Computational estimation of fluid mechanical benefits from a fluid deflector at the distal end of artificial vascular grafts.

Intimal hyperplasia at the distal anastomosis is considered to be an important determinant for arterial and arteriovenous graft failure. The connection between unhealthy hemodynamics and intimal hyperplasia motivates the use of computational fluid dynamics modeling to search for improved graft design. However, studies on the fluid mechanical impact on intimal hyperplasia at the suture line intrusion have previously been scanty. In the present work, we focus on intimal hyperplasia at the suture line and illustrate potential benefits from the introduction of a fluid deflector to shield the suture line from unhealthily high wall shear stress.

Differential early mitogen-activated protein kinase activation in hyperglycemic ischemic brain injury in the rat.

BACKGROUND: Hyperglycemia aggravates brain injury induced by focal ischemia-reperfusion. The mitogen-activated protein kinase (MAPK) members extracellular-signal regulated kinase (Erk) and c-Jun N-terminal kinase (JNK) have been proposed as mediators of ischemic brain injury, and Erk is strongly activated by combined hyperglycemia and transient global ischemia. It is unclear whether similar MAPK activation appears in focal brain ischemia with concomitant hyperglycemia. DESIGN: Hyperglycemia was induced in rats by an intraperitoneal bolus of glucose (2 g kg(-1)). The rats were then subjected to 90 min of transient middle cerebral artery occlusion (MCAO). Erk and JNK activation were investigated with immunofluorescence and Western blot along with infarct size measurement based on tetrazolium staining and neurological score. RESULTS: The hyperglycemic rats showed increased tissue damage and impaired neurological performance after 1 day compared with controls. The hyperglycemia was generally moderate (< 15 mM). Erk activation was increased after 30 min of reperfusion in the ischemic cortex of the hyperglycemic rats, while JNK activation was present on the contralateral side. Phospho-Erk immunofluorescence revealed marked neuronal activation of Erk in the ischemic cortex of hyperglycemic rats compared with controls. CONCLUSION: Besides confirming the detrimental effects of hyperglycemia on focal ischemia-reperfusion, this study shows that hyperglycemia strongly activates the pathogenic mediator Erk in the ischemic brain in the early phase of reperfusion. JNK activation at this stage is present in the nonischemic hemisphere. The functional relevance of these findings needs further investigation.

Theoretical local freezing times of small rodent brains submerged in situ in liquid nitrogen.

In situ freezing is a standard procedure, typically applied in neuroscience, to stop post-mortem metabolism and diffusion. However, the concentration of a compound under study may well change before the tissue is completely frozen. Knowing the approximate local freezing time should make it possible to control this problem. A mathematical model of in situ freezing in liquid nitrogen has recently been introduced, and freezing times derived from this model are presented here. The hope is that this information will be considered useful when in situ freezing of small rodent brains is applied.

Effects of hyperglycemia on small cerebral infarctions in awake rabbits.

This study concerns the effects of hyperglycemia on small infarctions in the rabbit brain. Small ischemic foci were produced in both normoglycemic (6 mM) and hyperglycemic (25 mM) rabbits, by injecting small plastic beads into the left heart ventricle under short-acting anaesthesia. 2-deoxy-D-[14C]glucose (2-DG) autoradiography was used to trace ischemic regions in which glucose uptake was increased, either shortly after, or six hours after, the embolization (in awake rabbits). A lesion was characterized by a 2-DG activity > 120%. The obtained freeze-dried sections were inspected for infarcts (with lost tissue structure and increased transparency to light). In the short experiments (< 1 hour), lesions could be detected throughout the brains, indicating hypoxic regions with enhanced glycolysis. In some foci, mostly located in the basal ganglia (the region containing the largest lesions), a central dip could be seen in the 2-DG accumulation, suggesting a poor glucose supply to the ischemic core. The lesions in the basal ganglia of rabbits that were made hyperglycemic were smaller and did not show such dips. No infarcts could be found in the tissue sections. In the long experiments (6 hours), both infarcts and lesions could be found. The impact of hyperglycemia on the infarction process in different brain regions was evaluated by measuring the infarct volumes, and by evaluating the fraction of infarcts--number of infarcts found in freeze-dried sections/number of foci (both lesions and infarcts) found in the 2-DG autoradiograms. Hyperglycemia reduced the fraction of infarcts in the cortex, and reduced the size of infarcted areas in the brain stem. In summary, this study shows that the impact of hyperglycemia on the ischemic outcome depends on where in the brain the ischemic focus is located. This adds interesting information as to what is known about the general effects of glucose on cerebral ischemia.

