CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown.

Children are at greater risk than adults of permanent brain damage and mortality following head injury or infection [1-5]. Rodent models have demonstrated a 'window of susceptibility' in young animals during which the brain parenchyma is at greater risk of acute neutrophil-mediated breakdown of the blood-brain barrier [6-7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be defined, but animal models have revealed that the potent pro-inflammatory cytokine interleukin-1beta (IL-1beta) initiates an intense acute neutrophil-mediated inflammatory response in the brains of young rats and mice that is not seen in adults [6]. Here, we demonstrate the rapid induction of CXC chemokines (which contain a Cys-X-Cys motif), in particular the cytokine-induced neutrophil chemoattractant CINC-1, following the intracerebral administration of IL-1beta. The CXC chemokines produced a more intense neutrophil response in young rats than in adults. The IL-1beta-induced blood-brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These results show that the immature central nervous system (CNS) is dramatically more susceptible to the chemotactic effects of CXC chemokines. Blocking the CXC chemokine activity associated with brain inflammation inhibits neutrophil-mediated blood-brain barrier damage and represents a significant therapeutic possibility.

Nanoscale petrographic and geochemical insights on the origin of the Palaeoproterozoic stromatolitic phosphorites from Aravalli Supergroup, India.

Stromatolites composed of apatite occur in post-Lomagundi-Jatuli successions (late Palaeoproterozoic) and suggest the emergence of novel types of biomineralization at that time. The microscopic and nanoscopic petrology of organic matter in stromatolitic phosphorites might provide insights into the suite of diagenetic processes that formed these types of stromatolites. Correlated geochemical micro-analyses of the organic matter could also yield molecular, elemental and isotopic compositions and thus insights into the role of specific micro-organisms among these communities. Here, we report on the occurrence of nanoscopic disseminated organic matter in the Palaeoproterozoic stromatolitic phosphorite from the Aravalli Supergroup of north-west India. Organic petrography by micro-Raman and Transmission Electron Microscopy demonstrates syngeneity of the organic matter. Total organic carbon contents of these stromatolitic phosphorite columns are between 0.05 and 3.0 wt% and have a large range of δ(13) Corg values with an average of -18.5‰ (1σ = 4.5‰). δ(15) N values of decarbonated rock powders are between -1.2 and +2.7‰. These isotopic compositions point to the important role of biological N2 -fixation and CO2 -fixation by the pentose phosphate pathway consistent with a population of cyanobacteria. Microscopic spheroidal grains of apatite (MSGA) occur in association with calcite microspar in microbial mats from stromatolite columns and with chert in the core of diagenetic apatite rosettes. Organic matter extracted from the stromatolitic phosphorites contains a range of molecular functional group (e.g. carboxylic acid, alcohol, and aliphatic hydrocarbons) as well as nitrile and nitro groups as determined from C- and N-XANES spectra. The presence of organic nitrogen was independently confirmed by a CN(-) peak detected by ToF-SIMS. Nanoscale petrography and geochemistry allow for a refinement of the formation model for the accretion and phototrophic growth of stromatolites. The original microbial biomass is inferred to have been dominated by cyanobacteria, which might be an important contributor of organic matter in shallow-marine phosphorites.

Cytokine-induced acute inflammation in the brain and spinal cord.

