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Ferrets are an attractive mammalian model for several diseases, especially those affecting the lungs, liver, brain, and kidneys. Many chronic human diseases have been difficult to model in rodents due to differences in size and cellular anatomy. This is particularly the case for the lung, where ferrets provide an attractive mammalian model of both acute and chronic lung diseases, such as influenza, cystic fibrosis, A1A emphysema, and obliterative bronchiolitis, closely recapitulating disease pathogenesis, as it occurs in humans. As such, ferrets have the potential to be a valuable preclinical model for the evaluation of cell-based therapies for lung regeneration and, likely, for other tissues. Induced pluripotent stem cells (iPSCs) provide a great option for provision of enough autologous cells to make patient-specific cell therapies a reality. Unfortunately, they have not been successfully created from ferrets. In this study, we demonstrate the generation of ferret iPSCs that reflect the primed pluripotent state of human iPSCs. Ferret fetal fibroblasts were reprogrammed and acquired core features of pluripotency, having the capacity for self-renewal, multilineage differentiation, and a high-level expression of the core pluripotency genes and pathways at both the transcriptional and protein level. In conclusion, we have generated ferret pluripotent stem cells that provide an opportunity for advancing our capacity to evaluate autologous cell engraftment in ferrets.

Classical interpretation of cystic fibrosis (CF) lung disease pathogenesis suggests that infection initiates disease progression, leading to an exuberant inflammatory response, excessive mucus, and ultimately bronchiectasis. Although symptomatic antibiotic treatment controls lung infections early in disease, lifelong bacterial residence typically ensues. Processes that control the establishment of persistent bacteria in the CF lung, and the contribution of noninfectious components to disease pathogenesis, are poorly understood.To evaluate whether continuous antibiotic therapy protects the CF lung from disease using a ferret model that rapidly acquires lethal bacterial lung infections in the absence of antibiotics.CFTR (cystic fibrosis transmembrane conductance regulator)-knockout ferrets were treated with three antibiotics from birth to several years of age and lung disease was followed by quantitative computed tomography, BAL, and histopathology. Lung disease was compared with CFTR-knockout ferrets treated symptomatically with antibiotics.Bronchiectasis was quantified from computed tomography images. BAL was evaluated for cellular differential and features of inflammatory cellular activation, bacteria, fungi, and quantitative proteomics. Semiquantitative histopathology was compared across experimental groups. We demonstrate that lifelong antibiotics can protect the CF ferret lung from infections for several years. Surprisingly, CF animals still developed hallmarks of structural bronchiectasis, neutrophil-mediated inflammation, and mucus accumulation, despite the lack of infection. Quantitative proteomics of BAL from CF and non-CF pairs demonstrated a mucoinflammatory signature in the CF lung dominated by Muc5B and neutrophil chemoattractants and products.These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.

Rationale: Obliterative bronchiolitis (OB) is a major cause of mortality after lung transplantation. Depletion of airway stem cells (SCs) may lead to fibrosis in OB. Objectives: Two major SC compartments in airways are submucosal glands (SMGs) and surface airway p63 (also known as TP63 [tumor protein 63])-positive/K5 (also known as KRT5 [keratin 5])-positive basal cells (BCs). We hypothesized that depletion of these SC compartments occurs in OB. Methods: Ferret orthotopic left lung transplants were used as an experimental model of OB, and findings were corroborated in human lung allografts. Morphometric analysis was performed in ferret and human lungs to evaluate the abundance of SMGs and changes in the expression of phenotypic BC markers in control, lymphocytic bronchiolitis, and OB airways. The abundance and proliferative capacity of proximal and distal airway SCs was assessed using a clonogenic colony-forming efficiency assay. Measurements and Main Results: Ferret allografts revealed significant loss of SMGs with development of OB. A progressive decline in p63(+)/K5(+) and increase in K5(+)/K14(+) and K14(+) BC phenotypes correlated with the severity of allograft rejection in large and small ferret airways. The abundance and proliferative capacity of basal SCs in large allograft airways declined with severity of OB, and there was complete ablation of basal SCs in distal OB airways. Human allografts mirrored phenotypic BC changes observed in the ferret model. Conclusions: SMGs and basal SC compartments are depleted in large and/or small airways of lung allografts, and basal SC proliferative capacity declines with progression of disease and phenotypic changes. Global airway SC depletion may be a mechanism for pulmonary allograft failure.

