Experimental Observations of Laser-Driven Tin Ejecta Microjet Interactions.

The study of high-velocity particle-laden flow interactions is of importance for the understanding of a wide range of natural phenomena, ranging from planetary formation to cloud interactions. Experimental observations of particle dynamics are sparse given the difficulty of generating high-velocity flows of many particles. Ejecta microjets are micron-scale jets formed by strong shocks interacting with imprinted surfaces to generate particle plumes traveling at several kilometers per second. As such, the interaction of two ejecta microjets provides a novel experimental methodology to study interacting particle streams. In this Letter, we report the first time sequences of x-ray radiography images of two interacting tin ejecta microjets taken on a platform designed for the OMEGA Extended Performance (OMEGA EP) laser. We observe that the microjets pass through each other unattenuated for the case of 11.7±3.2 GPa shock pressures and jet velocities of 2.2±0.5 km/s but show strong interaction dynamics for 116.0±6.1 GPa shock pressures and jet velocities of 6.5±0.5 km/s. We find that radiation-hydrodynamic simulations of the experiments are able to capture many aspects of the collisional behavior, such as the attenuation of jet velocity in the direction of propagation, but are unable to match the full spread of the strongly interacting cloud.

Spinal cord injury as a result of Staphylococcus aureus pyogenic spinal infection complicating infected atopic eczema: two case reports.

INTRODUCTION: Pyogenic spinal infections (PSI) are a rare cause of spinal cord injury (SCI). These most often affect the lumbar spine, followed by the thoracic spine and least commonly the cervical spine, with Staphylococcus aureus being the most common causative organism. Atopic eczema is a dermatological condition which can lead to a breakdown of the skin's natural barrier function, allowing bacterial colonisation and infection. Haematological seeding of bacteria from a distant source of infection, including the skin and soft tissues, is a recognised aetiology of PSI. CASE PRESENTATION: We present two patients who sustained a SCI as a result of PSI secondary to infected atopic eczema. Methicillin-sensitive Staphylococcus aureus (MSSA) was identified as the causative organism in both patients. The two patients required prolonged courses of intravenous followed by oral antibiotics. Neurological outcomes varied between the two patients. One patient had incomplete tetraplegia (C3 AIS C), and upon discharge required hoisting from their bed to a power chair, had an indwelling urethral catheter and required bowel care. The other patient had incomplete paraplegia (L3 AIS D), and at discharge was independent with activities of daily living and was mobile with two elbow crutches. DISCUSSION: We believe that the two cases presented here represent the only examples of secondarily infected atopic eczema causing PSI and resultant SCI in the published literature. As SCI is a serious and potentially life-altering complication, medical professionals treating patients with atopic eczema should be aware of this risk.

A Review of the Metrics Used to Assess Auto-Contouring Systems in Radiotherapy.

Auto-contouring could revolutionise future planning of radiotherapy treatment. The lack of consensus on how to assess and validate auto-contouring systems currently limits clinical use. This review formally quantifies the assessment metrics used in studies published during one calendar year and assesses the need for standardised practice. A PubMed literature search was undertaken for papers evaluating radiotherapy auto-contouring published during 2021. Papers were assessed for types of metric and the methodology used to generate ground-truth comparators. Our PubMed search identified 212 studies, of which 117 met the criteria for clinical review. Geometric assessment metrics were used in 116 of 117 studies (99.1%). This includes the Dice Similarity Coefficient used in 113 (96.6%) studies. Clinically relevant metrics, such as qualitative, dosimetric and time-saving metrics, were less frequently used in 22 (18.8%), 27 (23.1%) and 18 (15.4%) of 117 studies, respectively. There was heterogeneity within each category of metric. Over 90 different names for geometric measures were used. Methods for qualitative assessment were different in all but two papers. Variation existed in the methods used to generate radiotherapy plans for dosimetric assessment. Consideration of editing time was only given in 11 (9.4%) papers. A single manual contour as a ground-truth comparator was used in 65 (55.6%) studies. Only 31 (26.5%) studies compared auto-contours to usual inter- and/or intra-observer variation. In conclusion, significant variation exists in how research papers currently assess the accuracy of automatically generated contours. Geometric measures are the most popular, however their clinical utility is unknown. There is heterogeneity in the methods used to perform clinical assessment. Considering the different stages of system implementation may provide a framework to decide the most appropriate metrics. This analysis supports the need for a consensus on the clinical implementation of auto-contouring.