Different compartments in the central nervous system mount distinct inflammatory responses. The meninges and choroid plexus respond to pro-inflammatory stimuli in a manner reminiscent of a peripheral inflammatory response, whereas the brain parenchyma is refractory. Trauma-induced lesions in brain and in spinal cord are associated with leukocyte infiltration, blood-brain barrier (BBB) breakdown, and secondary tissue destruction. Unexpectedly, these phenomena are generally more pronounced in the parenchyma of the spinal cord than in the parenchyma of the brain. To investigate whether these differences between brain and spinal cord can be attributed, at least in part, to differing sensitivities to proinflammatory cytokines, we stereotactically injected recombinant rat (rr) TNFalpha or rrIL-1beta into the striatum or the spinal cord of Wistar rats. In the brain, the injection of rrTNFalpha failed to evoke BBB breakdown or leukocyte recruitment, whereas in the spinal cord injection of TNFalpha resulted in marked BBB breakdown and leukocyte recruitment. Similarly, the injection of rrIL-1beta into the brain parenchyma failed to induce BBB breakdown and gave rise to only minimal neutrophil recruitment, whereas the injection of rrIL-1beta into the spinal cord induced significant BBB breakdown and recruitment of neutrophils and lymphocytes. Thus, using a minimally invasive injection technique, equivalent in both circumstances, we have shown that there are marked differences in the inflammatory response between the brain parenchyma and spinal cord parenchyma. This observation has important implications for the treatment of spinal cord injuries.

Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS.

In an experimentally-induced DTH model of MS, we examined mRNA and protein expression of a range of MMPs and of TNFalpha to establish the contribution that individual MMPs might make to the pathogenesis. In control rat brain, mRNA for all of the MMPs examined was detectable. However, by immunohistochemistry, only MMP-2 could be detected. In the DTH lesions, significant increases in the level of mRNA expression were observed for MMP-7, MMP-8, MMP-12, and TNFalpha. Where expression of MMP mRNA was increased, there was a corresponding increase in protein expression detected by immunohistochemistry. To determine whether the upregulated MMPs could invoke destructive events in the CNS, highly purified activated MMP-7, MMP-8, and MMP-9 were stereotaxically injected into the brain parenchyma. All provoked recruitment of leukocytes and BBB breakdown. In addition, MMPs 7 and 9 induced loss of myelin staining. In conclusion, specific MMPs are upregulated in DTH lesions; for the most part, measurement of mRNA was a predictor of increased protein expression. From our injections of MMPs, it is clear that the upregulated MMPs in the DTH lesions could participate in the disruption of the BBB, leukocyte recruitment, and tissue damage.

Glyceryl trinitrate enhances nitric oxide mediated perfusion within the equine hoof.

Laminitis, a microvascular disease of the equine hoof leads to severe lameness. Exogenous iv 1-arginine and transdermal nitric oxide donors, such as GTN, applied to the pasterns improve lameness during acute laminitis. Near Infrared spectroscopy in an earlier study showed haemostasis and ischaemia in the hoof during acute laminitis, both were alleviated by 1-arginine. Quantitative NIRS in the present study shows that transdermal GTN increases blood flow in the equine hoof. It is concluded that glyceryl trinitrate enhances nitric oxide mediated perfusion within the equine hoof in normal and chronically laminitic horses and ponies.

Cerebral injury during cardiopulmonary bypass: emboli impair memory.

OBJECTIVES: Cognitive deficits occur in up to 80% of patients after cardiac surgery. We investigated the influence of cerebral perfusion and embolization during cardiopulmonary bypass on cognitive function and recovery. METHODS: Cerebrovascular reactivity was measured in 70 patients before coronary operations in which nonpulsatile bypass was used. Throughout the operations, middle cerebral artery flow velocity and embolization were recorded by transcranial Doppler and regional oxygen saturation was recorded by near-infrared spectroscopy. Cognitive function was measured by a computerized battery of tests before the operation and 1 week, 2 months, and 6 months after surgery. Elderly patients undergoing urologic surgery served as controls. RESULTS: Cerebrovascular reactivity was impaired preoperatively in 49 patients. Median (interquartile range) regional cerebral oxygen saturation fell during bypass by 10% (6%-15%), indicating increased oxygen extraction, whereas mean middle cerebral flow velocity increased significantly by a median of 6 cm/s (both P <.0001, Wilcoxon), suggesting increased arterial tone. More than 200 emboli were detected in 40 patients, mainly on aortic clamping and release, when bypass was initiated, and during defibrillation. Cognitive function deteriorated more in patients having cardiopulmonary bypass than in control patients having urologic operations but recovered in most tests by 2 months. Measures of cerebral perfusion (poor cerebrovascular reactivity, low arterial pressures, and flow velocity in the middle cerebral artery) predicted poor attention at 1 week (r = 0.3, P <.01, Spearman). Emboli were associated with memory loss (r = 0.3, P <.02, Spearman). CONCLUSIONS: Cognitive deficits were common after cardiopulmonary bypass. Occult cerebrovascular disease was more severe than expected and predisposed to attention difficulties, whereas emboli caused memory deficits. We believe this to be the first report of differing cognitive effects from emboli and hypoperfusion.

