Analysis of haemodynamic factors involved in carotid atherosclerosis using computational fluid dynamics.

Atherosclerosis presents a massive healthcare burden in both the developing and developed world. There is mounting evidence relating to the involvement of haemodynamic factors in the pathogenesis of this process. This article aims to review the current understandings that have developed in this area, and to present a demonstrative case study obtained using state of the art computational fluid dynamics (CFD) methodology to model and analyse haemodynamic factors within the atheromatous carotid artery bifurcation.

Temporary alopecia after subarachnoid haemorrhage.

Primary endovascular intervention is increasingly the first choice of treatment for cerebral aneurysms, particularly for those with complex anatomy in the posterior circulation. However, their clinical management and follow-up continue to be predominantly in the hands of neurosurgeons. In this report, the development of alopecia following the coiling of posterior circulation aneurysms is described. The alopecia was transient and lasted for approximately 6 months, and occurred in the occipital and suboccipital regions of the scalp. This report aims to highlight this condition, which has not been previously reported in the neurosurgical literature. The potential hazards of irradiation should be borne in mind while carrying out complex endovascular procedures. The patient should be counselled and all necessary steps undertaken to limit radiation exposure.

Evaluation of cross-sectional luminal morphology in carotid atherosclerotic disease by use of spiral CT angiography.

BACKGROUND AND PURPOSE: This study sought to determine the frequency of noncircular lumens in patients with significant carotid atherosclerotic disease and to evaluate the effect of noncircular lumens on stenosis measurement derived from angiographic projections. METHODS: One hundred consecutive patients presenting with an internal carotid artery stenosis of at least 50% were imaged with spiral CT angiography. The transverse morphology of the diseased lumen was assessed on axial images, and the frequency of noncircular lumens was determined. In these cases, maximum intensity projection angiograms were reconstructed in standardized angiographic planes and in a plane selected according to the luminal obliquity, which was chosen to optimize the angiographic representation of the maximal stenosis. North American Symptomatic Carotid Endarterectomy Trial (NASCET) measurements were calculated from the maximum intensity projection images, and differences between values obtained from standard and optimized projections were recorded. RESULTS: Noncircular lumens were observed in 18 of 100 patients and consisted of elliptical and linear transverse profiles. The transverse orientation of the lumen in these cases ranged from +90 degrees to -87 degrees relative to the anteroposterior plane. An increase in the calculated NASCET stenosis was demonstrated when measurements were obtained from angiographic reconstructions obtained in the exact plane of the luminal obliquity compared with standard angiographic projections. As a result, the stenosis severity was upgraded from moderate to severe in 2 patients. CONCLUSIONS: Noncircular transverse luminal profiles are not uncommon and may introduce error into NASCET calculations obtained from standard angiographic projections.

Behavioral interventions reduce infant distress at immunization.

OBJECTIVE: To assess the effectiveness of simple behavioral interventions at immunization on behavioral and biochemical indicators of distress in infants and parents in a primary care setting. DESIGN: Subjects were enrolled sequentially to control (standard care) and intervention groups. Intervention parents (n=57) were provided information about techniques to help their infants at immunization. Standard care parents (n=45) did not receive this information. Immunizations were videotaped and coded for infant and parent behaviors. Using a visual analog scale, parents rated their infant's and their own comfort at study enrollment, immediately after immunization, and at check-out. Saliva samples collected from infants and parents at study enrollment and at 15, 30, and 60 minutes after immunization were assayed for cortisol concentration by standard radioimmunoassay. Data were analyzed using chi2, analysis of variance, and general linear modeling. Patterns of salivary cortisol change after immunization were analyzed using hierarchical linear modeling. SETTING: A single, urban pediatric practice during 2 summers (1997 and 1998). SUBJECTS: Infants 2 to 24 months of age (n= 102) and their parents. MAIN OUTCOME MEASURES: Duration of infant distress (in seconds); parent use of behavioral intervention; infant and parent salivary cortisol concentrations (in nanomoles per liter). RESULTS: Intervention parents were more likely to use a behavioral technique with their infants before immunization (P<.05). Total infant distress was shorter for intervention infants at immunization (P<.01), and these infants were rated as more comfortable by their parents (P<.001) immediately after immunization. Salivary cortisol levels were lower for intervention infants at 15, 30, and 60 minutes after immunization (P<.05). CONCLUSION: Simple behavioral interventions before immunization are associated with reductions in behavioral and biochemical indicators of infant distress.