Artificial Intelligence for Radiotherapy Auto-Contouring: Current Use, Perceptions of and Barriers to Implementation.

AIMS: Artificial intelligence has the potential to transform the radiotherapy workflow, resulting in improved quality, safety, accuracy and timeliness of radiotherapy delivery. Several commercially available artificial intelligence-based auto-contouring tools have emerged in recent years. Their clinical deployment raises important considerations for clinical oncologists, including quality assurance and validation, education, training and job planning. Despite this, there is little in the literature capturing the views of clinical oncologists with respect to these factors. MATERIALS AND METHODS: The Royal College of Radiologists realises the transformational impact artificial intelligence is set to have on our specialty and has appointed the Artificial Intelligence for Clinical Oncology working group. The aim of this work was to survey clinical oncologists with regards to perceptions, current use of and barriers to using artificial intelligence-based auto-contouring for radiotherapy. Here we share our findings with the wider clinical and radiation oncology communities. We hope to use these insights in developing support, guidance and educational resources for the deployment of auto-contouring for clinical use, to help develop the case for wider access to artificial intelligence-based auto-contouring across the UK and to share practice from early-adopters. RESULTS: In total, 78% of clinical oncologists surveyed felt that artificial intelligence would have a positive impact on radiotherapy. Attitudes to risk were more varied, but 49% felt that artificial intelligence will decrease risk for patients. There is a marked appetite for urgent guidance, education and training on the safe use of such tools in clinical practice. Furthermore, there is a concern that the adoption and implementation of such tools is not equitable, which risks exacerbating existing inequalities across the country. CONCLUSION: Careful coordination is required to ensure that all radiotherapy departments, and the patients they serve, may enjoy the benefits of artificial intelligence in radiotherapy. Professional organisations, such as the Royal College of Radiologists, have a key role to play in delivering this.

Whole grain wheat sourdough bread does not affect plasminogen activator inhibitor-1 in adults with normal or impaired carbohydrate metabolism.

BACKGROUND AND AIMS: Epidemiological studies suggest whole grain consumption is associated with a reduced risk of cardiovascular disease (CVD), possibly through alterations in glucose metabolism and subsequent effects on plasminogen activator inhibitor (PAI)-1, a novel biomarker for CVD. Our aim was to investigate the effect of 6 wk of whole grain wheat sourdough bread consumption versus refined white bread on PAI-1. METHODS AND RESULTS: Normoglycemic/normoinsulinemic (NGI; n = 14; age 53 ± 6 y; BMI 26.5 ± 2.9 kg/m(2)) and hyperglycemic/hyperinsulinemic (HGI; n = 14; age 57 ± 7 y; BMI 35.7 ± 5.7 kg/m(2)) adults incorporated whole grain wheat sourdough (162.5 g) or white (168.8 g) bread into their diet, for 6 wk in a randomized crossover study. Pre- and post-intervention, fasting blood samples were analyzed for PAI-1 (primary outcome), as well as glucose, insulin and glucagon (secondary outcomes) at fasting and postprandially after an oral glucose tolerance test (OGTT). Anthropometric measures, fasting glucose, insulin, glucagon and PAI-1 antigen and activity were not different between treatments in either NGI or HGI adults. Glucose incremental area under the curve (iAUC) was lower (19%, P = 0.02) after 6 wk consumption of whole grain wheat sourdough bread compared to white bread in the HGI group, with no differences in insulin or glucagon iAUC in either group. CONCLUSION: Our data showed decreased glucose iAUC after an OGTT following 6 wk whole grain wheat bread consumption in adults with differing glycemic/insulinemic status, but no improvements in PAI-1 or fasting glycemic parameters.

A Randomized Controlled Study of a Cognitive Behavioral Planning Intervention for College Students With ADHD: An Effectiveness Study in Student Counseling Services in Flanders.

Objective: The effectiveness of a short (six session) individual cognitive behavioral planning intervention for college students with attention-deficit/hyperactivity disorder (ADHD) was tested. Method: In three student counseling services in Flanders, individuals with ADHD (N = 58) were randomized to the intervention or waitlist condition. Pre- and posttreatment assessments were conducted, and within the intervention group, a 4-month follow-up was conducted. Primary outcomes were ADHD symptoms and study skills; secondary outcomes were comorbid symptoms and planning skills on a neuropsychological task. Results: Intent-to-treat analyses showed a significant interaction on one outcome: inattention symptoms. The treatment condition improved from pretest to posttest, whereas the waitlist did not. Other measures showed large significant time effects (improved skills, reduction of symptoms in both groups) but no interactions. Stability analyses were not possible due to substantial dropout at follow-up. Conclusion: Specific treatment effects are on one outcome (inattention) and modest; for further implementation, the treatment needs adaptation.