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT1aR−/−), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT1aR−/− vs. AT1aR+/+ mice. ICV leptin in rats increased AT1aR and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT1aR mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.

Background Pulseless electrical activity is an important cause of cardiac arrest. Our purpose was to determine if induction of hypothermia with a cold perfluorocarbon-based total liquid ventilation (TLV) system would improve resuscitation success in a swine model of asphyxial cardiac arrest/PEA. Methods Twenty swine were randomly assigned to control (C, no ventilation, n =11) or TLV with pre-cooled PFC ( n =9) groups. Asphyxia was induced by insertion of a stopper into the endotracheal tube, and continued in both groups until loss of aortic pulsations (LOAP) was reached, defined as a pulse pressure less than 2mmHg. The TLV animals underwent asphyxial arrest for an additional 2min after LOAP, followed by 3min of hypothermia, prior to starting CPR. The C animals underwent 5min of asphyxia beyond LOAP. Both groups then underwent CPR for at least 10min. The endpoint was the resumption of spontaneous circulation maintained for 10min. Results Seven of 9 animals achieved resumption of spontaneous circulation (ROSC) in the TLV group vs. 5 of 11 in the C group ( p =0.2). The mean pulmonary arterial temperature was lower in total liquid ventilation animals starting 4min after induction of hypothermia (TLV 36.3±0.2°C vs. C 38.1±0.2°C, p p O 2 was higher in total liquid ventilation animals at 2.5min of CPR (TLV 76±12mmHg vs. C 44±2mmHg; p =0.03). Conclusion Induction of moderate hypothermia using perfluorocarbon-based total liquid ventilation did not improve ROSC success in this model of asphyxial cardiac arrest.

Recent financial scandals have raised the awareness that accountants should be alert to potential fraud and other economic disputes and can provide significant assistance in preventing, investigating, and resolving such matters. Forensic accountants provide these services with knowledge of court requirements and proceedings so that effective legal action is possible, even though most actions are concluded without the involvement of the courts. Although forensic accounting was growing in importance even before Enron and the Sarbanes-Oxley Act, the ensuing tightening of the securities regulations in both Canada and the United States triggered recognition that accounting students and professionals need a fuller understanding of fraud and other economic crimes, and how to find, prevent, and resolve them, as well as the career choices that could be involved. While some of this material is covered in auditing texts and courses, emerging expectations will require the enhancement and restructuring of forensic accounting education within university programs, and will encourage more interest in graduate specialist professional designations. This paper has two objectives: to offer insights into the design and delivery of forensic accounting programs, and into the availability of professional programs; and to provide some exploratory evidence on the type of services currently rendered by investigative and forensic accountants in Canada.

Routine analytical means to estimate Campylobacter numbers per milliliter of carcass rinses are needed in high-sample-throughput poultry laboratories. We compared three serological confirmatory tests that were amenable to such a setting when used in conjunction with Campy-Line and Campy-Cefex Campylobacter selective agars. Pre- and post-chlorinated chiller carcass rinse samples were obtained and held on ice, then analyzed 24 h later in two separate laboratories. Presumptive counts on both pre- and postchiller samples from between laboratories on individual agars and between both agars were highly correlated. Agreement among the three serological tests was nearly complete. The use of a premeasured and dried latex anti-Campylobacter antibody agglutination test format was superior to that of either a liquid latex agglutination format or a direct phosphate-buffer microscopic technique in terms of practicality as was the inclusion of an unarmed latex control to detect auto agglutination. A routine procedure for Campylobacter level estimation was suggested. This procedure, when used in conjunction with a serological confirmatory step, should provide processors with a means to assess reductions in numbers per milliliter of carcass rinses versus strictly presence-absence testing.

