Robust, defensible, and fair: The AMEE guide to selection into medical school: AMEE Guide No. 153.

Selection is the first assessment of medical education and training. Medical schools must select from a pool of academically successful applicants and ensure that the way in which they choose future clinicians is robust, defensible, fair to all who apply and cost-effective. However, there is no comprehensive and evidence-informed guide to help those tasked with setting up or rejuvenating their local selection process. To address this gap, our guide draws on the latest research, international case studies and consideration of common dilemmas to provide practical guidance for designing, implementing and evaluating an effective medical school selection system. We draw on a model from the field of instructional design to frame the many different activities involved in doing so: the ADDIE model. ADDIE provides a systematic framework of Analysis (of the outcomes to be achieved by the selection process, and the barriers and facilitators to achieving these), Design (what tools and content are needed so the goals of selection are achieved), Development (what materials and resources are needed and available), Implementation (plan [including piloting], do study and adjust) and Evaluation (quality assurance is embedded throughout but the last step involves extensive evaluation of the entire process and its outcomes).HIGHLIGHTSRobust, defensible and fair selection into medical school is essential. This guide systematically covers the processes required to achieve this, from needs analysis through design, development and implementation, to evaluation of the success of a selection process.

Advancing quality culture in health professions education: experiences and perspectives of educational leaders.

The concept of quality culture has gained increased attention in health professions education, drawing on insights that quality management processes and positive work-related attitudes of staff in synergy lead to continuous improvement. However, the directions that guide institutions from quality culture theory to educational practice have been missing so far. A prospective qualitative case study of three health professions education programmes was conducted to explore how a quality culture can be enhanced according to the experiences and perspectives of educational leaders. The data collection was structured by an appreciative inquiry approach, supported with vignette-based interviews. A total of 25 participants (a selection of course coordinators, bachelor coordinators and directors of education) reflected on quality culture themes to learn about the best of what is (Discover), envision positive future developments (Dream), identify actions to reach the desired future (Design), and determine how to support and sustain improvement actions (Destiny) within their own educational setting. The results are presented as themes subsumed under these four phases. The experiences and perspectives of educational leaders reveal that peer learning in teams and communities, attention to professional development, and embedding support- and innovation networks, are at the heart of quality culture enhancement. An emphasis on human resources, (inter)relations and contextual awareness of leaders stood out as quality culture catalysts. Educational leaders are therefore encouraged to especially fuel their networking, communication, coalition building, and reflection competencies.

Endothelial glycocalyx thickness and platelet-vessel wall interactions during atherogenesis.

The endothelial glycocalyx (EG), the luminal cover of endothelial cells, is considered to be atheroprotective. During atherogenesis, platelets adhere to the vessel wall, possibly triggered by simultaneous EG modulation. It was the objective of this study to investigate both EG thickness and platelet-vessel wall interactions during atherogenesis in the same experimental model. Intravital fluorescence microscopy was used to study platelet-vessel wall interactions in vivo in common carotid arteries and bifurcations of C57bl6/J (B6) and apolipoprotein E knock-out (ApoE-/-) mice (age 7 - 31 weeks). At the same locations, EG thickness was determined ex vivo using two-photon laser scanning microscopy. In ApoE-/- bifurcations the overall median level of adhesion was 48 platelets/mm2 (interquartile range: 16 - 80), which was significantly higher than in B6 bifurcations (0 (0 - 16), p = 0.001). This difference appeared to result from a significant age-dependent increase in ApoE-/- mice, while no such change was observed in B6 mice. At the same time, the EG in ApoE-/- bifurcations was significantly thinner than in B6 bifurcations (2.2 vs. 2.5 µm, respectively; p < 0.05). This resulted from the fact that in B6 bifurcations EG thickness increased with age (from 2.4 µm in young mice to 3.0 µm in aged ones), while in bifurcations of ApoE-/- mice this growth appeared to be absent (2.2 µm at all ages). During atherogenesis, platelet adhesion to the wall of the carotid artery bifurcation increases significantly. At the same location, EG growth with age is hampered. Therefore, glycocalyx-reinforcing strategies could possibly ameliorate atherosclerosis.

Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model.