Transforming growth factor-beta. Murine glomerular receptors and responses of isolated glomerular cells.

Proliferation of resident glomerular cells and the accumulation of mesangial matrix are histologic abnormalities which are observed in the course of many progressive glomerular diseases. We explored the potential regulatory effects of transforming growth factor-beta (TGF-beta) on these processes. We found that cultured mouse glomerular endothelial, mesangial, and epithelial cells as well as isolated intact rat glomeruli possess high-affinity receptors for TGF-beta. We also found that, although TGF-beta consistently inhibited the proliferation of glomerular endothelial and epithelial cells, it acted as a bifunctional regulator of mesangial cell proliferation. TGF-beta significantly increased the production of collagen and fibronectin by glomerular mesangial cells whereas only fibronectin production was augmented in glomerular epithelial cells. The presence of TGF-beta receptors on intact glomeruli and on each glomerular cell type and the demonstrated responsiveness of these cells to TGF-beta combine to suggest that potentially important interactions may occur between resident glomerular cells and TGF-beta in vivo.

To what extent have functional studies of ischaemia in animals been useful in the assessment of potential neuroprotective agents?

A general consensus is being reached on the use of a combination of mortality and functional end-points in clinical trials of neuroprotective agents. However, to date, few preclinical studies have examined the effects of putative neuroprotective agents on functional outcome after ischaemia. The data described in this review show the importance of combining both histopathological and neurobehavioural studies when evaluating the neuroprotective efficacy of anti-ischaemic agents in animal models of cerebral ischaemia. Here, Jackie Hunter, Ken Mackay and Derek Rogers argue that measures of functional improvement in models of ischaemia should be incorporated to characterize further the neuroprotection afforded by a compound that could aid the selection of doses and end-point measures in early clinical trials.

Arachidonic acid protects neonatal rat cardiac myocytes from ischaemic injury through epsilon protein kinase C.

OBJECTIVES: Arachidonic acid is a second messenger which activates protein kinase C (PKC) and is released from the heart during ischaemic preconditioning. The purpose of this study was to examine the effect of arachidonic acid on activation of PKC in cardiac myocytes and the cellular consequences. METHODS: Neonatal rat cardiac myocytes were isolated and maintained in culture. Arachidonic acid-induced activation of PKC was examined by cell fractionation and western blot analysis. Contraction frequency was measured by visual inspection under a microscope. Ischaemia was simulated by subjecting cells to an atmosphere of lower than 0.5% oxygen in the absence of glucose and cell damage determined by release of cytosolic lactate dehydrogenase or direct cell viability assay. RESULTS: Arachidonic acid resulted in translocation of delta and epsilonPKC but not alpha, betaII, eta or zetaPKC isozymes, indicating activation of only delta and epsilonPKC. Arachidonic acid induced a dose-dependent decrease in spontaneous contraction rate of cardiac myocytes which was blocked by a selective peptide translocation inhibitor of epsilonPKC. Pretreatment with arachidonic acid partially protected cardiac myocytes against ischaemia. Down-regulation of PKC with 24 h 4beta-phorbol,12-myristate,13-acetate treatment, inhibition of PKC by chelerythrine and selective inhibition of epsilonPKC translocation all decreased the protective effect of arachidonic acid. Pretreatment with eicosapentaenoic acid or oleic acid also protected cardiac myocytes against ischaemia. CONCLUSIONS: These results demonstrate that arachidonic acid selectively activates delta and epsilonPKC in neonatal rat cardiac myocytes, leading to protection from ischaemia. We suggest this is a potential mechanism of PKC activation during PC. In addition, our results suggest that different classes of free fatty acid directly exert cardioprotection from ischaemic injury in cardiac myocytes.

Studies on binding and mitogenic effect of insulin and insulin-like growth factor I in glomerular mesangial cells.