[Measurement of intracranial pressure as a factor in the prognosis of the course of serious cranio-encephalic injuries]. / Medición de la presión intracraneal como factor pronóstico en la evolución de los traumatismos craneoencefálicos graves.

We have analyzed the course and outcome in 100 consecutive cases with severe head injuries, all were treated in a uniform manner. Surgery was performed immediately in patients with extracerebral or intracerebral hematomas. Intracranial pressure (ICP) was monitored in all. Forty-five patients recovered with no or minimal neurological deficit, fifteen patients are moderately disabled, four are severely disabled and eight remain in a persistent vegetative state. The mortality was 28%. The favourable outcome in this series suggests that control of intracranial hypertension with careful attention to medical complication can improve the outcome in patients with severe head injuries.

Audit of head injury management in the Northern Region. Northern Regional Head Injury Group.

Head injury is a major cause of mortality and morbidity in the UK and is more prevalent among children and young adults. However, certain factors that contribute to deaths and brain damage can be audited. This article describes an audit of head injury management conducted by the Northern Regional Head Injury Group.

A randomized trial of nimodipine in severe head injury: HIT I. British/Finnish Co-operative Head Injury Trial Group.

We studied the efficacy of nimodipine in severely head-injured patients in a randomized study. Of 176 patients who received nimodipine, 2 mg/h iv for 2 day, 53% had a favorable outcome (moderate or good recovery). Of 175 control patients, 49% had a favorable outcome. This difference was not statistically significant but does not exclude the possibility that a study of a larger number of patients could show a clinically useful benefit.

Inducible synthesis of collagenase and other neutral metalloproteinases by cells of aortic origin.

In view of the possible link between collagenase and the formation of aortic aneurysms we have determined whether cells within the aorta are able to synthesize this enzyme. Explanted cells obtained from fragments of lapine abdominal aorta secreted little or no collagenase. Two related metalloproteinases, gelatinase and stromelysin, were also produced at very low levels. Treatment with purified human monocyte interleukin-1 beta, partially purified lapine, synovial IL-1 or phorbol myristate acetate strongly induced the synthesis of all these enzymes. These activators also increased synthesis of prostaglandin E2. The identity of collagenase was confirmed by detection of the characteristic TCA and TCB breakdown fragments of collagen and by demonstration of collagenase mRNA within activated aortic cells. Unactivated aortic cells contained no detectable collagenase mRNA, suggesting a pretranslational level of regulation. Aortic cells thus possess the ability to express several neutral metalloproteinases and, if a sufficient inflammatory stimulus was present, they might do so in arteries undergoing aneurysmal degeneration.

A trial of the effect of nimodipine on outcome after head injury.

We performed a randomised prospective double blind trial to study the effect of the calcium antagonist nimodipine on the outcome of head injured patients. The subjects were not obeying commands at the time of entry to the study, within 24 hours of injury. One hundred and seventy-five patients received nimodipine IV, 2 mg per hour for up to 7 days and 176 received placebo. The two groups were well matched for important prognostic features. Six months after injury 93 (53%) of the nimodipine group and 86 (49%) of the control group had a favourable outcome (moderate/good recovery). The relative increase in favourable outcomes (8%) was not significant but is compatible (95% C.I.) with an increase in favourable outcomes in treated patients by 33% or a decrease by 12%. Nimodipine was well tolerated and there were few adverse reactions; means of systolic and diastolic blood pressures and the intracranial pressure did not differ between the groups. It is unlikely that nimodipine has a marked effect on outcome (ie an increase in favourable outcome of greater than 15%) after head injury of this severity but the study does not exclude a modest but clinically useful benefit.

Experimental intracerebral hemorrhage: early removal of a spontaneous mass lesion improves late outcome.