BACKGROUND: Atherothrombosis is a major cause of cardiovascular events. However, animal models to study this process are scarce. OBJECTIVES: We describe the first murine model of acute thrombus formation upon plaque rupture to study atherothrombosis by intravital fluorescence microscopy. METHODS: Localized rupture of an atherosclerotic plaque in a carotid artery from Apoe(-/-) mice was induced in vivo using ultrasound. Rupture of the plaque and formation of localized thrombi were verified by two-photon laser scanning microscopy (TPLSM) in isolated arteries, and by immunohistochemistry. The thrombotic reaction was quantified by intravital fluorescence microscopy. RESULTS: Inspection of the ultrasound-treated plaques by histochemistry and TPLSM demonstrated local damage, collagen exposure, luminal thrombus formation as well as intra-plaque intrusion of erythrocytes and fibrin. Ultrasound treatment of healthy carotid arteries resulted in endothelial damage and limited platelet adhesion. Real-time intravital fluorescence microscopy demonstrated rapid platelet deposition on plaques and formation of a single thrombus that remained subocclusive. The thrombotic process was antagonized by thrombin inhibition, or by blocking of collagen or adenosine diphosphate receptor pathways. Multiple thrombi were formed in 70% of mice lacking CD40L. CONCLUSIONS: Targeted rupture of murine plaques results in collagen exposure and non-occlusive thrombus formation. The thrombotic process relies on platelet activation as well as on thrombin generation and coagulation, and is sensitive to established and novel antithrombotic medication. This model provides new possibilities to study atherothrombosis in vivo.

Leucocyte and platelet adhesion in different layers of the small bowel during experimental total warm ischaemia and reperfusion.

BACKGROUND: Ischaemia and reperfusion (IR) of the small bowel is involved in many clinical conditions. A key component in IR-induced tissue damage is microvascular dysfunction. The aim was to investigate the role of leucocytes and platelets in capillary flow impediment and tissue damage. METHODS: Anaesthetized rats were subjected to 30 min warm ischaemia of the small bowel, followed by 1 h reperfusion. To elucidate the influence of leucocytes on platelet adhesion, leucocyte-vessel wall interactions induced by IR were prevented by anti-platelet activating factor (PAF) or anti-intercellular adhesion molecule (ICAM)-1. Intravital videomicroscopy was performed and tissue injury was evaluated histologically. RESULTS: In submucosal venules, IR induced an increase in the median number of interacting leucocytes from 3 to 10 and 20 leucocytes per 100-microm venule segment after 10 and 60 min reperfusion respectively. Anti-PAF or anti-ICAM-1 completely attenuated this increase, resulting in an eightfold improvement in submucosal capillary flow and reduced tissue injury. Shedding of villi no longer occurred. Platelet-vessel wall interactions occurred particularly in submucosal venules, but were not affected by anti-PAF or anti-ICAM-1. CONCLUSION: Small bowel IR initiated an inflammatory and thrombotic response in the submucosal layer only. Attenuation of leucocyte adhesion improved submucosal capillary perfusion, preventing shedding of mucosal villi.

Two-photon microscopy of vital murine elastic and muscular arteries. Combined structural and functional imaging with subcellular resolution.

Understanding vascular pathologies requires insight in the structure and function, and, hence, an imaging technique combining subcellular resolution, large penetration depth, and optical sectioning. We evaluated the applicability of two-photon laser-scanning microscopy (TPLSM) in large elastic and small muscular arteries under physiological conditions. Elastic (carotid) and muscular (uterine, mesenteric) arteries of C57BL/6 mice were mounted in a perfusion chamber. TPLSM was used to assess the viability of arteries and to visualize the structural components elastin, collagen, nuclei, and endothelial glycocalyx (EG). Functionality was determined using diameter changes in response to noradrenaline and acetylcholine. Viability and functionality were maintained up to 4 h, enabling the assessment of structure-function relationships. Structural vessel wall components differed between elastic and muscular arteries: size (1.3 vs. 2.1 microm) and density (0.045 vs. 0.57 microm(-2)) of internal elastic lamina fenestrae, smooth muscle cell density (3.50 vs. 1.53 microm(-3)), number of elastic laminae (3 vs. 2), and adventitial collagen structure (tortuous vs. straight). EG in elastic arteries was 4.5 microm thick, covering 66% of the endothelial surface. TPLSM enables visualization and quantification of subcellular structures in vital and functional elastic and muscular murine arteries, allowing unraveling of structure-function relationships in healthy and diseased arteries.

Capillaries and flow redistribution play an important role in muscle blood flow reserve capacity.