The mesangial cells, as part of their smooth muscle cell function, are actively involved in regulating glomerular hemodynamics. Their overlying endothelium is fenestrated; therefore, these cells are directly exposed to plasma substances, including hormones such as insulin and insulin-like growth factor I (IGF-I). These peptides may contribute to the mesangial sclerosis and cellular hyperplasia that characterize diabetic glomerulopathy. We report herein the characterization of the receptors and the mitogenic effects of IGF-I and insulin on mouse glomerular mesangial cells in culture. The IGF-I receptor was characterized on intact cells. The Kd of the IGF-I receptor was 1.47 X 10(-9) M, and the estimated number of sites was 64,000 receptors/cell. The binding was time, temperature, and pH dependent, and the receptor showed down-regulation after exposure to serum. The expression of the receptor did not change on cells at different densities. The specific binding for insulin was too low to allow characterization of the insulin receptor on intact cells. However, it was possible to identify the insulin receptor in a wheat germ agglutinin-purified preparation of solubilized mesangial cells. This receptor showed the characteristic features of the insulin receptor, including pH dependence of binding and a curvilinear Scatchard plot. The mitogenic effects of insulin and IGF-I on mesangial cells were measured by the incorporation of [3H]thymidine into DNA. IGF-I was more potent than insulin. The half-maximal response to IGF-I stimulation occurred at 1.3 X 10(-10) M, and a similar increase with insulin was observed at concentrations in the range of 10(-7) M, suggesting that this insulin action was mediated through the IGF-I receptor. These data show that the mouse microvascular smooth muscle cells of the glomerulus express a cell surface receptor for IGF-I in vitro and that this peptide is a potent mitogen for these mesangial cells. It may, therefore, play a role in glomerular proliferative lesions. The insulin receptor is present in small numbers and does not mediate mitogenesis in mesangial cells.

Neuroprotective effects of the CRF1 antagonist R121920 after permanent focal ischemia in the rat.

The neuroprotective effects of a systemically active, highly selective, corticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipropylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] pyrimidine), was assessed in two rat models of permanent focal cerebral ischemia, where the middle cerebral artery (MCA) was occluded either through the subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood-brain barrier after intravenous (IV) bolus administration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 +/- 0.40 microg/mL), which were approximately 2-fold greater than those in plasma (0.98 +/- 0.24 microg/mL). Treatment with R121920 (10 mg/kg IV followed by 5 mg/kg subcutaneously at hourly intervals for 4 hours) significantly (P < 0.001) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO model, IV administration of R121920 (10 mg/kg) at the time of ischemia onset (and at multiple times thereafter) reduced both hemispheric infarct volume (by 34%, P < 0.001) and brain swelling (by 50%, P < 0.001) when assessed at 24 hours. In this model of focal ischemia, significant reduction (P < 0.05) in both outcome measures was obtained when R121920 administration was delayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF 1 antagonists in two experimental models of permanent focal cerebral ischemia.

Characterization of the mouse pancreatic/mammary gland cholesterol esterase-encoding cDNA and gene.

Pancreatic cholesterol esterase (CEase) is involved in cholesterol ester hydrolysis and transport of cholesterol into intestinal cells. Isolation and sequencing of the mouse CEase cDNA indicates that the murine enzyme is very similar to the human enzyme, with the exception of the highly repeated C-terminal Pro-rich repeats. Reverse transcription-polymerase chain reaction analysis reveals that the message is synthesized in the pancreas of mice, but not in the liver.

Atrial natriuretic peptide effects in AtT-20 pituitary tumour cells.

Whether atrial natriuretic peptide (ANP)-evoked inhibition of corticotrophin-releasing factor (CRF)-stimulated ACTH secretion was also manifest in ACTH secreting AtT-20 pituitary tumour cells was investigated. ANP stimulated increases in cGMP accumulation at concentrations of the peptide above 10(-8) M which indicates the presence of the ANP receptors on these cells. CRF stimulated a concentration-dependent increase in ACTH secretion from AtT-20 cells which was unaffected by ANP, 8-bromo-cGMP, or sodium nitroprusside (SNP). Calcium stimulated a concentration-dependent increase in ACTH secretion from electrically permeabilised cells which was unaffected by co-incubation with cGMP but potentiated by cAMP. These results reveal the presence of ANP receptors on AtT-20 cells but suggest that an incomplete expression of the stimulus-secretion coupling mechanisms for ANP, at some point after cGMP production, prevents the effects of natriuretic peptides upon ACTH secretion being manifest in these cells.

BMS-204352 (Bristol Myers Squibb).