This paper reviews the experience of 174 of Canada's largest 1500 public and private sector corporations which have begun to incorporate sustainable development management and reporting as part of their operations. Answers are provided to three main questions: Why have they implemented this initiative? What progress has been made in terms of sustainability audit practice – frequency, focus, organization of the audit team –, internal communication, and external reporting? And where has, and will the leadership for the sustainability audit movement come from as why? Sustainable development auditing and reporting in Canada is voluntary. Practice varies from an elementary level to a sophisticated integrated assessment of social, environmental, labour, sourcing and trading, and governance issues. The depth of practice and experience in this area depends on several factors, including: corporate commitment, the degree of public perception of sector-wide environmental issues, exposure to legal liability, and the extent of dialogue and transparency associated with the auditing process. Differences of opinion about accounting and auditing standards as well as whether all, or parts of, audits should be independent are explored. The sources of data used for this paper include the EthicScan Corporate 1500 DataBase, The Corporate Ethics Monitor, various reports prepared by EthicScan Canada, and the consultancies of both authors.

Objective: Studies have suggested that collateral vessels of the coronary and hind-limb circulations are more sensitive to activation of ATP-sensitive K+ channels than are non-collateral vessels. The objective of the present study was to compare responses of microvascular non-collaterals, native collaterals and stimulated collaterals in the heart to three vasodilators which act through different mechanisms: activation of ATP-sensitive K+ channels with aprikalim, release of nitric oxide with acetylcholine, and endothelium-independent activation of soluble guanylate cyclase with nitroglycerin. Methods: Collateral growth was stimulated by placing an Ameroid occluder on the proximal left circumflex artery in dogs. Non-collaterals, native collaterals and stimulated collaterals (100–220 μm in diameter) were isolated, cannulated on micropipettes and pressurized in vitro. Vessel diameters were measured using videomicroscopy. Results: Dilation to aprikalim (10−8–10−5 M), acetylcholine (10−9–10−6 M) and nitroglycerin (10−8–3×10−4 M) were similar in non-collateral, native collateral and stimulated collaterals. Dilation of native collaterals to aprikalim and acetylcholine was attenuated by glibenclamide (10 μM), an inhibitor of ATP-sensitive K+ channels, but not by tetraethylammonium (1 mM), a non-selective inhibitor of K+ channels. Dilation of native collaterals to acetylcholine but not aprikalim was also inhibited by nitro-l-arginine (10 μM), an inhibitor of nitric oxide synthase. Conclusion: These findings suggest that microvascular native and stimulated collaterals respond to activation of ATP-sensitive K+ channels and acetylcholine similar to non-collaterals of similar size. Thus, changes in reactivity of collaterals to activation of ATP-sensitive K + channels are not related to changes in the ability of the vessels to respond to vasodilators but may primarily be determined by a change in the distribution of collateral vessel size.

This article examines the pressures and players that have shaped business ethics in Canadian corporations, and reports on the status of Canadian corporate social performance in 1995. Business in Canada has not been subject, up to 1996, to a powerful national institutional framework such as the US Securities and Exchange Commission and the Foreign Corrupt Practices Act. Consequently, business ethics in Canada have developed primarily in response to broader socio-political and socio-economic factors than in the US, and will probably continue to do so. Interestingly, the issues, policies and practices developed in Canada may provide insights for US corporations as they respond to broadened pressures. Business ethics in Canada, on the other hand, will benefit increasingly from the US experience as pressures grow for national regulation and statutes governing corruption.