Perfusion of skeletal muscle varies considerably during rest, exercise, or when arteries are occluded. The extent that a muscle can adapt to changes in flow demand is often expressed as the ratio of the highest inducible flow and control flow, the microvascular blood flow reserve capacity (MBFRC). However, perfusion of the nutritive capillaries of skeletal muscle may not only be improved by the increase in blood flow proportional to the increase in arterial flow, but also by diverting originally shunted flow towards the muscle proper. Consequently, MBFRC is not a good measure of capillary flow reserve, unless the assessed flow in both conditions is purely nutritive in nature. Therefore, in critical conditions, flow measurements in large vessels are not appropriate to assess MBFRC. In muscle, capillaries are compliant, i.e., with varying transmural pressure capillary diameter varies. During high perfusion states, when capillary transmural pressure is increased, capillary compliance results in increased capillary diameter and, hence, in reduced resistance and increased exchange surface area. This results in improved perfusion and enlarged capillary exchange surface area. In low perfusion states, capillary diameter is reduced. This augments the detrimental effects of the low perfusion status. Operative restoration of perfusion pressure not only increases the driving force for perfusion, but also leads to (passive) dilatation of the capillary bed and an extra reduction in resistance to flow, and, hence, a disproportional increase in flow.

Effects of experimental lower-limb ischaemia-reperfusion injury on the mesenteric microcirculation.

BACKGROUND: Ischaemia-reperfusion (I-R) of the leg is associated with functional and structural changes in the intestine. This study assessed whether acute hind-limb I-R in rats induced a reduction in perfusion and/or signs of an inflammatory response in the intestine. METHODS: Rats were subjected to 2 h of unilateral hind-limb ischaemia followed by 2 h of reperfusion (I-R group, n = 9) or to a sham procedure (control group, n = 9). Mesenteric microvascular diameters, red blood cell velocity, blood flow and leucocyte-vessel wall interactions during reperfusion were measured using intravital microscopy. RESULTS: Blood pressure and heart rate decreased from 30 min of reperfusion onwards in the I-R group compared with controls. From 15 min after the start of reperfusion, mesenteric arteriolar and venular red blood cell velocity and blood flow decreased by 40-50 per cent. Microvascular diameters and leucocyte-vessel wall interactions did not change. CONCLUSION: Restoration of blood flow to an acutely ischaemic hind limb led to a significant decline in the splanchnic microcirculatory blood flow. There were, however, no signs of an early inflammatory response in the gut.

The human internal thoracic artery releases more nitric oxide in response to vascular endothelial growth factor than the human saphenous vein.

OBJECTIVE: Endothelial nitric oxide inhibits smooth muscle cell proliferation, reducing the chance of vascular intimal thickening. In this study we investigated whether the superior long-term patency of the internal thoracic artery in human coronary bypass grafting compared with that of the saphenous vein could be explained by different levels of nitric oxide production. METHODS: The baseline endogenous nitric oxide production appeared to be 50% higher in the internal thoracic artery than in the saphenous vein. Previously, it was shown that vascular endothelial growth factor and the vascular endothelial growth factor receptors KDR (Flk-1) and Flt-1 are expressed in both internal thoracic arteries and saphenous veins and that vascular endothelial growth factor receptor density was higher in internal thoracic arteries than in saphenous veins. Therefore, we also investigated the influence of vascular endothelial growth factor on nitric oxide release in both the internal thoracic artery and the saphenous vein. RESULTS: Vascular endothelial growth factor augmented nitric oxide production by approximately 50% in the saphenous vein and 100% in the internal thoracic artery. As shown by means of immunohistochemistry, expression of endothelial constitutive nitric oxide synthase was similar in the internal thoracic artery and the saphenous vein, and no inducible nitric oxide synthase was expressed in any of the vascular segments. CONCLUSION: Vascular endothelial growth factor augments endothelial constitutive nitric oxide synthase-dependent nitric oxide release to a greater extent in the internal thoracic artery than in the saphenous vein. These findings may help to explain the long-term superiority of the internal thoracic artery versus the saphenous vein as a conduit for coronary artery bypass.

Microcirculatory effects of experimental acute limb ischaemia-reperfusion.