BMS-204352 is a fluoro-oxindole potassium channel opener being developed by Bristol-Myers Squibb as a potential neuroprotectant for the treatment of acute ischemic stroke. Phase I trials were underway in Japan in 1998 [288541]. By July 1999, it was in phase II trials in the US [331682] and by October 2000, phase II trials had also begun in Japan [384751]. At the 219th American Chemical Society meeting in March 2000, it was reported that BMS-204352 had entered worldwide phase III trials involving patients with suspected acute stroke [362077], [361291]. In February 2001, Credit Suisse First Boston predicted sales of $111 million in 2005 [399484]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2004. The analysts predicted peak sales would occur in 2008, with sales of $500 million in the US at that time [319225].

Distribution of effects of the kappa-opioid agonist CI-977 on cerebral glucose utilization in rat brain.

The effects of the kappa-opioid agonist CI-977 upon local cerebral glucose utilization have been examined in conscious, lightly restrained rats to gain insight into the potential adverse effects of this neuroprotective agent. Cerebral glucose utilization was assessed quantitatively in 45 anatomically discrete brain regions by means of [14C]2-deoxyglucose autoradiography. The i.v. administration of CI-977 (0.03-3 mg/kg) induced relatively homogeneous patterns of altered cerebral glucose utilization with moderate statistically significant reductions (approximately 25%) being observed in 29 brain regions, and a statistically significant increase (approximately 40%) in one brain region, the lateral habenular nucleus. Glucose use throughout the entire neocortex and inferior colliculus was particularly sensitive to reduction (approximately 35%) following CI-977 administration, although there was only a limited dose dependency to the response. Minimal alterations in glucose use were observed in 15 of the 45 brain regions, particularly in the lower brain stem (e.g. superior olives, cochlear nucleus and median raphe) and forebrain limbic regions (e.g. septal nucleus, nucleus accumbens and mediodorsal thalamus). These data demonstrate that CI-977 produces widespread, anatomically organized alterations in function-related glucose use which contrast those seen previously with the NMDA receptor antagonists, thereby suggesting that CI-977 may be intrinsically safer as an in vivo neuroprotective agent.

The effect of the kappa-opioid receptor agonist CI-977 in a rat model of focal cerebral ischaemia.

The effect of a novel, highly potent and selective kappa-opioid receptor agonist CI-977 upon ischaemic brain damage and brain swelling has been examined in a rat model of focal cerebral ischaemia. Focal ischaemia was produced by the permanent occlusion of the left middle cerebral artery (MCA) during a brief period of halothane anaesthesia. The animals were sacrificed 24 h after MCA occlusion and the amount of ischaemic brain damage and swelling was assessed in coronal sections at 8 predetermined stereotactic planes. Treatment with CI-977 (0.03, 0.3 or 3 mg/kg), initiated 30 min prior to MCA occlusion (and at multiple times thereafter) produced dose-dependent reductions in the volumes of infarction and of brain swelling, with the most marked reductions being noted with CI-977 (0.3 mg/kg) in both infarction (reduced by 38% from controls; P less than 0.02) and swelling (reduced by 31%; P less than 0.002). There was an excellent correlation between the volume of brain swelling and ischaemic damage which was similar with saline-treated and CI-977-treated animals (overall correlation coefficient r = 0.896). These results indicate that CI-977 is effective in reducing infarction in a model of focal cerebral ischaemia, and that the reduction in brain swelling occurs in parallel with the reduction in ischaemic damage.

Effect of the kappa-1 opioid agonist CI-977 on ischemic brain damage and cerebral blood flow after middle cerebral artery occlusion in the rat.

The effects of the kappa-1 opioid agonist CI-977 upon the volume of ischemic brain damage (defined using quantitative neuropathology) and local cerebral blood flow (CBF) (defined using quantitative [14C]iodoantipyrine autoradiography) have been examined at 4 h and 30 min, respectively, after permanent middle cerebral artery (MCA) occlusion in halothane-anesthetised rats. Treatment with CI-977 (0.3 mg/kg, s.c.) 30 min before and 30 min after occlusion of the MCA reduced the volume of infarction in the cerebral hemisphere (reduced by 27% when compared to vehicle; P < 0.05) and cerebral cortex (reduced by 32%; P < 0.05), despite a marked and sustained hypotension, with only minimal effect on damage in the caudate nucleus. In the hemisphere contralateral to the occluded MCA, treatment with CI-977 (0.3 mg/kg, s.c.) 30 min prior to the induction of ischemia failed to demonstrate any significant effect on either the level of local CBF in any of the 25 regions examined or on the volume of low CBF determined by frequency distribution analysis. In the hemisphere ipsilateral to MCA occlusion, CI-977 failed to produce statistically significant alterations in either the level of local CBF in 23 of the 25 regions or on the volume of low CBF, but areas of hyperemia were observed in both the medial caudate nucleus and lateral thalamus (local CBF increased by 65% and 86%, respectively, when compared to vehicle).(ABSTRACT TRUNCATED AT 250 WORDS)

Differential alterations in adenosine A1 and kappa 1 opioid receptors in the striatum in Alzheimer's disease.