The hypothesis that coronary microvascular responses to ischemia are impaired in diabetes was tested in 9 alloxan-treated (60 mg/kg i.v.), 8 hyperglycemic, and 16 control dogs. Arteriolar diameters were measured in intact beating left ventricle by use of stroboscopic epi-illumination and intravital microscopy with fluorescence microangiography. Coronary arterial diameters were measured during graded reductions in mean coronary perfusion pressure to 60 +/- 1 (SE) mmHg (mild stenosis), 39 +/- 1 mmHg (severe stenosis), and 26 +/- 1 mmHg (coronary artery occlusion). Blood glucose levels were 95 +/- 5, 264 +/- 17, and 277 +/- 15 mg/dl in control, diabetic, and hyperglycemic animals, respectively. In control dogs, arteriolar microvessels (< 100 microns) dilated (24 +/- 5, 31 +/- 5, and 26 +/- 6% change in diameter from baseline during mild stenosis, severe stenosis, and coronary occlusion, respectively). Diabetes or hyperglycemia prevented the normal dilatory response and resulted in decreases in microvascular diameter during decreases in perfusion pressure (-2 +/- 3, -4 +/- 3, and -15 +/- 4% change in diameter in diabetic animals and -11 +/- 2, -9 +/- 4, and -8 +/- 5% change in diameter in hyperglycemic animals). Large-vessel (> 100 microns) dilation was also significantly impaired in diabetic and hyperglycemic animals. Myocardial perfusion was significantly lower in the epicardium during a severe stenosis in diabetic and hyperglycemic than in control dogs. Because the ATP-sensitive K+ (KATP) channel mediates this response in normal animals, we tested the hypothesis that KATP channel responsiveness is impaired in diabetes and hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid intra-arrest induction of hypothermia using total liquid ventilation (TLV) with cold perfluorocarbons improves resuscitation outcome from ventricular fibrillation (VF). Cold saline intravenous infusion during cardiopulmonary resuscitation (CPR) is a simpler method of inducing hypothermia. We compared these 2 methods of rapid hypothermia induction for cardiac resuscitation.Three groups of swine were studied: cold preoxygenated TLV (TLV, n=8), cold intravenous saline infusion (S, n=8), and control (C, n=8). VF was electrically induced. Beginning at 8 min of VF, TLV and S animals received 3 min of cold TLV or rapid cold saline infusion. After 11 min of VF, all groups received standard air ventilation and closed chest massage. Defibrillation was attempted after 3 min of CPR (14 min of VF). The end point was resumption of spontaneous circulation (ROSC).Pulmonary arterial (PA) temperature decreased after 1 min of CPR from 37.2 degrees C to 32.2 degrees C in S and from 37.1 degrees C to 34.8 degrees C in TLV (S or TLV vs. C p0.0001). Coronary perfusion pressure (CPP) was higher in TLV than S animals during the initial 3 min of CPR. Arterial pO(2) was higher in the preoxygenated TLV animals. ROSC was achieved in 7 of 8 TLV, 2 of 8 S, and 1 of 8C (TLV vs. C, p=0.03).Moderate hypothermia was achieved rapidly during VF and CPR using both cold saline infusion and cold TLV, but ROSC was higher than control only in cold TLV animals, probably due to better CPP and pO(2). The method by which hypothermia is achieved influences ROSC.

Induced external hypothermia during ventricular fibrillation (VF) improves resuscitation outcomes. Our objectives were twofold (1) to determine if very rapid hypothermia could be achieved by intrapulmonary administration of cold perfluorocarbons (PFC), thereby using the lungs as a vehicle for targeted cardiopulmonary hypothermia, and (2) to determine if this improved resuscitation success.Part 1: Nine female swine underwent static intrapulmonary instillation of cold perfluorocarbons (PFC) during electrically induced VF. Part 2: Thirty-three female swine in VF were immediately ventilated via total liquid ventilation (TLV) with pre-oxygenated cold PFC (-15 degrees C) or warm PFC (33 degrees C), while control swine received no ventilation during VF. All swine in both Parts 1 and 2 underwent VF arrest for 11 min, then defibrillation, ventilation and closed chest massage until resumption of spontaneous circulation (ROSC). The endpoint was continued spontaneous circulation for 1h without pharmacologic support.Static intrapulmonary instillation of cold PFC achieved rapid cardiopulmonary hypothermia; pulmonary artery (PA) temperature of 33.5+/-0.2 degrees C was achieved by 10 min. Nine of 9 achieved ROSC. Hypothermia was achieved faster using TLV: at 6 min VF, cold TLV temperature was 32.9+/-0.4 degrees C vs. cold static instillation temperature 34.3+/-0.2 degrees C. Nine of 11 cold TLV swine achieved ROSC for 1h vs. 3 of 11 control swine (p=0.03). Warm PFC also appeared to be beneficial, with a trend toward greater achievement of ROSC than control (ROSC; warm PFC 8 of 11 vs. control 3 of 11, p=0.09).Targeted cardiopulmonary intra-arrest moderate hypothermia was achieved rapidly by static intrapulmonary administration of cold PFC and more rapidly by total liquid ventilation with cold PFC; resumption of spontaneous circulation was facilitated. Warm PFC showed a trend toward facilitating ROSC.

