Do leukocytes have a role in the cerebral no-reflow phenomenon?

The possible role of leukocytes in the cerebral microcirculation following ischaemia was assessed in the gerbil. The no-reflow phenomenon seen after 30 minutes of severe bilateral hemispheric ischaemia during hypotensive reperfusion was compared in control animals and in a group made leukopenic by pretreatment with cyclophosphamide. Neither the incidence nor the severity of the no-reflow phenomenon differed between the two groups. The evidence from this study casts doubt on the hypothesis that leukocyte plugging plays a major role in the cerebral microcirculation's response to ischaemia.     

Middle cerebral artery occlusion in the rat: consistent protocol for a model of stroke

Variability in the effects of the intraluminal suture method of middle cerebral artery occlusion (MCAO) in the rat has been a common and disadvantageous finding. Therefore, we systematically investigated the effects of suture type and rat strain on outcome. First, the clinical and neuropathological effects of permanent MCAO with either an uncoated or a silicone-coated nylon suture were studied over 7  days in Sprague–Dawley rats ( n =36 for each type of suture). Outcome was less severe with the uncoated compared with the silicone-coated suture (e.g. total cerebral infarct volume at 24  h before any fatalities was 119.9±79.8  mm³ , cf. 183.0±36.5 mm³ , n =12 for each, P <0.05; and overall mortality rate was 12.5% cf. 33%, respectively), but much more variable (coefficient of variation was 66.6% cf. 19.9%, respectively). Second, being more consistent in its effects, the silicone-coated suture was further studied in Wistar and Fischer-344 rats ( n =12 for each). Seventy-five per cent of the Wistar's died prematurely from gross hemispheric oedema. Motor deficit and extent of infarction in the Fischer-344 rats were both significantly greater compared with Sprague-Dawley rats (e.g. total cerebral infarct volume at 24  h in the former was 253.6±25.4  mm³ , n =11, P <0.05), and more consistent (coefficient of variation was only 10.0%). It was concluded that the silicone-coated suture and the Fischer-344 rats strain produced the most consistent results and their novel combination provides a reliable acute stroke model.     

Effects of Combined Glutamate and Platelet-Activating Factor Inhibition on the Outcome of Focal Cerebral Ischaemia - an Initial Screening Study

Since both glutamate excitotoxicity and inflammatory responses have been implicated in ischaemic neuronal death, we questioned whether joint inhibition of both processes would be more neuroprotective than either on its own. Therefore we assessed the effects of combined inhibition of both glutamate release (with a use-dependant sodium channel blocker, 619C89) and inflammatory processes (with a platelet-activating factor (PAF) receptor antagonist, BB-823) on the degree of motor deficit and the extent of cerebral (cortical and sub-cortical grey matter) infarction produced by middle cerebral artery occlusion (MCAO) in the rat, and compared results to appropriate single agent, vehicle and positive controls. The combination of both agents produced the greatest reduction in motor deficit, but the effect was only significant (p<0.05) acutely (4 to 6 hours post-MCAO). The extent of cortical infarction at 24 hours post-MCAO was significantly reduced in all experimental groups compared to vehicle-controls (p<0.05) and the greatest reduction occurred in the combination group (55%), though it was not significantly better than either of the single agent groups. Similarly the greatest reduction in sub-cortical infarction was in the combination group, but this was also not significantly better than the single agents. The results of this novel combination of pharmacological interventions suggest that inhibition of both glutamate excitotoxicity and inflammatory responses afforded an overall enhanced, if modest, neuroprotective effect, compared to inhibition of either process alone. The possible mechanisms involved are discussed, but warrant further clarification before therapeutic strategies are developed.     

The combined effects of hypertension,hemodilution, and osmotherapy on the metabolic sequelae of acute experimental cerebral ischemia

The effects of induced hypertension, hemodilution, and osmotherapy (mannitol) have been assessed singly and in combination on the metabolic sequelae 2 hr after middle cerebral artery (MCA) occlusion in the anesthetized rat. All regimes that included hypertension and monotherapy with mannitol significantly reduced the rise in hemispheric lactate produced by vessel occlusion. No treatment caused increased cerebral edema, and mannitol produced a slight reduction in the hemisphere water content. The significance of the results is discussed.     

