Cerebralischaemia, which results from stroke, cardiac arrest and cardiac surgery, is one of the most common causes of death and disability worldwide (Flynn et al., 2008; Kim and Johnston 2011). In acute ischemic stroke a blood vessel in the brain gets occluded by thrombosis or embolism, resulting in neuronal damage and death in an area surrounding the occluded vessel (focal ischaemia) whereas global cerebralischaemia, which is caused by cardiac arrest and cardiac surgery, encompasses wide areas of brain tissue. The pathophysiology resulting from cerebralischaemia is a leading cause of death and adult disability and a major risk factor for later development of various neurogenerative diseases including Alzheimer’s disease and vascular dementia (De la Torre, 2004a; 2004b; Hazell, 2007; Pluta et.al., 2013) , A significant proportion (60-90%) of Alzheimer’s disease and vascular dementia patients exhibit cerebrovascular pathology including cerebral infarcts and ischaemic lesions leading to more rapid cognitive decline in patients diagnosed with these diseases (Kalaria, 2000). However, cerebralischaemia induced cellular damage that initiates cerebrovascular pathology and related memory dysfunction remain poorly understood and this has mired the development of new drug treatment strategies. The possible reasons for this failure include lack of a clinically relevant model that is highly reproducible as the pathophysiology of cerebralischaemia injury in animal models is influenced by numerous factors including the species, type of blood vessels occluded, occlusion period and reperfusion time (Hossmann, 1998).
However, these trials will not provide information about the mechanism by which tranexamic acid might exert its effects in TBI. If tranexamic acid reduces mor- tality by reducing intracranial haemorrhage, we would expect there to be less blood on head CT scans of tran- examic acid-treated patients, particularly those treated soon after injury . If tranexamic acid increases the risk of cerebralischaemia, we would expect to see more ischaemic lesions in tranexamic acid-treated patients, particularly in those treated after a more prolonged period following injury . The CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) will examine the effect of tranexamic acid on intracranial haemorrhage and cerebralischaemia in a cohort of patients enrolled in the CRASH-3 trial. This paper outlines the protocol for the CRASH-3 IBMS and is in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The SPIRIT checklist and figure have been included as Additional file 1 and Fig. 1, respectively.
angiogenic factor in vitro and in matrigel or alginate bead implants ex vivo [34,35]. In contrast, our data show that PTX3 exerts pro-angiogenic actions on the cerebrovascu- lar endothelium, indicating that PTX3 actions could be different in the brain after injury compared to peripheral organs. Indeed, our earlier studies showed that central and peripheral PTX3 expression is differently regulated . Supporting a beneficial role for PTX3 in angiogenesis, the lack of PTX3 reduced the amount of capillaries in the reperfused area, as well as inducing a worse outcome in a study of cardiac ischaemia . The effect of PTX3 in other mechanisms of repair  may benefit the overall recovery and indirectly facilitate angiogenesis, overruling the anti-angiogenic actions of PTX3. Baldini and colleagues found elevated levels of both PTX3 and VEGF in samples of patients suffering from arterial inflammation , and we observed a lower amount of VEGFR2 in blood vessels of PTX3 KO mice. VEGF is thought to be produced by astrocytes after cerebralischaemia [38,39] and then binds to VEGFR2 in endothelial cells, promoting angiogenesis . Lower VEGFR2 levels could reflect a lower level of