Premotor cortex in the rat.

Donoghue and Wise (1982) identified an area AGm in the rat that they take to be a nonprimary motor area. In the present experiments, therefore, this area was removed bilaterally in rats. The animals were poor at relearning a visual conditional motor task but were able to learn spatial delayed alternation as rapidly as unoperated animals. Thus removing this area in rats has a similar effect to removing premotor cortex in monkeys. It is argued that this dorsomedial shoulder area should not be regarded as part of prefrontal cortex in the rat.

Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease.

Elevated plasma cysteine to sulphate ratios were found in patients with Motor neurone disease (MND), Parkinson's disease (PD) and Alzheimer's disease (AD). Cysteine and sulphate were measured by colourimetric methods. Following recent discovery of a defect in sulphoxidation and sulphation of xenobiotics in these diseases, this finding confirms that endogenous sulphur metabolism is disturbed. The mean cysteine:sulphate ratios (x 10(3] in fasting early morning plasma were 506, 521 and 477 for MND, PD and AD whereas it was 96 for normal controls (P less than 0.001). This excess of cysteine thiol groups may interfere with neural protein function. The deficiency of sulphate ions may lead to reduced xenobiotic detoxification.

Cerebral embolisation during modern cardiopulmonary bypass.

OBJECTIVES: Cerebral microembolisation still occurs during cardiopulmonary bypass and may cause both stroke and postoperative cognitive impairment. We investigated the frequency of cerebral embolisation during coronary artery bypass surgery with modern cardiopulmonary bypass and related these to ascending aortic atherosclerosis. METHODS: Transcranial Doppler monitoring for cerebral embolisation to both middle cerebral arteries was performed in 65 patients undergoing coronary artery surgery with non-pulsatile alpha-stat hypothermic bypass. Epicardial ultrasound imaging of ascending aortic atherosclerosis was performed in 14 patients. RESULTS: Thirty patients (56.9%) had more than 200 emboli entering the middle cerebral artery territories during surgery; most at the start of bypass and during defibrillation. Readjustment of aortic clamps and aortic cannulation also caused a large number of emboli which were probably particulate. Aortic disease was mild (mean plaque thickness 1 mm, interquartile range 0.9-1.2 mm) and did not relate to the number of cerebral emboli produced by aortic manipulation. CONCLUSIONS: Cerebral embolisation remains common during coronary surgery despite advances in filter and bypass pump technology. Aortic manipulation and clamping was associated with emboli but epicardial ultrasound imaging was of little help in its prediction.

Near infrared spectroscopy of pedal haemodynamics and oxygenation in normal and laminitic horses.