Methotrexate pneumonitis precipitated by switching from oral to parenteral administration

SIR, Methotrexate pneumonitis is well recognized as an acuterespiratory illness which can complicate rheumatoid arthritis(RA) in around 1 in every 100 patient-years of methotrexate(MTX) therapy [1]. Mortality is significant at 25% [2, 3],and the differential diagnosis includes atypical infection and     

Chronic Cutaneous Lupus Erythematosus: Depression Burden and Associated Factors

American Journal of Clinical Dermatology - Depression may occur in up to 30% of individuals with cutaneous lupus erythematosus (CLE), many of whom may also have systemic manifestations. Chronic...     

An assessment of the possible protective effect of allopurinol in acute stroke.

Allopurinol has been shown to have a protective effect on ischaemic tissue by the indirect prevention of excessive purine loss. This property was tested in the gerbil model of acute stroke. A total of 69 animals were pretreated with an intraperitoneal injection of either allopurinol (50 mg/kg) or sterile water and then subjected to unilateral ligation of the left common carotid artery under general anaesthesia. The clinical effect of the ligation was grouped into three categories of normal, mild to moderate defect (splayed leg, turning behaviour) and severe defect (death, nonresponsiveness and seizures). More normal animals and fewer severely affected animals were present in the allopurinol treated group compared to controls, but only at 2 to 4 hours after carotid ligation (p less than 0.05). Histological examination of brain tissue from the normal category failed to reveal any difference in subclinical ischaemic damage between the two groups. It was concluded that allopurinol may have a protective effect in acute stroke and that this property warrants further elucidation.     

The effect of increased blood pressure on hemispheric lactate and water content during acute cerebral ischaemia in the rat and gerbil.

Infusions of metaraminol and angiotensin were used to test the effect of increased perfusion pressure on tissue metabolism and oedema after induction of regional cerebral ischaemia in the rat and the gerbil. An increase of mean arterial blood pressure of 30-40 mm Hg in the rat over the first 2 hours after diathermy of the middle cerebral artery prevented the 100% rise in hemisphere lactate seen in normotensive control animals. Angiotensin infusion also prevented early hemispheric oedema in this model. In the gerbil, 4 hours after placing a clip on one carotid artery, metaraminol-induced increases in blood pressure had no such protective effect on the metabolic changes or on oedema. When the clip was removed after 3 hours to permit 1 hour of reperfusion, lactate levels returned to normal but the degree of oedema was unchanged. Hypertension in this reperfusion model caused a slight but not statistically significant increase in oedema. The evidence suggests that moderate increases in blood pressure may be protective against the early metabolic sequelae of focal cerebral ischaemia, but there are potential problems with oedema formation. It is argued that a clinical trial should study the potentially beneficial effects of a brief early increase in blood pressure in the acute aftermath of ischaemic stroke.     

Sex difference in antithrombotic effect of aspirin

A number of clinical trials suggest that the antithrombotic effect of aspirin is limited to men. To test the possibility that this is due to a sex difference in the inhibitory effect of aspirin on platelet behavior, we studied whole-blood platelet aggregation in men and women and in male patients with carcinoma of the prostate receiving hormone therapy. The in vitro inhibitory effect of aspirin on so-called spontaneous platelet aggregation induced by stirring whole blood and monitored by the decrease in the number of singleton platelets was greater in men (mean +/- SD inhibitory ratio 1.54 +/- 0.30 in men, 1.23 +/- 0.22 in women; p less than 0.001). The inhibitory effect of aspirin was reduced in orchiectomized male patients and was restored by the addition of testosterone to blood samples. Estradiol had no detectable influence on the inhibitory effect of aspirin. Testosterone thus seems to influence platelet aggregation and its inhibition by aspirin as assessed by whole-blood in vitro aggregometry. Possible mechanisms for this effect of testosterone and its relevance to the choice of antithrombotic therapy are discussed.