BACKGROUND: The object of this study was to develop an animal model in which changes in microvascular haemodynamics and leucocyte-vessel wall interactions due to acute limb ischaemia-reperfusion (I/R) can be measured in the skin. Furthermore, it was investigated whether these changes are related to local muscle injury. METHODS: Male Lewis rats were subjected to unilateral limb ischaemia for 1 h (n = 8) or 2 h (n = 8) by cuff inflation, or to a sham protocol (n = 6). Intravital video microscopic measurements of leucocyte-vessel wall interactions, venular diameter, red blood cell velocity and reduced velocity (which is proportional to wall shear rate) were performed in skin venules before ischaemia and at 0.5, 1, 2, 3 and 4 h after the start of reperfusion. Oedema and leucocyte infiltration of ischaemic/reperfused skeletal muscle were quantified histologically. RESULTS: In skin venules, both 1 and 2 h of ischaemia induced a significant increase in leucocyte rolling (six and five times baseline, respectively; P < 0.05) and adherence during reperfusion (eight and four times baseline; P < 0.05). No significant increase in muscular leucocyte infiltration was detected. After an initial hyperaemic response of 180 per cent of baseline values (P < 0.05), blood flow decreased to about 60 per cent after 4 h of reperfusion in skin venules of both experimental groups. I/R induced tibial muscle oedema, the severity of which depended on the ischaemic interval (wet to dry ratio: control, 4.0; 1 h, 4.5 (P not significant); 2 h, 5.8 (P < 0.05)). CONCLUSION: A non-invasive animal model was developed that enables investigation of the consequences of acute limb I/R.

Endogenous nitric oxide and prostaglandins synergistically counteract thromboembolism in arterioles but not in venules.

It has been shown that NO and prostacyclin (prostaglandin I(2)) from cultured endothelium synergistically inhibit blood platelet aggregation in vitro. However, it is unknown whether this synergism is also effective in the inhibition of thromboembolism in vivo and, if it is, whether it differs between vessel types. Therefore, the effect of endogenous NO and prostacyclin, in combination or alone, on thromboembolism was studied in an in vivo model. Thromboembolism was induced by micropipette puncture of rabbit mesenteric arterioles and venules (diameter 18 to 40 micrometer). In addition, the influence of wall shear rate was analyzed. In arterioles, the combined inhibition of NO synthase (N(G)-nitro-L-arginine [L-NA] 0.1 mmol/L; local superfusion) and of cyclooxygenase (aspirin [ASA] 100 mg/kg IV) resulted in a pronounced, significant prolongation of embolization duration (median >600 seconds) compared with control (median 153 seconds) or treatment with either L-NA (234 seconds) or ASA (314 seconds). This combined effect of L-NA+ASA was greater than the sum of the individual effects of L-NA and ASA. In contrast, in venules L-NA+ASA had no additional effect on embolization duration (209 seconds) compared with the effect of L-NA alone (230 seconds); ASA alone had no effect (122 seconds; control 72 seconds). Interestingly, only in the L-NA+ASA arterioles did embolization correlate positively with wall shear rate (r(s)=0.687; P=0.028). In conclusion, this study indicates that in arterioles, but not in venules, endogenous NO and prostaglandins synergistically counteract ongoing thromboembolism after vessel wall injury and that the combination of endogenous NO and prostaglandins appears to protect against enhancement of arteriolar thromboembolism by wall shear rate.

Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release: endothelial beta(2)-adrenergic receptor-mediated nitric oxide production.

BACKGROUND: Nebivolol is a beta(1)-selective adrenergic receptor antagonist with proposed nitric oxide (NO)-mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production. METHODS AND RESULTS: Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective beta(2)-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of beta(2)- but not beta(1)-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca(2+) concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment. CONCLUSIONS: In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial beta(2)-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca(2+)](i) and endothelial NO synthase-dependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.

Pain relief in complex regional pain syndrome due to spinal cord stimulation does not depend on vasodilation.

BACKGROUND: Spinal cord stimulation (SCS) is known to relieve pain in patients with complex regional pain syndrome (CRPS) and, in general, to cause vasodilation. The vasodilatory effect of SCS is hypothesized to be secondary to inhibition of sympathetically mediated vasoconstriction, or through antidromic impulses resulting in release of vasoactive substances. The aim of the present study was to assess whether pain relief in CRPS after SCS is, in fact, dependent on vasodilation. In addition, we tried to determine which of the potential mechanisms may cause the vasodilatory effect that is generally found after SCS. METHODS: Twenty-four of 36 patients with unilateral CRPS responded to the test of SCS. Twenty-two of these 24 responders (hand, n = 14; foot, n = 8) who had undergone previous sympathectomy were enrolled for the study. In addition, 20 control subjects (10 controls for each extremity) were studied. By means of laser Doppler flowmetry, the skin microcirculation of the patients was measured bilaterally while the SCS system was switched off and while it was activated. Control subjects (n = 20) were tested once only. The ratio of the rest flow at heart level and the dependent position was defined as the vasoconstriction index. RESULTS: Both in affected hands and feet, patients were found to have lower vasoconstriction indices (P < 0.01) as compared with controls, indicating a decreased sympathetic tone. Applying SCS did not result in any microcirculatory change as compared with baseline or the contralateral clinically unaffected side. CONCLUSIONS: The current study failed to show that SCS influences skin microcirculation in patients with CRPS and a low sympathetic tone. Therefore, we may conclude that pain relief in CRPS due to SCS is possible without vasodilation. Because sympathetic activity was greatly decreased in our patients, these results support the hypothesis that the vasodilation that is normally found with SCS is due to an inhibitory effect on sympathetically maintained vasoconstriction.