The present study applies near infrared spectroscopy (NIRS) to the haemodynamics of the pedal circulation in normal and laminitic horses. NIRS is a noninvasive technique which uses changes in light absorption at 4 wavelengths to provide information on the changes in cytochrome aa3 (cyt aa3) reduction-oxidation (redox) status, and changes in the tissue concentration of oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb) and therefore total haemoglobin (tHb). Other studies have shown NIRS to be sensitive to changes in tissue oxygenation and perfusion in human cerebral and limb circulation. In this study, the NIRS sensor was applied to the dorsal surface of horses' hooves. Normal and laminitic animals (acute and chronic) were subjected to manoeuvres (cuff tourniquet; digital vessel occlusion at the palmar surface of the pastern; lifting of contralateral limb) predicted to change pedal haemodynamics. The procedures produced changes in pedal haemodynamics and oxygenation, which were similar to those observed in the ischaemic/reperfused human forearm. Laminitic differed from normal horses: return of HHb to baseline was slower and the change in cyt aa3 more rapid than normal in cases of chronic laminitis, taken to indicate reduced O2 stores as a result of compromised basal perfusion. In acute laminitis, baseline values did not fluctuate following any of the manoeuvres, suggesting haemostasis in the diseased hoof. NIRS is a useful noninvasive method to assess pedal vascular function in normal and laminitic horses.

Nitric oxide donors as treatment for grass induced acute laminitis in ponies.

The potential for participation of the arginine-nitric oxide system in the aetiology of acute equine laminitis has been assessed. Nitric oxide (NO), produced by the action of NO synthase (NOS) on its substrate l-arginine, relaxes vascular smooth muscle to cause vasodilation. An attenuated normal vasodilatory tone may characterise the pathogenesis of acute equine laminitis. An intravenous infusion of 10% l-arginine in 0.9% saline caused vasodilatation in the hoof of a normal pony and immediate reperfusion of laminal tissues in an acutely laminitic pony, detected noninvasively by near infrared spectroscopy (NIRS), but the amino acid had little effect on systemic blood pressure. Treatment of acute laminitis with glyceryl trinitrate applied topically to the pasterns reduced the typical 'bounding pulses' in treated limbs, reduced lameness and lowered systemic blood pressure. Nitric oxide is likely to participate in the multifactorial pathogenesis of equine laminitis.

Detection of first-order liquid/liquid phase transitions in yttrium oxide-aluminum oxide melts.

We combine small-angle x-ray scattering (SAXS) and wide-angle x-ray scattering (WAXS) with aerodynamic levitation techniques to study in situ phase transitions in the liquid state under contactless conditions. At very high temperatures, yttria-alumina melts show a first-order transition, previously inferred from phase separation in quenched glasses. We show how the transition coincides with a narrow and reversible maximum in SAXS indicative of liquid unmixing on the nanoscale, combined with an abrupt realignment in WAXS features related to reversible shifts in polyhedral packing on the atomic scale. We also observed a rotary action in the suspended supercooled drop driven by repetitive transitions (a polyamorphic rotor) from which the reversible changes in molar volume (1.2 +/- 0.2 cubic centimeters) and entropy (19 +/- 4 joules mole(-1) kelvin(-1)) can be estimated.

Functional ceramic materials database: an online resource for materials research.

We present work on the creation of a ceramic materials database which contains data gleaned from literature data sets as well as new data obtained from combinatorial experiments on the London University Search Instrument. At the time of this writing, the database contains data related to two main groups of materials, mainly in the perovskite family. Permittivity measurements of electroceramic materials are the first area of interest, while ion diffusion measurements of oxygen ion conductors are the second. The nature of the database design does not restrict the type of measurements which can be stored; as the available data increase, the database may become a generic, publicly available ceramic materials resource.

Development of structural order during supercooling of a fragile oxide melt.

The authors have studied the structural evolution of the fragile glass-forming liquid CaAl2O4 during supercooling from the stable liquid phase to the cold glass below Tg. The evolution is characterized by a sharpening of the first diffraction peak and a shortening of the average nearest-neighbor bond length around 1.25Tg, indicating an increase in the degree of both intermediate-range and short-range orders occurring close to the dynamical crossover temperature. The cooling curve developed a kink at this temperature, indicating a simultaneous change in thermodynamic properties.

Value of diffusion-weighted MRI during carotid angioplasty and stenting.