Previous in vivo studies have shown that vasopressin, which releases the endothelium-derived relaxing factor and constricts coronary smooth muscle, produces augmented constriction of coronary microvessels perfused by mature collaterals. We hypothesized that chronic perfusion through collaterals produces endothelial dysfunction in the recipient vasculature. Mature collaterals were stimulated in mongrel dogs by the ameroid constrictor technique. After 3-6 months, rings of conduit vessels (obtuse marginals) were studied in organ chambers, and coronary microvessels (100-220 microns) were studied in a pressurized, no-flow state with a microvessel imaging apparatus. Eleven dogs were used as controls. Large vessels were preconstricted with prostaglandin F2 alpha to 30-70% of the maximum potassium chloride tension, and microvessels were preconstricted to 20-60% of the baseline diameter with the thromboxane mimetic U46619. Relaxations to the receptor-mediated agents acetylcholine and ADP were markedly impaired in collateral-dependent coronary microvessels, whereas relaxations to nitroglycerin were enhanced compared with microvessels from control dogs. Relaxation to the calcium ionophore A23187, which releases the endothelium-derived relaxing factor through nonreceptor-mediated mechanisms, were similar in control and ameroid microvessels. Constriction to vasopressin was augmented in collateral-dependent microvessels compared with controls. Responses to all agonists were similar between control and collateral-dependent large vascular rings. In conclusion, chronic perfusion through collateral vessels selectively impairs receptor-mediated endothelium-dependent relaxations and augments constriction to vasopressin in the coronary microcirculation. These findings may have important implications regarding neurohumoral regulation of perfusion to collateral-dependent myocardium.

Background: Depolarization of myocytes requires less energy when electrical current flows along the longitudinal axis compared to the transverse axis of myocytes. Since ventricular fibrillation (VF) amplitude in ECG leads reflects the functional electrical orientation of the majority of myocytes, we hypothesized that a defibrillation shock would be more effective if the shock vector was oriented along the functional electrical axis of the majority of myocytes, and this axis could be determined in real time from the relative amplitudes of the VF signal measured in three orthogonal ECG leads. Methods: In closed-chest, anesthetized, swine (22.0 ± SE0.8 kg, n=9), a new directional defibrillation device was used to simultaneously measure the VF amplitude through three orthogonal pairs of defibrillation electrodes: anterior-posterior, lateral-lateral, and superior-inferior. VF was electrically induced and persisted for 15 seconds. During defibrillation, the device identified the electrode pair that measured the largest or smallest peak amplitudes (+ or −) within the previous 100msec through which to deliver the shock. Defibrillation success for the electrodes measuring the largest or smallest VF amplitude was evaluated by delivering four 50J shocks for VF through each of these electrode pairs (in random order). The electrode pair measuring the largest VF signal amplitude was considered to be most closely aligned with the functional VF vector. Results: Fifty J shocks (n=37) delivered through the electrode pair measuring the largest VF signal amplitude had higher defibrillation success than 50J shocks (n=37) delivered through the electrodes measuring the smallest VF signal amplitude (62 ± 10% vs.19 ± 8%, p Conclusions: By using a directional defibrillation device which instantaneously measures the peak VF signal amplitude in three pairs of orthogonally oriented defibrillation electrodes, it is feasible to determine which set of electrodes is oriented more favorably to the functional VF vector and to direct the shock through that set of electrodes. Matching the defibrillation vector to the fibrillation vector improves shock success.