Experiments in animal preparations have shown a variety of functional changes during cerebralischaemia. Studies in primates following acute middle cerebral artery occlusion have shown that when CBF drops below 18 ml 100 g'1 min*1 the EEG becomes isoelectric, and evoked potentials are diminished when flow is reduced to 15 ml 100 g 1 min'1 (Branston et a l, 1974; Astrup et al, 1977). At CBF values below about 10 to 12 ml 100 g'1 min'1 ionic pump function is severely altered. There is a massive efflux of K+ in exchange for Na+, and a net NaCl influx followed by water. Associated alterations include membrane depolarisation, and shrinking o f the extracellular space (Astrup et a l, 1982). The underlying cause of these changes is ATP depletion and failure of the Na+-K+ transport system. A net influx of Ca++ is evidence for the concomitant failure o f the Ca++ transport mechanism (Siemkowicz & Hansen, 1981). It is not until CBF has been reduced to levels of about 6 to 10 ml 100 g*1 min'1 that irreversible cellular disruption occurs (Astrup et < 2 /, 1977; Astrup,
CerebralIschaemia/reperfusion injury(I/RI)is a common cause of brain damage. The use of antioxidants has beneficial effects in I/RI, as they protect against brain damage by inhibiting reperfusion injury. The present study was conducted to investigate the role of vitamin C in the protection against cerebral I/RI, induced in rats and its effect on biomarkers of oxidative and nitrosative stress, and on markers of inflammation. Male rats were divided into six groups: The first was sham operated group, the second group was I/RI and the last four received intravenous (IV) vitamin C in doses 50 and 100mg/kg before and after I/RI. Reduced glutathione, malondialdehyde, nitric oxide, tumour necrosis factor alpha and interleukin one beta were measured in brain homogenates. Results showed that both doses of vitamin C given before and after I/RI induction had protective effect on brain tissue against I/RI
The major advantage of the preparation is that continuous changes in Cl can be measured and these reflect the immediate and delayed phases of cerebral injury (Williams CE et al 1991). By simultaneously measuring other parameters, the cascade of processes that culminate in hypoxic-ischaemic brain injury can be elucidated. Delayed cerebral injury is an important feature of perinatal asphyxia in term infants, and has been repeatedly measured with MRS (Azzopardi D and Edwards AD, 1995). The similarities of clinical and pathological consequences of transient cerebralischaemia in the late gestation sheep and those of certain asphyxiated infants imply that the flndings of these studies may have important clinical implications (Williams CE et al 1992). Clinically, delayed seizures are frequently observed in asphyxiated infants and occur earlier if the insult is severe (Wical BS, 1994; Legido A et al 1991). Furthermore early MRI studies following asphyxia have revealed the presence of cerebral oedema at a time during which there was EEG evidence of seizure activity (Rollins NK et al 1994). Although studies on the histopathological features of birth asphyxia are sparse, MRI studies have indicated injury is prominent in the basal ganglia, striatum, hippocampus and parasagittal cortex (Barkovich AJ et al 1995; Kuenzle C et al 1994; Menkes JH and Curran J,
The measurement of tissue perfusion is of critical importance to our understanding and assessment of many of the major human diseases, since cerebral vascular disorders are among the most common causes of death and disease in the Western world. Perfusion is defined as the volume of blood delivered to the capillary beds of a block of tissue in a given period of time, and its units are therefore ml/lOOg/minute. It is important to distinguish between perfusion and bulk flow: perfusion is flow at the capillary level, where exchange of nutrients between the blood and tissue occurs, whereas bulk flow corresponds to flow through major vessels such as veins and arteries, where no exchange takes place (see figure 3.1). Perfusing blood delivers substances such as oxygen and glucose to the tissue, which are necessary for cellular metabolism, and carries away the waste products. The survival of the brain is dependent on a continuous and adequate supply of oxygen and nutrients, and failure of the cerebral circulation results in the death of nerve cells within 5 minutes. For these reasons, the ability to measure perfusion accurately and with good spatial precision would offer the chance to assess which regions of an organ are at risk following a stroke or thrombosis. Various attempts have been made to develop techniques that achieve this goal.