N-tert-butyl-alpha-phenylnitrone reduces the number of microinfarctions in the rabbit brain cortex.

Dementia due to cerebral ischemic lesions is relatively common in the elderly. Since many of these lesions are probably caused by emboli, studying emboli-induced cerebral lesions in rabbits should, hopefully, provide information that is useful when searching for a means of preventing and treating vascular dementia in humans. Using magnetic resonance imaging we have found that N-tert-butyl-alpha-phenyl-nitrone (a free radical scavenger) reduced the number of emboli-induced cerebral microinfarctions in the rabbit cortex but did not have any impact on the number of infarctions found in the subcortical structures. The results suggest that significant amount of free radicals are produced in the ischemic foci located in the cortex, but not in the ischemic foci located in the subcortical structures. This finding may be of importance when considering treatments for cerebral ischemia in humans.

A qualitative study on changes in local brain pH due to discrete cerebral microembolism.

In this work autoradiography of 14C-5,5-dimethyl-2,4-oxazolidinedione (14C-DMO) was used to trace changes in local cerebral pH in embolized awake rabbits. One hour after i.v. injection of 14C-DMO small cerebral ischemic foci were produced in rabbits by injecting plastic beads into the left heart ventricle under short-acting anaesthesia, and after another hour the animals were put to death and their brains processed for autoradiography of 14C-DMO. Evidence of acidosis was in general not found in the microischemic regions, though there were a few possible exceptions. However in the hippocampus a diffuse acidosis involving a large part of the structure, could be found in 2 of the 4 experiments. This hippocampal phenomenon probably reflected the same process as has been observed using autoradiography of 2-deoxyglucose (reflecting cellular glucose uptake) on the same ischemic model increased 2-deoxyglucose phosphorylation. Because the hippocampus is involved in the memory function and the fact that small infarcts are coupled to dementia, this phenomenon should be drawn into focus for further studies.

A mathematical model of in situ freezing in liquid nitrogen.

In situ freezing is a procedure, typically applied in neuroscience, to halt metabolism and diffusion. However, the freezing process is not instantaneous, and the regional concentrations of a compound under study may change before the tissue is completely frozen. Knowing the local freezing time, metabolic rate and the diffusion coefficient of the compound of interest, it should be possible to reconstruct the spatial concentration profile prevailing before the object was placed in the cryogen. A mathematical model for calculating the temperature changes at different depths in rabbit and rat heads cooled in liquid nitrogen has been developed. By comparing with experimental results it has been found that the mathematical model can be used for prediction of the local freezing time with a small error.

Effects of microemboli on local blood flow in the rabbit brain.

This work describes changes in relative blood flow caused by discrete emboli reaching the brain of conscious rabbits. With [14C]iodoantipyrine autoradiography, small ischemic foci were observed scattered throughout the brain. After correction for tracer diffusion from the surroundings, the ischemic regions located in the deeper parts of the brain were found to have a lower blood flow than the foci in the cortex. Further, the cortical foci were significantly smaller than those in the basal ganglia (the area where the average size of the foci was found to be largest). The results and conclusions of this work should aid in interpretation of future experiments with potential treatments. Microinfarctions may well need different treatments depending on their localization.

In situ freezing of the rabbit and rat brain.