Previous studies showed that nitric oxide (NO) plays an important role in coronary arteriolar dilation to increases in myocardial oxygen consumption (MV˙o 2). We sought to evaluate coronary microvascular responses to endothelium-dependent and to endothelium-independent vasodilators in an in vivo model. Microvascular diameters were measured using intravital microscopy in 10 normal (N) and 9 hyperglycemic (HG; 1 wk alloxan, 60 mg/kg iv) dogs during suffusion of acetylcholine (1, 10, and 100 μM) or nitroprusside (1, 10, and 100 μM) to test the effects on endothelium-dependent and -independent dilation. During administration of acetylcholine, coronary arteriolar dilation was impaired in HG, but was normal during administration of nitroprusside. To examine a physiologically important vasomotor response, 10 N and 7 HG control, 5 HG and 5 N during superoxide dismutase (SOD), and 5 HG and 4 N after SQ29,548 (SQ; thromboxane A2/prostaglandin H2receptor antagonist) dogs were studied at three levels of MV˙o 2: at rest, during dobutamine (DOB; 10 μg · kg−1 · min−1 iv), and during DOB with rapid atrial pacing (RAP; 280 ± 10 beats/min). During dobutamine, coronary arterioles dilated similarly in all groups, and the increase in MV˙o 2 was similar among the groups. However, during the greater metabolic stimulus (DOB+RAP), coronary arterioles in N dilated (36 ± 4% change from diameter at rest) significantly more than HG (16 ± 3%, P< 0.05). In HG+SQ and in HG+SOD, coronary arterioles dilated similarly to N, and greater than HG ( P < 0.05). MV˙o 2 during DOB+RAP was similar among groups. Normal dogs treated with SOD and SQ29,548 were not different from untreated N dogs. Thus, in HG dogs, dilation of coronary arterioles is selectively impaired in response to administration of the endothelium-dependent vasodilator acetylcholine and during increases in MV˙o 2.

Previous studies have demonstrated that vascular responses to acetylcholine (ACh) are impaired in diabetes mellitus (DM). Objective: Since reactive oxygen species (ROS) generation is increased in various disease states including DM, and a direct reaction between nitric oxide (NO) and superoxide anion has been demonstrated, we tested the hypothesis that inhibition of ROS will restore coronary microvascular responses to ACh in a dog model of DM (alloxan 60 mg/kg, i.v., 1 week prior to study). Methods: Changes in coronary microvascular diameters in diabetic (blood glucose >200 mg%) and normal animals to ACh (1–100 μM, topically) in the presence and absence of superoxide dismutase and catalase were measured using intravital microscopy coupled to stroboscopic epi-illumination and jet ventilation. Results: In diabetic animals in the absence of ROS scavengers, ACh induced coronary microvascular dilation was impaired when compared to normal animals (ACh 100 μM: DM=25±5%; normal=64±13%, P

In the canine coronary microcirculation, acetylcholine (ACh)-induced vasodilation of large (or = 100 microns) epicardial arterioles (LgA), but not small (100 microns) epicardial arterioles (SmA), is blocked by nitric oxide (NO) synthase inhibitors in vivo. We hypothesized that the ACh-induced vasodilation of SmA is mediated by a cytochrome P-450 metabolite of arachidonic acid (AA). Epicardial coronary microvascular diameters in dogs were measured at baseline and after treatment with topically applied ACh (1, 10, and 100 microM), AA (1, 5, and 10 microM), or sodium nitroprusside (SNP; 10-100 microM). Coronary microvascular diameters were compared among control dogs (group OO); dogs pretreated with N omega-nitro-L-arginine (L-NNA; 70 microM topically) (group NO); dogs pretreated with L-NNA plus clotrimazole (Clo; 1.6 microM topically) or 17-octadecynoic acid (ODYA; 2 microM topically), cytochrome P-450 monooxygenase inhibitors (groups NC and NY, respectively); dogs pretreated with Clo alone (group OC); and dogs pretreated with L-NNA plus Clo with AA as the agonist (group AA). ACh-induced vasodilation of LgA was abolished by L-NNA alone, whereas in SmA, L-NNA was without effect. Clo alone did not inhibit ACh-induced dilation in either SmA or LgA. However, the combinations of L-NNA plus either Clo or ODYA abolished ACh- and AA-induced dilation of SmA (100 microM ACh: NC, 3 +/- 5%; NY, 8 +/- 2%; 10 microM AA: 6 +/- 3%) but did not affect responses to SNP. These results suggest that the ACh-induced vasodilation of SmA is mediated in part by cytochrome P-450 metabolites of AA and provide the first evidence that the cytochrome P-450 pathway contributes to the regulation of coronary resistance vessels in vivo.