The alterations in Alzheimer's disease (AD) of two binding sites in the striatum suggested to have a presynaptic localisation have been investigated by quantitative ligand binding autoradiography. Adenosine A1 binding sites labelled with [3H]cyclohexyladenosine (CHA) and kappa 1 opioid binding sites labelled with [3H]U-69593 were studied in adjacent sections of the striatum obtained postmortem from 10 patients with AD and 9 matched controls. In AD, there was a significant reduction of [3H]CHA binding sites in the caudate nucleus (control = 88 +/- 4; AD = 56 +/- 6 pmol/g tissue; mean +/- S.E.M.) and putamen (control = 83 +/- 4; AD = 58 +/- 7 pmol/g). In control subjects, highest levels of [3H]U-69593 binding were localised to patches within the caudate nucleus (9.66 +/- 0.58 pmol/g) with lower levels in the matrix (5.54 +/- 0.48 pmol/g). There was no alteration in [3H]U-69593 binding sites in either the caudate nucleus (patches and matrix) or putamen of AD patients. The activity of choline acetyltransferase (ChAT), determined in the same tissue samples used for autoradiographic analysis, was significantly reduced in AD (control = 124 +/- 11; AD = 64 +/- 14 nmol/h/mg protein). There was a positive correlation between ChAT activity and [3H]CHA binding (r = 0.769), but not [3H]U-69593 binding (r = 0.197). The results indicate that a marked loss of adenosine A1 receptors occurs in the striatum of AD with no loss of kappa 1 opioid receptors, and that the loss of A1 receptors parallels the loss of choline acetyltransferase activity.

Focal cerebral ischemia in the cat: pretreatment with a kappa-1 opioid receptor agonist, CI-977.

The effects of the kappa-1 opioid receptor agonist (5R)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-4- benzofuranacetamide monohydrochloride (CI-977) upon ischemic brain damage have been examined in 15 halothane-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery (MCA), and the animals killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotactic planes. Pretreatment with CI-977 (0.3 mg/kg i.v. followed by continuous infusion at 0.15 mg/kg/h until death), initiated 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 2345 +/- 675 mm3 of the cerebral hemisphere in vehicle-treated cats to 1569 +/- 370 mm3 in CI-977-treated cats; P < 0.01). These data indicate that the kappa-1 opioid agonist CI-977 is neuroprotective in a model of focal cerebral ischemia in a gyrencephalic species where key systemic variables have been assessed throughout the entire post-ischemic period.

Pharmacological modification of glutamate neurotoxicity in vivo.

The ability of five agents (dizocilpine [MK-801], 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline [NBQX], enadoline [CI-977], L-nitroarginine methyl ester [L-NAME] and BW 1003c87) with well defined, distinct pharmacological profiles and with established anti-ischemic efficacy, to modify neuronal damage has been examined in a simple in vivo model of glutamate excitotoxicity. Cortical lesions were produced in physiologically-monitored halothane-anesthetised rats by reverse dialysis of glutamate. The volume of the lesion was quantified histologically by image analysis of approximately 20 sections taken at 200 microm intervals throughout the lesion. The AMPA and NMDA receptor antagonists (NBQX and MK-801) and the inhibitor of nitric oxide synthase (L-NAME) significantly reduced the lesion volume by a similar extent (by approximately 30% from vehicle). Two agents (the kappa opioid agonist, CI-977 and the sodium channel blocker, BW 1003c87) which putatively inhibit the release of endogenous glutamate presynaptically, had dissimilar effects on lesion size. CI-977 failed to alter the amount of damage produced by exogenous glutamate, whereas BW 1003c87 reduced the lesion size by approximately 50%. Using this model, the neuroprotective effects of anti-ischemic drugs can be explored in vivo, uncomplicated in contrast to experimental ischemia by reduced oxygen delivery, drug effects on tissue blood flow and compromised energy generation. In consequence, additional mechanistic insight into anti-ischemic drug action in vivo can be obtained.