Tumor angiogenesis factors reduce leukocyte adhesion in vivo.

Leukocyte-endothelium interactions are diminished in tumors. It is reported here that, in a tumor-free in vivo model, angiogenic factors can down-regulate leukocyte adhesion to endothelium. Slow releasing pellets were loaded with either basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor (VEGF) or vehicle alone and were placed in the scrotum of mice. After 3 days, a single intrascrotal injection of 1 microg/kg IL-1beta was given 4 h before vessels of the cremaster muscle were investigated for leukocyte rolling and adhesion by means of intravital microscopy. Exposure of normal tissue to either bFGF or VEGF resulted in markedly decreased levels of cytokine-induced leukocyte adhesion. Suppression of leukocyte rolling was not observed. Instead a moderate enhancement of rolling by VEGF was found. The observed differences could not be explained by differences in fluid dynamic parameters or systemic leukocyte counts. In conclusion, evidence is presented that, in vivo, angiogenic factors significantly reduce leukocyte adhesion, the final step preceding leukocyte infiltration. This observation may explain why tumors escape from immune surveillance.

The influence of prostaglandins on leukocyte-endothelium interactions in rabbit mesenteric venules.

Contradictory results have been reported concerning the effects of prostaglandins (PGs) on leukocyte-endothelium interactions. Therefore, we investigated the in vivo effects of PGE1, PGE2, Iloprost (a stable PGI2-analogue), and also of a combination of these PGs on leukocyte rolling and FMLP-induced leukocyte adhesion in venules of rabbit mesentery. This preparation was used because of its low level of vasoactivity, eliminating hemodynamic effects on leukocyte-endothelium interactions. The mesentery was superfused with PGs or vehicle. After 30 min FMLP was added to the PG-solution for 15 min, whereupon the tissue was superfused with the PG-solution alone for another 30 min. Neither the PGs nor the cocktail influenced leukocyte rolling. During FMLP administration leukocyte adhesion increased and leukocyte rolling decreased; adhesion was highest in the presence of PGE2. The FMLP-induced decrease in leukocyte rolling was similar in all groups. After FMLP administration had been stopped the number of adherent cells almost returned to baseline and the level of leukocyte rolling increased, the baseline level being reached only in the presence of PGE2. In conclusion, these findings indicate that the effects of PGs on leukocyte-endothelium interactions are limited.

Total warm ischemia and reperfusion impairs flow in all rat gut layers but increases leukocyte-vessel wall interactions in the submucosa only.

OBJECTIVE: To study the effect of warm ischemia and reperfusion (I/R) on local perfusion and leukocyte-vessel wall interactions in vivo in all small bowel layers, and to quantify small bowel tissue injury histologically and by measuring intestinal fatty acid binding protein (I-FABP) release from the enterocytes. SUMMARY BACKGROUND DATA: Gut injury as a result of I/R plays a pivotal role in a variety of clinical conditions, such as small bowel transplantation, heart or aortic surgery, and (septic) shock. The precise mechanism behind I/R injury and the role of microvascular changes remain unclear. The influence of warm I/R of the gut on microvascular parameters in the different gut layers has not been studied before. METHODS: Anesthetized Lewis rats were either subjected to 30 minutes of ischemia and 1 hour of reperfusion or sham-treated as controls. After ligating the inferior mesenteric artery, total warm ischemia was induced by clamping the superior mesenteric artery. Intravital video microscopic measurements were obtained at intervals. Tissue injury of the small bowel and other organs was histologically evaluated afterward. In addition, plasma levels of I-FABP were determined to measure enterocyte damage. RESULTS: After ischemia, mean red blood cell velocity decreased significantly in all layers of the small bowel, but no diameter changes were observed. Leukocyte-vessel wall interactions increased in the submucosa but not in the muscle layers. Plasma levels of I-FABP significantly increased from 30 minutes of reperfusion onward. The intestinal mucosa was severely injured; no histologic damage was detected in other tissues. CONCLUSIONS: This is the first in vivo study showing that total warm ischemia of the rat gut impairs perfusion in the whole small bowel, whereas leukocyte-vessel wall interactions increase in the submucosal layer only. Therefore, the early inflammatory response to I/R seems to be limited to the submucosa. Both microvascular effects may have contributed to the severe morphologic and functional mucosal injury observed after I/R.

