfusion leads to an increase in heme oxygenase activity within the small intestine, which modulates intercellular adhesion molecule-1 dependent intestinal leukocyte adhesion.

Animals↗

PubMed2005

Endovascular management of traumatic thoracic aortic injuries.

BACKGROUND: Endovascular surgery has recently been extended to the treatment of blunt traumatic aortic injuries. Since most of these injuries occur at the aortic isthmus, graft fixation in proximity to the origin of the left subclavian artery (LSA) has been a concern. Covering the LSA with graft fabric lengthens the proximal fixation site and should minimize proximal endoleaks. We therefore wished to evaluate the feasibility and safety of endovascular repair of thoracic aortic injuries after blunt trauma, both with and without deliberate coverage of the LSA. METHODS: At a tertiary care teaching hospital in London, Ont., we reviewed our experience with endovascular repair of 7 traumatic aortic injuries. We reviewed the technical success rate and the incidence of left subclavian coverage. Major morbidity, including rates of paraplegia and death were noted. The patients were followed-up with serial CT to look for endoleaks, stent migration or aneurysm growth and to determine whether they had symptoms related to left subclavian coverage. RESULTS: The time from injury to treatment ranged from 7 hours to 7 days (mean 36 h). The mean Injury Severity Score was 36. All injuries were at the aortic isthmus, and among the 7 patients treated, 6 had deliberate coverage of the LSA. One patient underwent carotid-to-subclavian artery bypass, but the other 5 did not. There were no cases of paraplegia; 1 patient had symptoms of claudication in the left arm but did not want revascularization. No procedure-related complications occurred, and all patients survived the event. Follow-up ranged from 2 to 30 (mean 13) months, and no endoleaks, stent migration or aneurysm expansion were noted in follow-up. CONCLUSIONS: Although long-term results are unknown, we conclude that endovascular repair of traumatic aortic injuries after blunt trauma can be performed safely with low morbidity and mortality and that coverage of the LSA without revascularization is tolerated by most patients.

Accidents, Traffic↗

PubMed2005

Current status of Canadian vascular surgery training: a survey of program directors.

BACKGROUND: With the aging of the North American population and therefore the need for more modern vascular surgeons familiar with open operations and less invasive diagnostic and therapeutic regimens, we wished to obtain suggestions and recommendations that would allow our training programs to more adequately fulfil these needs. Our objectives were to assess recent trends in Canadian vascular surgery training with respect to the trainee's operative and nonoperative experience. METHODS: We mailed a survey to the directors of the 8 Canadian vascular surgery training programs, to ascertain the yearly operative volumes of their 3 most recent trainees with respect to 6 index operations: carotid endarterectomy (CEA), types I-IV thoracoabdominal aortic aneurysm (TAA) repair, elective open infrarenal aortic aneurysm (eAAA) repair, ruptured abdominal aortic aneurysm (rAAA) repair, endovascular abdominal aortic aneurysm repair (EVAR) and lower extremity arterial bypass (LEB). Additionally, information pertaining to nonvascular surgery rotations and the final practice location and type of practice for each trainee was requested. RESULTS: Seven (88%) of 8 program directors completed the survey. Between 1999 and 2002, vascular surgery trainees in Canadian training programs were exposed to the following yearly clinical volumes (expressed as mean [and standard deviation]): CEA 55.4 (33.9), TAA 6.2 (3.8), eAAA 63.8 (30.0), rAAA 13.5 (9.4), EVAR 14.9 (9.6) and LEB 74.5 (34.5). The range of yearly clinical volumes were: CEA 21-124, TAA 1-18, eAAA 30-133, rAAA 3-45, EVAR 0-34 and LEB 20-143. Nonvascular surgery rotations included: endovascular therapy, interventional radiology, noninvasive diagnostics and research. Forty-five (80.4%) of 56 recent graduates practise only vascular surgery. Most (73.2%) of our recent trainees have remained in Canada, with 41.1% settling in the province in which they trained. CONCLUSIONS: Canadian vascular surgery training programs provide more than sufficient operative experience for their trainees. Although some programs have been successful at providing training in endovascular therapies, the integration of such experience in our training programs continues to be a challenge.

Canada↗

PubMed2005

On dissatisfaction.

Explore the source record for details and available documents.

Burnout, Professional↗

PubMed2004

Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion.