demonstrated by Quast et al., who described absence of contrast agent passage on DSCI in the ischaemic core of a focal lesion in the rat (Quast et a l 1993). Interestingly, in the periphery of the lesion, they detected marginal perfusion without DWI changes. This was similar to a study using DW I and DSCI in a unilateral M CAO cat model, in which perfusion deficits not great enough to cause energy failure may go unnoticed on DW I (Morawetz et a l 1974; Roberts et a l 1993). The sensitivity of perfusion measurements to minor alterations in blood flow is illustrated in a cat model of hypoperfusion (Derugin and Roberts, 1994). The diffusion-weighted images show no evidence of abnormality in the territory of the occluded MCA, whereas the DSCI blood flow measurements show decreased CBF throughout the MCA region. DSCI may also be applied to examine haemodynamic alterations following reperfusion of the brain. A study into the effects of reperfusion after MCAO in cats revealed three types of reflow outcome: complete reperfusion (normalised tpeak); initial hyperaemia (short tpeak) and persistent hypoperfusion (longer tpeak)- These three CBF patterns have now been quantified (ml/lOOg/min) using a pulsed ASL technique (Pell et a l 1999b). In addition, in studies of transient ischaemia or hypoxic ischaemia, DSCI has been used to detect the change in CBV during and after the insult (D'Arceuil et a l 1998). These data illustrate that CBF measured with either contrast agent or arterial spin labelling techniques, can explicitly measure responses of various haemodynamic parameters under conditions of ischaemia and reperfusion, and provided additional information to that of DW I alone.
Apoptosis is a dynamic process and can be regulated by a series of genes and proteins [14, 15]. In ischaemic stroke studies, apoptosis usually occurred in the penumbra region. Pr- evious research indicated that at certain tim- es after ischaemia, brain tissue in the isch- aemic core region would become necrotic, wh- ich occurred rapidly and was not reversible. Around the core region was the penumbra region, and cells in this portion would become apoptotic, which could be blocked by emergen- cy measures [11, 16, 17]. Cell apoptosis is the most important injury type in CIRI , and BMECs are the most common cells involved. Tie-2 is a tyrosine kinase receptor expressed especially on the membrane of endothelial cells [19, 20]. Studies have proved that Tie-2 participated in regulation of apoptosis in endo- thelial cells through inhibition of nucleus lysing by the caspase family [21, 22]. Another open question is whether LS could affect apoptosis of BMECs in CIRI.
F ollo w i n g MCAO, the greatest reductions in tissue oxygen tension were recorded in areas of the b r a i n w here the largest reductions in cerebral b l ood flow occurred. Figure 4 .5.a, d emonstrates a linear r e l a t i o n s h i p b e t w e e n mean cerebral b l o o d flow and PtOg in the ischaemic hemisphere following MCAO. It is interesting that the slope of the curve indicates that a zero tissue o x ygen tension would occur at a blood flow of 10ml/1 OOg/min, or possi b l y even higher if we look at the scattering of data points around the b aseline at blood flows around 2 0 m l / 1OOg/min. This suggests that the tissue oxygen tension is not linearly related to blood flow at these low flow levels and that other factors are causing oxygen tension to fall. As o utli n e d above, these factors could include a fall in blood oxygen content or an increase in tissue oxygen metabolism. The former is most likely, due to the r e d uced b l o o d flow allowing increased extraction of o x y g e n by the tissues and thereby leaving the blood to carry less o x ygen further down the vascu l a r network. This would explain the apparent fall off in oxyg e n tension as b lood flow was reduced to around 2 0 m l / 1 O O g / m i n . The further r e duction in o x ygen tension to zero at b e t ween 10 and 20ml/1 OOg/min ties in w ith the thresholds for the loss of cellular ion h o m e o s t a s i s (Harris et al, 1987) and cellular function (Branston et al 1974) which are secondary to hypoxia induced d i s r u p t i o n of cellular m e t a b o l i s m (Siesjo 1981).