Previous studies from our laboratory have shown that coronary microvascular dilation to increased myocardial oxygen consumption (MVO2) is greater in vessels

Thromboxane has been shown to contribute to coronary constriction in conduit coronary arteries during platelet aggregation at the site of a critical stenosis. Previous studies from our laboratory suggest that following a critical coronary stenosis, persistent vasomotor tone occurs. We tested the hypothesis that thromboxane is responsible for that increased tone.To test this hypothesis, 14 mongrel dogs of either sex were anesthetized and subjected to a critical coronary stenosis where distal coronary perfusion pressure was reduced to 36 +/- 2 mm Hg. During the coronary stenosis, SQ 29,548 (thromboxane/endoperoxide receptor antagonist) was administered intravenously (0.2 mg/kg and 2.0 mg/kg). Coronary microvascular responses were observed by directly visualizing the epicardial microcirculation. Diameters were measured using intravital microscopy coupled to stroboscopic epi-illumination and jet ventilation to compensate for cardiac and respiratory-induced motion.Coronary microvessels were divided into small (150 microns) and large (150 microns) arterioles. During SQ 29,548 administration, small coronary arterioles demonstrated no additional dilation during a critical coronary stenosis. In contrast, coronary microvessels150 microns demonstrated a dose-dependent vasodilation to SQ 29,548 (0.2 mg/kg: 6 +/- 2%; 2.0 mg/kg: 11 +/- 4%; P0.05 vs. no change). A time control study in six additional animals demonstrated no significant microvascular diameter changes following a critical stenosis over the time course of SQ 29,548 administration.Endoperoxides contribute to poststenotic microvascular vasoconstriction in vessels 150-300 microns.

We examined the effects of ischemia with and without reperfusion on endothelium-dependent and -independent vascular relaxation in both conduit and resistance coronary arteries. Studies were performed on dogs under control conditions (n = 13) or after 1 hour of circumflex coronary artery occlusion with (n = 10) or without (n = 8) 1 hour of reperfusion. Rings of obtuse marginal branches of the left circumflex coronary artery (conduit arteries) were studied in organ chambers. Coronary microvessels (110-220-microns diameter) were studied in a pressurized state with an in vitro microvessel imaging apparatus. Relaxation was evaluated after preconstriction with prostaglandin F2 alpha and U46619 (a thromboxane A2 analogue) in conduit and resistance vessels, respectively. Conduit vessel function was not altered by ischemia with or without reperfusion. Endothelium-dependent microvascular relaxation was depressed in response to acetylcholine, ADP, and calcium ionophore A23187 after ischemia with reperfusion compared with control relaxation (ED50 as -log[M]: 6.0 +/- 0.2 [p less than 0.05], 5.1 +/- 0.4 [p less than 0.05], and 5.8 +/- 0.1 versus 6.8 +/- 0.2, 6.8 +/- 0.2, and 6.6 +/- 0.2, respectively). Ischemia without reperfusion modestly altered microvascular endothelium-dependent relaxation. Microvascular relaxation to nitroglycerin was not altered by ischemia with reperfusion. We conclude that 1) endothelium-dependent relaxation in large epicardial coronary arteries is relatively refractory to ischemia with or without reperfusion, 2) ischemia alone produces mild alterations of coronary microvascular reactivity, 3) ischemia followed by reperfusion produces a marked and selective impairment of endothelium-dependent responses in the coronary microcirculation.

Current trends toward increased pace, more complex substance and lower tolerance of error have caused the financial marketplace to rely more heavily on the integrity of financial data and, therefore, of those who prepare the financial statements. At the same time, these trends place higher challenges before professional accountants and it is essential that they have excellent ethical guidance to live up to modern expectations. However, in view of the current codes of conduct, an accountant may not have a clear understanding of what priority of interests to satisfy, who can be consulted for advice, to whom to report misdeeds, what protection is offered a ‘right-doer’ and what sanction will be forthcoming for ‘doing wrong’. Possible solutions are offered to these problems in ways that ought to strengthen the accounting profession and prevent unscrupulous companies from taking advantage of both members of the profession and the unsuspecting public. To provide the appropriate quality of service to society in the future, the Canadian accounting profession should offer its members the improved guidance and enhanced mechanisms for confidential consultation, assistance and protection outlined herein.