Effect of repetitive asphyxia on leukocyte-vessel wall interactions in the developing chick intestine.

BACKGROUND/PURPOSE: Information on leukocyte-vessel wall interactions (LVWI) during development of the immature intestine is scarce. The authors designed an experimental model for studying the microcirculation in the developing intestine of chick fetuses at days 13 (n = 12), 15 (n = 17), and 17 (n = 19) of incubation (0.6, 0.7, and 0.8 of the incubation time, respectively) using intravital microscopy. METHODS: The authors investigated whether episodes of asphyxia increase LVWI and induce tissue damage in the developing intestine. Asphyxia was induced by clamping of the chorioallantoic vein for 6 periods of 5 minutes each, with 5-minute intervals, whereas in sham groups a sham procedure was performed. Video recordings were made before as well as 10, 20, and 30 minutes after the end of the asphyxia or sham protocol. RESULTS: Baseline number of rolling leukocytes per minute significantly increased (P < .001) from 0 at 0.6 incubation to 1.5 and to 4 at 0.7 and 0.8 incubation time, respectively. At 0.6 and 0.7 incubation no adherent leukocytes were observed under baseline conditions, whereas at 0.8 incubation single leukocytes adhered to the venular wall. LVWI variably increased during the course of the experiments. Asphyxia neither enhanced LVWI nor induced histological damage in the intestine. CONCLUSIONS: These findings indicate that (1) leukocyte-vessel wall interactions mature during fetal development, and (2) repetitive episodes of asphyxia induce neither an inflammatory response nor histological tissue injury in the developing intestine from 0.6 to 0.8 incubation. The authors hypothesize that immaturity of leukocyte-vessel wall interactions, as part of the nonspecific host defense to invading bacteria, might play a role in the development of necrotizing enterocolitis in premature neonates.

Effects of surgical sympathectomy on skin blood flow in a rat model of chronic limb ischemia.

The role of lumbar sympathectomy in the treatment of limb ischemia secondary to arteriosclerosis obliterans has been controversial. Increased temperature and rubor of the skin, which usually follow sympathectomy, have generally been interpreted as indicative of improved nutritive skin blood flow. However, the existence of a (nonnutritive) thermoregulatory level of skin microcirculation makes such an extrapolation questionable. We investigated the total (mainly thermoregulatory) skin blood flow (TSBF) in the hindlimb of 15 male Lewis rats by means of laser Doppler flowmetry and the nutritive skin blood flow (NSBF) by means of capillary microscopy (red blood cell velocity). Transcutaneous oximetry was used to assess skin oxygenation (SO). Measurements were performed before and 2 and 28 days after ligation of the common iliac and iliolumbar artery. Subsequently, either a surgical resection of the sympathetic chain (L2-L6) was performed or a sham operation. Measurements were repeated 2 and 28 days later. For the group of 15 rats as a whole, TSBF (p < 0.05), NSBF (p < 0.05), and SO (p < 0.05) were found to be drastically reduced at day 2 after litigation compared to preligation values. This reduction partially recovered during the following weeks. TSBF (p < 0.05) and NSBF (p < 0.05), however were still reduced at day 28 after ligation compared to preligation values, whereas the SO at this time tended to be lower (p = 0.11). In the sympathectomy group the TSBF was found to be increased at day 2 (p < 0.05) and day 28 (p < 0.05) after sympathectomy, both compared to values obtained at day 28 after ligation. Sympathectomy did not have an effect on NSFB and SO. The sham procedure had no effect on the TSBF, NSBF, or SO. These results indicate that in case of lower limb ischemia, sympathectomy improves skin blood flow at the thermoregulatory but not the nutritive level of skin microcirculation. This may be related to the fact that the thermoregulatory vessels are mainly sympathetically controlled, whereas the nutritive capillaries are mainly controlled by local (nonneural) factors.