The purpose of the present study was to determine whether early removal of an experimental intracerebral mass altered cerebral blood flow, brain water content, neuropathological findings, or neurological function 24 hours later. In three experimental series, a 50-microliter balloon was inflated within the right caudate nucleus in rats. At 24 hours after inflation, we studied cerebral blood flow by quantitative autoradiography, brain specific gravity, and qualitative histopathology by light microscopy. The animals were also assessed using a simple neurological deficit scale. In each series, half of the animals had the balloon inflated for 10 minutes (Group 1), and half had the balloon inflated permanently (Group 2). After transient inflation, there were surprisingly small differences in the blood flow between the two cerebral hemispheres at 24 hours. By contrast, in animals with permanent inflation, several indices of blood flow were significantly worse in the hemisphere ipsilateral to the balloon: the mean and median blood flow levels in the caudate nucleus; the mean blood flow in the cerebral cortex; and the area of cortex with ischemic levels of blood flow. The specific gravity was reduced in areas surrounding the site of balloon insertion after either transient or permanent inflation, and there was evidence of ischemic cell damage in all animals studied. These changes were more severe after permanent inflation, but the differences were not significant. Neurological outcome was significantly better after transient as compared with permanent inflation. The present findings contradict previous results and suggest that early removal of an intracerebral mass may have subsequent benefits.

Chondrocyte activation by interleukin-1: analysis of the synergistic properties of fibroblast growth factor and phorbol myristate acetate.

Following activation, monolayers of lapine articular chondrocytes secreted into their culture media large amounts of prostaglandin E2 (PGE2) and the neutral metalloproteinases collagenase and gelatinase. Partially purified preparations of synovial "chondrocyte activating factors" (CAF), which contain interleukin-1 (IL-1), generally proved stronger activators of chondrocytes than recombinant, human, IL-1 alpha (rHIL-1 alpha) or IL-1 beta (rHIL-1 beta). The presence of synergistic cytokines within the synovial material provides one possible explanation of this discrepancy. As first reported by K. Phadke (1987, Biochem. Biophys. Res. Commun. 142, 448-453) fibroblast growth factor (FGF) synergized with rHIL-1 in promoting the synthesis of neutral metalloproteinases. In our hands FGF alone did not induce neutral metalloproteinases and increased PGE2 synthesis only modestly. However, at doses from 1 ng/ml to 1 microgram/ml, FGF progressively enhanced the synthesis of PGE2, collagenase, and gelatinase by chondrocytes responding to rHIL-1. Acidic and basic FGF synergized equally well with both rHIL-1 alpha and rHIL-1 beta. Phorbol myristate acetate (PMA), but not the Ca2+-ionophore A23187, could substitute for FGF as a synergist. PMA alone was a poor inducer of collagenase or gelatinase but, unlike FGF, it greatly enhanced the synthesis of PGE2 by chondrocytes. Dot-blot analyses with a cDNA probe to collagenase mRNA confirmed that partially purified synovial CAF induced collagenase mRNA more effectively than rHIL-1, with rHIL-1 alpha being superior to rHIL-1 beta in this regard. The synergistic effects of both FGF and PMA upon IL-1-mediated collagenase induction were associated with increased abundance of collagenase mRNA.

Chondrocyte activation by interleukin-1: synergism with fibroblast growth factor and phorbol myristate acetate.

Exposure to synovial factors or purified interleukin-1 (IL-1) induces the production of prostaglandin E2 (PGE2) and the neutral proteinases (NP) collagenase, gelatinase and stromelysin by lapine articular chondrocytes. Having frequently found our partially purified synovial preparations to elicit this process of chondrocyte activation more strongly than recombinant IL-1, Phadke's report of synergism between IL-1 and fibroblast growth factor (FGF) intrigued us. In our hands, basic FGF (1 ng/ml-1 micrograms/ml) did not activate chondrocytes but, in a dose-dependent manner, enhanced the production of PGE2 and NP by chondrocytes exposed to IL-1 alpha or IL-1 beta (1-10 U/ml). Further examination determined that the basic FGF was a better synergist than acidic FGF. In view of reports that FGF activates protein kinase C, we tested whether phorbol myristate acetate (PMA) could substitute for FGF as a synergist. Not only did it do so, but PMA alone (0.1 ng/ml-100 ng/ml), unlike FGF, provoked the production of PGE2 by chondrocytes. The Ca2+ ionophore A23187 could not substitute for FGF in enhancing induction of the NP. Using a cDNA probe, we confirmed that the synergistic effects of both FGF and PMA upon IL-1 mediated collagenase induction, were associated with an increased abundance of collagenase mRNA.