The majority of North American corporations awakened to the need for their own ethical guidelines during the late 1970s and early 1980s, even though modern corporations are subject to a surprising multiplicity of external codes of ethics or conduct. This paper provides an understanding of both internal and external codes through a discussion of the factors behind the development of the codes, an analysis of internal codes and an identification of problems with them.

Executives, professionals, educators and labour leaders are requesting an update on corporate ethical trends. This article presents an examination of why the interest in corporate ethics is growing both in society and in corporations. An analysis follows of how corporations are responding to this interest, and of how that response might be enhanced through improved second-generation codes of ethical performance.

Coronary vascular responses to stimulation of chemoreceptors were studied in anesthetized, artificially ventilated dogs. The circumflex coronary artery was perfused at constant flow so that changes in perfusion pressure reflected changes in coronary resistance. Practolol, a myocardioselective beta-receptor antagonist, and pacing were used to minimize indirect effects of myocardial responses on coronary resistance. Carotid and aortic injections of nicotine produced decreases in coronary perfusion pressure averaging -21 mm Hg and -22 mm Hg, respectively. Decreases with carotid and aortic injections of cyanide averaged -8 mm Hg and -17 mm Hg, respectively. These coronary dilator responses were abolished by bilateral vagotomy or atropine. Changes in perfusion pressure with carotid injections of nicotine averaged +3 mm Hg after vagotomy and +2 mm Hg after administration of atropine. The coronary dilator responses to carotid chemoreceptor stimulation were accompanied by increases in coronary sinus Po 2 in five studies and no change in two studies. Carotid sinus nerve stimulation caused abrupt and sustained coronary vasodilatation. After vagotomy or administration of atropine, the response to carotid sinus nerve stimulation was no longer abrupt but occurred gradually, suggesting that a component of the reflex response was blocked. These studies indicate that stimulation of chemoreceptors activates a vagal cholinergic vasodilator pathway to coronary vessels in the dog. Activation of this pathway appears also to contribute to reflex coronary responses to stimulation of baroreceptors.

These studies were performed to test the hypothesis that left ventricular hypertrophy arising as a complication of chronic hypertension is associated with impaired coronary autoregulation. Twelve dogs with hypertension and left ventricular hypertrophy (one-kidney, one-clip model) and 11 normal dogs were instrumented and subsequently studied while conscious. Circumflex pressure, measured with an intracoronary catheter, was adjusted to 100, 75, and 40 mm Hg with a hydraulic occluder that was placed proximally. At each circumflex pressure, myocardial perfusion was measured with radioactive microspheres. Reduction of circumflex pressure over this range did not significantly alter heart rate, left atrial pressure, or arterial pressure. In normal dogs, reduction of circumflex pressure did not alter total myocardial perfusion or the transmural distribution of perfusion. In contrast, in dogs with hypertension and left ventricular hypertrophy, circumflex subendocardial perfusion decreased 46% when pressure was decreased from 100 to 40 mm Hg (p less than .05 compared with normal). Autoregulation was quantified for each third of myocardium with the use of autoregulatory gain values (1 = perfect autoregulation; 0 = the absence of autoregulation). For pressure changes of 100 to 75 mmHg, values for autoregulatory gain were near unity for all layers of myocardium in both groups of animals. When pressure was decreased from 75 to 40 mm Hg, values for autoregulatory gain among the normal and hypertensive groups were, respectively: for subepicardium 1 +/- 0.2 (mean +/- SE) vs 0.9 +/- 0.2 (p = NS), for the midwall 0.8 +/- 0.2 vs 0.5 +/- 0.2 (p = NS), and for the subendocardium 0.8 +/- 0.1 vs 0.1 +/- 0.2 (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)