T he interference in blood flow causing a stroke may be due a variety o f events (em bolus, haem orrhage or throm bosis). The com m on outcom e is that o f cerebral ischaem ia (deficient blood supply to the brain and the consequent im pairm ent in the availability o f oxygen and glucose). It has long been thought that a stroke causes im m ediate and irreversible dam age and that it is, therefore, unlikely that any therapeutic strategy in the acute stage of the condition will prove to be effective. Indeed, the etym ological source of the term itself derives from the pessim istically described “stroke o f G o d ’s H and” that becam e associated with the condition of apoplexy tow ards the end o f the Century. A num ber of prom ising drug treatm ents derived from research using experim ental animal models of stroke, have been ineffectual when applied to the clinical setting. However, in 1996, the first successful, clinical trial of a therapeutic intervention for the treatm ent of acute stroke was reported (The N ational Institute of N eurological D isorders and Stroke rt-PA Stroke Study Group, 1996). The throm bolytic agent, recom binant tissue plasm inogen activator (rt-PA), was found to im prove outcom e if applied w ithin 3 hours of the onset of stroke. The investigation of this treatm ent had been accom panied by rigorous studies of throm bolysis perform ed using experim ental m odels o f cerebral and myocardial ischaemia. A m ore com plete understanding of the pathogenesis of stroke remains the foundation o f the developm ent of such therapeutic strategies. T he highly controllable and reproducible animal m odels o f stroke are the optim al m eans to gain this inform ation. The use of M R I in such investigations is attractive due to its inherent characteristics of non-invasiveness, sensitivity to a variety o f contrast m echanism s, and its high tem poral and spatial resolution. Longitudinal investigation o f brain metabolism, function and physiology thereby becom es feasible.
As both elicitation and propagation of SD require activation o f the NMDA receptor ionophore complex (Lauritzen and Hansen, 1992; Sheardown, 1993), probenecid may inhibit SD by reducing NMDA receptor activation. Inhibition of NMDA receptors could result from extracellular acidosis associated with the probenecid-induced increase in extracellular lactate. Excitatory currents associated with activation of NMDA receptors are very sensitive to changes in pH^; decreases in pHg reduced the magnitude of such currents in cultured neurons by a non-competitive action of on an extracellular site of the complex (Tang et al., 1990; Vyklicky et al., 1990; Traynelis and Cull-Candy, 1991). However, the probenecid-induced increase in extracellular lactate in this study was not associated with a significant reduction in dialysate pH, suggesting that increases in extracellular H^ may have been buffered. Another plausible mechanism may be increased extracellular kynurenic acid. Kynurenic acid, the only known endogenous antagonist of glutamate receptors (Swartz et al., 1990), has affinity for the agonist recognition site of the NMDA-receptor channel complex, and is several times more potent at the glycine allosteric site (Birch et al., 1988; Kessler et al., 1989). Administered systemically kynurenic acid protects against ischaemia (Germano e ta l., 1987; Andine e ta l., 1988) and experimental brain injury (Hicks et al., 1994). Probenecid increased the concentrations of kynurenic acid in brain tissue, ECF and CSF by blocking its excretion (Moroni et al., 1988; Swartz et al., 1990; Miller et al., 1992; Nozaki and Beal, 1992; Russi et al., 1992; Vecsei et al., 1992a). Either alone or in combination with L-kynurenine (the precursor of L-kynurenic acid), probenecid protected against hypoxia-ischaemia, NMDA neurotoxicity and NMDA induced seizures (Nozaki and Beal, 1992; Vecsei et al., 1992b; Kravzov et al., 1993).
Migraine and cerebralischaemia sharing a common cause Migraine and cerebralischaemia sharing a common cause include syndromes in which both migraine and stroke are major clinical features. These conditions are characterised by chronic alterations of the vessel wall of small arteries and include cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoen- cephalopathy (CADASIL), mitochondrial encephalopa- thy, lactic acidosis and stroke-like episodes (MELAS), and autosomal dominant vascular retinopathy, migraine and Raynaud’s phenomenon. The first two conditions are also described in Chapter 6 of ICHD-II (6.7.1 and 6.7.2) (Table 9) .
Abdominal radiographs and ultrasound (US) are of limited value, with poor sensitivity and specificity in diagnosing mesenteric ischaemia, but may be performed in patients with nonspecific abdominal pain [2, 6]. Radiographs are usually only abnormal with frank bowel infarction . Although Doppler US can be used to assess for proximal mesen- teric artery occlusion and signs of bowel compromise, this can be technically challenging and dependent on a number of factors, including patient body habitus, pa- tient compliance and mobility, the presence of bowel gas and local expertise . In patients with CMI, Doppler US peak systolic velocity measurements of greater than 275 cm/s in the SMA and 200 cm/s in the CA correspond to at least 70 % stenosis of these vessels. Like MRA, US cannot be used to assess for distal arterial occlusion or NOMI.