INTRODUCTION: The incidence of neurological injury following carotid angioplasty and stenting is of great interest to those advocating it as an alternative to endarterectomy in the management of critical carotid stenosis. A significant inter-observer variation exists in determining the presence or absence of a neurological deficit following the procedure objective imaging would be advantageous. In this study, we sought to assess diffusion weighted MRI as a diagnostic tool in evaluating the incidence of neurological injury following carotid angioplasty and stenting (CAS). PATIENTS AND METHODS: The first 110 cases of CAS in our unit were included in this series. The procedure was abandoned in three patients. Patients underwent intracranial and extracranial MR angiography, together with diffusion-weighted MRI (DWI) prior to and following CAS and had a formal neurological assessment in the intensive care unit after the procedure. RESULTS: One hundred and ten Procedures were attempted in 98 patients. Twenty-eight percent were asymptomatic. Following CAS, 7.2% of patients had a positive neurological exam (two major strokes with one fatality) and 21% had positive DWI scans, equating to a sensitivity of 86% and a specificity of 85% for DWI in detecting cerebral infarction following CAS. The positive predictive value of the test was 0.3 and negative predictive value 0.99. The major stroke and death rate was 1.8%. While the use of a cerebral protection device appeared to significantly reduce the incidence of cerebral infarction (5% vs. 25%, p = 0.031) this may be a reflection of the learning curve encountered during the study. CONCLUSION: The incidence of subclinical DWI detected neurological injury was significantly higher than clinical neurological deficit following CAS. Conventional methods of neurological assessment of patients undergoing CAS may be too crude to detect subtle changes and more sensitive tests of cerebral function are required to establish whether these subclinical lesions are relevant.

Shortening and reimplantation for tortuous internal carotid arteries.

PURPOSE: The purpose of this study was to assess the outcome after the shortening and reimplantation of tortuous internal carotid arteries to prevent kinking after endarterectomy. METHODS: Through a review of prospective records, we studied patients who underwent carotid endarterectomy (CEA) (n = 233) between 1993 and 1996 who had symptomatic stenosis of the internal carotid artery (ICA) of more than 70%. An elongated proximal ICA was excised, and the ICA was reimplanted into the bifurcation in 30 (13%) patients, with additional patch angioplasty in 5 patients. Of the remaining 203 patients, 50 (21%) had Dacron patch angioplasty, and the rest had conventional CEA with simple closure. RESULTS: In the reimplanted group, one patient had a minor stroke with complete recovery on discharge. Three patients (10%) had neck hematomas requiring reexploration, but in none of these was the bleeding from the artery. At mean follow-up of 15 months, 93% of the arteries were widely patent. Significant stenosis secondary to neointimal hyperplasia was detected in only two patients, for a restenosis rate of 6.7%, which is in line with other published reports. In the control group, 8 (3.9%) patients had perioperative transient ischemic attacks, 5 (2.5%) had strokes, and 13 (6.4%) had hematomas requiring evacuation. At follow-up, 14 (6.9%) of the arteries had restenosed. CONCLUSION: In carotid surgery, reconstructive techniques must be tailored to operative findings. Excision of a tortuous elongated proximal ICA with reimplantation is not associated with additional mortality or morbidity rates over those of conventional CEA alone and has the advantage of removing disease at the bifurcation. This procedure was carried out in 13% of our patients and should be a procedure with which the vascular surgeon is familiar.

Altered antigen expression of microglia in the aged rodent CNS.

Microglia, the resident macrophages of the central nervous system, are characterised by a highly specialized morphology and unusual antigenic phenotype. Microglia appear to be downregulated by their microenvironment when compared to other tissue macrophages. We have studied the microglia in brains of healthy, aged rats with a panel of monoclonal antibodies. We have found that microglia in the brains of these aged rats express antigens that are downregulated or absent from microglia of juvenile rats. The stimuli which give rise to this upregulated phenotype are not known. Age related changes in the phenotype of microglia should be taken into account when considering the possible role of microglia in neuropathological conditions.