HIG-82: an established cell line from rabbit periarticular soft tissue, which retains the "activatable" phenotype.

We have isolated a continuous cell line from soft tissue lining the knee joints of rabbits. Designated HIG-82, this line was produced by spontaneous establishment of an aging, late-passage culture of primary cells. Like unpassaged, primary cells, HIG-82 cells can be activated by a number of stimuli, including phorbol myristate acetate (PMA), interleukin-1 (IL-1), and the endocytosis of latex beads. Activated cells secrete collagenase, gelatinase, caseinase (stromelysin), and prostaglandin E2 (PGE2) into their culture medium. Pseudodiploid, HIG-82 cells combine a high plating efficiency with a doubling time of approximately 24 h. As primary tissue of this origin is difficult to obtain in large quantities and shows cellular heterogeneity, the HIG-82 cell line should facilitate research into the biology and biochemistry of the fibroblastic cells that line the diarthrodial joints of mammals. Such cells are likely to be important in the pathophysiology of various arthritides.

Characterisation of chondrocyte activation in response to cytokines synthesised by a synovial cell line.

The lapine, synovial cell line, HIG-82, secretes 'chondrocyte activating factors' (CAF) which induce the synthesis of collagenase (EC 3.4.24.7), gelatinase, caseinase and prostaglandin E2 (PGE2) by confluent, monolayer cultures of lapine, articular chondrocytes. Partially purified CAF increased the production of PGE2 by chondrocytes within 3 h; in certain cultures this occurred in as little as 1 h. Increased levels of the three neutral metalloproteinases, in contrast, were only measurable in the conditioned medium after a delay of 9-18 h. After removal of the CAF, the synthesis of PGE2 reverted to basal levels within 1-4 h, but synthesis of the three proteinases remained high for an additional 4 days. Indomethacin, at concentrations which completely inhibited PGE2 synthesis, had no effect upon the coordinate induction of collagenase, gelatinase and caseinase. However, cycloheximide, alpha-amanitin and 5,6-dichlororibosylbenzimidazole (DRB) suppressed induction of these proteinases suggesting that CAF derepressed the genes coding for these enzymes. Once the chondrocytes had been activated by CAF, the inhibitors of transcription had a much weaker effect on the production of the neutral proteinases, indicating that their mRNAs may be relatively stable. In the presence of CAF, inhibition under these conditions was weaker still, possibly due to stabilisation of these mRNA molecules. Experiments with a number of compounds which modulate cellular Ca2+, cAMP or cGMP failed to support a straightforward role for these mediators in the induction of neutral metalloproteinases in chondrocytes. High concentrations of phorbol myristate acetate (PMA) provoked only a slight synthesis of these enzymes.

Chondrocyte activation in response to factor(s) produced by a continuous line of lapine synovial fibroblasts.

We have established a permanent line of lapine synovial fibroblasts called HIG-82. Upon appropriate stimulation, these cells mimicked primary cultures of lapine synovial cells in producing substances which activated primary cultures of lapine articular chondrocytes. Activated chondrocytes secreted prostaglandin E2 (PGE2) and latent neutral collagenase, gelatinase, and caseinase, but not acid hydrolases, into their culture media. PGE2 itself did not activate the chondrocytes. Heating the crude, synovial-conditioned media at 70 degrees C for 30 min reduced their activating activity by 49.3 +/- 20.5% (n = 7). Production of PGE2 by chondrocytes was maximal during the first day of exposure to synovial conditioned media, whereas the production of neutral proteinases peaked during the second day. All the chondrocyte-stimulating activity was present in a fraction of Mr 10,000-25,000. Unlike the crude conditioned medium, this partially-purified material retained full activity following heating to 70 degrees C for 30 min. These data indicate that synovial fibroblasts (type B synoviocytes) are a source of chondrocyte activator(s) and that neutral, but not acid, proteinases may be involved in extracellular proteolysis which leads to the resorption of the cartilaginous matrix seen in bioassays of catabolin.