These studies reveal evidence that during even very brief periods of ischaemia and reperfusion in normal humans, monocytes and neutrophils are rapidly activated, accumu- late within the vasculature and produce potent reactive oxygen intermediates. We report that even following a mild ischaemic insult, this leukocyte response is immedi- ately followed by evidence of leukocyte activation and changes in inflammatory and coagulation markers. This study also provides an opportunity to investigate other markers of endothelial damage to support these findings. Further scientific research may also highlight potential points of therapeutic intervention for pathophysiological conditions. Indeed, the present investigation could pro- vide a model in normal human subjects to the study the effects of therapeutic agents for diseases involving ischae- mia-reperfusion injury.
Tissue hypoxia in patients during CPB may be induced by low blood pressure or by insufficient tissue perfusion due to limited pump flow, or both. The relative importance of flow versus pressure in splanchnic perfusion during CPB was recently studied in rabbits . Simultaneous measurements of tissue blood flow in four different splanchnic areas (gastric, jejunum, ileum, liver) were taken using laser Doppler flow- metry before and during CPB. Blood pressure and flow were maintained high or low in random order. The flow was better preserved in all organs but the liver when CPB flow was high, and this was independent of the pressure. Hence, it seems reasonable to focus more on preserving CPB flow rather than pressure to avoid splanchnic ischaemia during CPB. In humans undergoing elective coronary artery bypass grafting, jejunal mucosal perfusion appeared to be well maintained during mild hypothermic CPB, when pump flow was main- tained at around 2.5 l/min per m 2 .
an initial experiment early ACs were administered prior to 25 mins of ischaemia but no preservation of renal function was observed (Figure 2A). The resulting level of functional injury was high with markedly elevated levels of plasma creatinine and thus unlikely to be responsive to any the- rapeutic modulation. Further studies adopted a slightly reduced level of injury (classified according to plasma cre- atinine). In light of work demonstrating that late ACs may exert anti-inflammatory effects  the influence of late ACs upon moderate kidney dysfunction was examined. However, the administration of late ACs resulted in a sig- nificant increase in plasma creatinine indicative of a wor- sening of kidney function (Figure 2B). This suggested that the administration of cells with significant PI positivity was detrimental and we therefore focused upon early ACs in a milder model of renal injury. Somewhat unexpectedly the administration of early ACs also resulted in a sig- nificant increase in plasma creatinine with no protection evident (Figure 2C). On the basis of these data, we did not examine the effects of early ACs in moderate injury or late ACs in mild injury. ATN was evident with widespread tubular injury in the OSOM in the ischaemic kidneys of all PBS and AC treated mice (Figure 3A). Despite the dele- terious effect of early or late AC administration upon renal function in mice with mild or moderate renal IRI, the ATN scores of PBS treated and AC treated mice were comparable (Figure 3B). It is evident from the lower left quadrants of Figure 1D and E that both early and late ACs contained populations of viable non-apoptotic cells and that these cells might be responsible for the worsening of plasma creatinine. However, the administration of 20×10 6 viable thymocytes (~95% Annexin-V - PI - ) prior to renal IRI had no significant effect upon renal function measured by plasma creatinine or ATN (Additional file 2).