The induction of heme oxygenase (HO), the rate limiting enzyme in the conversion of heme into carbon monoxide (CO) and biliverdin, limits liver injury following remote trauma such as hind limb ischemia/reperfusion (I/R). Using intravital video microscopy, we tested the hypothesis that inhaled CO (250 ppm) would mimic HO-derived liver protection. Hind limb I/R significantly decreased sinusoidal diameter and volumetric flow, increased leukocyte accumulation within sinusoids, increased leukocyte rolling and adhesion within postsinusoidal venules, and significantly increased hepatocyte injury compared with naive animals. Inhalation of CO alone did not alter any microcirculatory or inflammatory parameters. Inhalation of CO following I/R restored volumetric flow, decreased stationary leukocytes within sinusoids, decreased leukocyte rolling and adhesion within postsinusoidal venules, and significantly reduced hepatocellular injury following hind limb I/R. HO inhibition did not alter microcirculatory parameters in naive mice, but did increase inflammation, as well as increase hepatocyte injury following hind limb I/R. Inhalation of CO during HO inhibition significantly reduced such microcirculatory deficits, hepatic inflammation, and injury in response to hind limb I/R. In conclusion, these results suggest that HO-derived hepatic protection is mediated by CO, and inhalation of low concentrations of CO may represent a novel therapeutic approach to prevent remote organ injury during systemic inflammatory response syndrome, or SIRS.

Administration, Inhalation↗

PubMed2004

Protective mechanisms during ischemic tolerance in skeletal muscle.

The purpose of this study was to test specific mechanisms of protection afforded the rat extensor digitorum longus (EDL) muscle during ischemic tolerance. Two days following five cycles of 10 min ischemia and 10 min reperfusion, heme oxygenase (HO) and calcium-dependent nitric oxide synthase (cNOS) activities were increased 2- and 2.5-fold (p <.05), respectively. Interestingly, calcium-independent NOS (iNOS) activity was completely downregulated (p <.05). The levels of superoxide dismutase (SOD) and catalase were increased 2-fold (p <.05), while glutathione peroxidase activity remained unchanged from non-preconditioned controls. Using intravital microscopy combined with chromium mesoporphyrin (CrMP), a selective HO inhibitor, and l-NAME, a NOS inhibitor, the roles of HO and cNOS were evaluated. Ischemic tolerance in the EDL muscle, 48 h after the preconditioning stimulus, was characterized by complete protection from both microvascular perfusion deficits and tissue injury after a 2-h period of ischemia. Removal of NOS activity completely removed the benefit afforded microvascular perfusion, while inhibition of HO activity prevented the parenchymal protection. These data suggest that ischemic tolerance within skeletal muscle is associated with the upregulation of specific cytoprotective proteins and that the benefits afforded by cNOS and HO activity are spatially discrete to the microvasculature and parenchyma, respectively.

Animals↗

PubMed2004

Endogenous heme oxygenase induction is a critical mechanism attenuating apoptosis and restoring microvascular perfusion following limb ischemia/reperfusion.

BACKGROUND: A protective role for endogenous heme oxygenase (HO) in the initiation of remote liver injury after limb ischemia/reperfusion has been established. This study expands on our previous work by investigating the role of endogenous HO on hepatocellular injury, hepatocyte death (necrotic and apoptotic), and microvascular perfusion at protracted post-reperfusion times. METHODS: Remote liver injury was studied after 1 hour of bilateral hind limb ischemia and 3, 6, or 24 hours of reperfusion in male C57BL6 mice. Inhibition of HO was achieved with the use of chromium mesoporphrin (CrMP). Established intravital videomicroscopy techniques were used to evaluate microvascular perfusion and hepatocyte death. Hepatocellular injury was quantified by serum alanine transaminase. Apoptosis was measured by using DNA laddering, Cell Death ELISA, and caspase-3 activity. RESULTS: Although significant perfusion deficits and hepatocellular injury/death occurred after 3 hours, progression of hepatocellular death beyond 6 hours was not observed. A transient increase in apoptosis was observed at 6 hours. By 24 hours, microvascular perfusion was completely restored. This lack of progression correlated with increased HO activity, observed throughout the protocol. Administration of CrMP reduced HO activity to sham nonstressed levels, and caused increased microvascular perfusion deficits, hepatocellular injury, and hepatocyte death over 24 hours. The transient increase in apoptosis was increased in duration and magnitude in CrMP-treated animals. CONCLUSIONS: These results suggest that endogenous HO activity prevents the progression of remote liver injury after limb ischemia/reperfusion.

Animals↗