We have measured the effectiveness of different standard cryogenic liquids (liquid nitrogen, chilled isopentane, chilled hexane, and chilled ethanol) and applied a mathematical model for calculating the temperature changes at different depths in rabbit and rat heads cooled in liquid nitrogen. We have also evaluated the extent to which the freezing time is shortened when the skin is removed prior to immersion. We conclude that: (i) of the coolants used, liquid nitrogen gives the most rapid freezing. (ii) dry ice-chilled ethanol is as effective as dry ice-chilled hexane. Liquid nitrogen and ethanol are safer for the environment than isopentane and hexane and should satisfy most needs. (iii) By removing the skin prior to immersion, the freezing time can be reduced by about 20 s for the rabbit cortex and rat hypothalamus, 30 s for the rat cortex, and 40 s for the rabbit hypothalamus.

A diffusion model of cerebral microischemia.

We have recently published an experimental method useful for causing discrete cerebral microischemic foci in rabbits. In that study it was shown that on reaching the brain, plastic beads (with an average diameter of 80 or 110 microns) give rise to foci of increased [14C]2-deoxyglucose accumulation, indicating anaerobic glycolysis. Further, it was suggested that the relatively low accumulation of [14C]2-deoxyglucose, as observed in the center of some of the ischemic foci located in areas which are thought to have a poor collateral blood supply, was an indication of glucose depletion. This work is intended to be a useful approach for the study of diffusion-limited consumption of glucose and oxygen in microischemic regions, located in endarterial regions. It is shown that a mathematical model with reasonable parameters can be fitted to a measured [14C]2-deoxyglucose profile. The results of this study are compatible with the view that the glucose concentration in the ischemic center is very low and limits the rate of energy turnover. Together with animal experiments, this mathematical model may impart new information of importance for evaluating the treatment of subcortical infarctions in humans.

Magnetic resonance imaging of experimental microinfarctions in the rabbit brain.

Small hyperintense lesions are frequently found with T2-weighted magnetic resonance imaging (MRI) of the human brain. A significant number of these lesions are probably infarctions. Because there is often a long delay between the microischemic impact and the autopsy, if any, and as the specificity of the MRI is low for detecting ischemic lesions, it is difficult to draw conclusions about the clinicotopographic correlations. This work concerns the usefulness of MRI in detecting experimental microischemic lesions in the rabbit brain about 24 h after the impact. It seems that the sensitivity of T2-weighted MRI in detecting foci of damaged areas in the rabbit brain is good enough to make it useful for evaluating tissue damage when screening for potential neuroprotective drugs and that the experimental model should be useful for developing diagnostically valuable MRI techniques.

An experimental model of cerebral microischemia in rabbits.

Multiinfarct dementia is the second most common form of dementia in the elderly. An animal model of microischemia may provide information about the pathophysiology relevant when searching for prevention or treatment of microinfarctions in humans. The purpose of the present study was to develop an experimental model useful for studying discrete microischemic foci. In order to achieve single cerebral microischemic foci plastic beads with diameters of about 100 microns were injected into the left heart ventricle of anesthetized rabbits. 2-Deoxy-[14C]glucose (2-DG) and autoradiography were used to detect regions with disturbed metabolism. The tissue sections were inspected for impacted beads. Foci with markedly increased 2-DG accumulation and with diameters of about 1 mm were detected in all parts of the brain, indicating hypoxic regions with enhanced glycolysis. In some foci, located mainly in the basal ganglia, a central dip in the 2-DG profile was seen, suggesting poor glucose supply to the central ischemic region. The ratio foci/beads was about 1 in the brain stem (diencephalon included) and about 0.5 in the cortex. Twenty-four hours after embolization, infarctions, mainly in the deeper brain regions, were seen. There were still foci with increased 2-DG uptake, which were mainly located in the cortex. The results suggest that microemboli reaching the deeper brain regions give rise to metabolic disturbances more often than emboli reaching the cortex and that the ischemic foci in deeper brain regions are more prone to develop further into infarctions.