adenosine triphosphate-regulated potassium channel (mitoKATP), (2) generation of a small reactive oxygen species (ROS) burst and (3) maintenance of the mPTP. It is very likely that these mechanisms are also involved in preconditioning by noble gases and other pharmacological interventions. Helium-induced preconditioning has been shown to be mediated via preventing mPTP opening : helium prevented mPTP opening by maintaining intracellular acidosis during early reperfusion. Additionally, the ROS scav- engers N-Acetylcysteine and N-2-mercaptopropionyl glycine or the K-ATP-channel blocker 5-hydroxydecanoate abolished helium-induced preconditioning in rabbits, link- ing also the other two mentioned key pathways in the mitochondria to helium-induced cardioprotection . This is supported by studies showing the involvement of mitochondria-related channels : measuring cardiac mitochondrial function by de- termining the rate of oxygen consumption in isolated mitochondria, a direct effect of helium conditioning on mitochondrial function was demonstrated: helium induced a mild uncoupling of mitochondrial respiration . Furthermore, the mitochondrial calcium-sensitive potassium (mKCa) channel blocker Iberotoxin abolished helium- induced infarct size reduction in these rats . These data were confirmed in another study: the role of mKCa channels in helium induced cardioprotection was demon- strated by using NS1619, an activator of mKCa channels, which reduced the infarct size in both, young and aged animals. Moreover, the protein kinase A (PKA) blocker H-89 completely blocked this helium induced cardioprotection . Looking more into detail of PKA regulation, it was found that the adenylyl cyclase activator forskolin reduced in- farct size only in young animals. Thus, helium preconditioning is mediated by activa- tion of PKA, and adaptions in PKA regulation might be an explanation for the age- dependent loss of cardioprotection by helium . In a study using different concentra- tions of helium in a late preconditioning model, a helium concentration of 30% was still protective, while a lower concentration of 10% was not . These data are of special interest for a clinical application of helium, as a low concentration of 30% of helium to achieve the threshold of protection allows the use of a significant amount of oxygen in critical ill patients. Helium was administered for 15 min 24 h before ischaemia/reperfu- sion, and cyclooxygenase 2 (COX2) was identified as a key mediator in helium late pre- conditioning . Regarding postconditioning, prolonged helium application did not induce cardioprotection .
65% of the cases occurred in the age group between 46 and 65. In the younger age group, it is imperative not to miss a condition like pre-eclampsia and Eales’ which present with feature of ischaemia and if caught in their prime, may not cause severe loss of vision. In our study 65% of the cases of retinal ischaemia were males and 35 % were females, the reason of which are manifold including greater susceptibility of male for atherosclerosis, hypertension and history of smoking. 54% of cases were of retinal venous occlusion including CRVO,BRVO and 1 case of HRVO. 24 % of cases were of PDR. The visual acuity varied between hand movements toperception of light in OIS to 6/36 in patients with BRVO. 27% of the cases had a history of smoking and 32% had raised lipid level. Lipid and cholesterol levels do contribute towards occurrence of retinal ischaemia and form a part of vicious cycle by which they lead to atherosclerosis, stroke and hypertension which can all predispose to retinal ischaemia. 35% of cases had raised homocysteine levels and were between 37 and 64 years of age. In the study conducted by Gao W. Et al  hyperhomocysteinemia and low folate levels were found to be risk factors for central retinal vein occlusion. The CRVO patients had a significantly higher homocysteine level than normal controls. Thus,our study had also shown that the raised homocysteine levels is a significant risk factor in the occurrence of the retinal ischaemia in middle aged individuals. The mean arteriolar and venular diameter was 75.81 microns and 162.21 microns in cases whereas the average retinal arteriolar and venulardiameter in controls was found to be 98.5 microns and 141.7 microns respectively taking into fact that according to the T test, a p<0.05 is significant, our findings proved to be highly significant and the arteriolar width of controls was also comparable with the study done by J.Jost B. et al  . The study conducted by Monique et al  was specifically designed for proliferative diabetic retinopathy.The 31 69 80 111
Acute mesenteric ischaemia (AMI) is an uncommon cause of acute hospital admission with high mortality rates (50–90%) that requires early diagnosis and treatment. With the increase in average life expectancy, AMI represents one of the most threatening abdominal conditions in elderly patients. Untreated, AMI will cause mesenteric infarction, intestinal necrosis, an overwhelming inflammatory response and death. Early intervention can reverse this process leading to a full recovery, but the diagnosis of AMI is difficult. The failure to recognise AMI before intestinal necrosis has developed is responsible for the high mortality of the disease. Unfortunately, common CT findings in bowel ischaemia are not specific. Therefore, it is often a combination of nonspecific clinical, laboratory and radiological findings that helps most in the correct interpretation of CT findings. The purpose of this article is to provide an overview of the anatomy, physiology of mesenteric perfusion and discussions of causes, patho- genesis and CT findings in various types of acute bowel ischaemia. Familiarity with various imaging features of mesenteric injury is essential to make a timely diagnosis that will lead to improved patient outcomes.