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Prion diseases are characteristically accompanied by marked astrocytic activation, which is initiated relatively early in the disease process. Using the intracerebrally injected ME7 strain of prion agent to model disease, we identified an expected increase in GFAP (glial fibrillary acidic protein) but additionally noted an accumulation of GFAP cleavage fragments in hippocampal homogenates. A time-dependent increase in hippocampal mu-calpain immunoreactivity within astrocytes suggests that its proteolytic activity may account for the cleavage of GFAP that is observed in the ME7 model. It may therefore contribute to the reactive gliosis that is characteristic of prion diseases.

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BACKGROUND: Control of eosinophil migration to sites of inflammatory responses is a potentially therapeutic intervention in diseases such as bronchial asthma. Chemoattractants, their receptors and the associated signalling pathways may, therefore, be important targets for novel therapeutics. While several potentially important chemoattractants have been identified, the signalling pathways mediating their actions are incompletely understood. AIMS OF THE STUDY: The role of phosphoinositide 3-kinase (PI3K) in responses of human eosinophils to two important eosinophil chemoattractants -- platelet-activating factor (PAF) and eotaxin (CCL11) -- was studied to determine whether this enzyme activity might be crucial for eosinophil migration. METHODS: Eosinophils were isolated from atopic donor blood by immunomagnetic selection. Chemotaxis was assayed in a 96-well blind-chamber cell fluorescence assay. Respiratory burst and leukotriene C(4) secretion were also assayed. RESULTS: Two PI3K inhibitors, wortmannin and LY294002, caused concentration-dependent inhibition of PAF-induced eosinophil chemotaxis (IC(50) = 0.54 nM and 0.15 microM, respectively) but exhibited at least 100-fold lower potency against eotaxin-induced responses (IC(50) = 48 nM and >100 microM, respectively), indicating that these responses were not dependent upon PI3K. Wortmannin and LY294002 also inhibited PAF induced respiratory burst but not PAF-induced LTC(4) secretion. CONCLUSIONS: We conclude that PI3K-dependence varies with stimulus and response, and that eotaxin-induced eosinophil migration is not controlled by PI3K. This may indicate a limit to the potential of PI3K inhibitors to suppress tissue eosinophilia in diseases such as asthma.

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OBJECTIVE: The authors determined whether carotid endarterectomy in patients with recurrent cerebrovascular disease poses a greater perioperative risk than for those individuals undergoing first-time carotid endarterectomy. SUMMARY BACKGROUND DATA: A percentage of patients undergoing carotid endarterectomy for atherosclerosis experience recurrent cerebrovascular disease. Reoperation may be difficult because of postoperative scarring of the soft tissues of the neck and the carotid artery itself. Such patients were believed to be at greater risk for perioperative morbidity than those undergoing first-time carotid endarterectomy. METHODS: To address this concern, the authors retrospectively reviewed their experience with 69 patients who underwent repeat carotid endarterectomies over a recent 10-year period of time. This subgroup represented 6.4% of 1072 total carotid endarterectomies performed during the same time period. The average extent of stenosis on the operated side was 81% and the time elapsed after previous endarterectomy averaged 83 months. Twelve patients (17.4%) had contralateral internal carotid occlusion, and 30 patients (43.5%) had undergone previous endarterectomies on the contralateral side. RESULTS: Complications within 30 days of operation included two deaths (2.9%) and one stroke (1.4%), for a combined stroke and death rate of 4.3%. Six patients developed cervical hematomas requiring drainage; one of these had rupture of a saphenous vein patch. No patient had a significant cranial nerve injury in the reoperative group, whereas 2.0% of patients undergoing first-time carotid endarterectomy had cranial nerve injuries. Overall, these results compared favorably with a combined stroke and death rate of 4.0% among 1003 patients who underwent first-time carotid endarterectomy during the same period. CONCLUSIONS: This review suggests that repeat carotid endarterectomy can be performed safely in individuals with severe recurrent carotid stenosis, with morbidity and mortality rates similar to those for patients undergoing first-time carotid endarterectomies. For this population, reoperative carotid endarterectomy represents a safe and important mechanism for the prevention of stroke.

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The occurrence of significant carotid disease in patients requiring coronary revascularization results in the dilemma of whether simultaneous or staged operations should be performed. To determine appropriate therapy we reviewed this experience at Emory University Hospital. During a 10-year period from 1983 to 1992, 110 patients underwent carotid endarterectomy during the same hospitalization or simultaneously with coronary artery bypass; 907 patients underwent carotid endarterectomy alone during the same period. The combined 30-day postoperative stroke and death rate was 18.2% for the 110 patients undergoing concomitant procedures. When comparing morbidity and mortality rates for those having simultaneous carotid endarterectomy and coronary artery bypass with those having delayed coronary artery bypass, the latter group was found to have a 6.6% combined risk of postoperative stroke or death within 30 days, whereas those undergoing simultaneous procedures had a 26.2% rate. In the control group of 907 patients undergoing carotid endarterectomy alone during the same period, the combined 30-day mortality and stroke morbidity rate was 2.1%. Although the patient population undergoing simultaneous carotid and coronary revascularization may have more severe disease, we believe that combining the procedures during the same operative setting results in an increased perioperative stroke and death rate. Consequently only extremely high-risk patients are selected for simultaneous procedures; otherwise our experience suggests that delaying coronary artery bypass by several days will reduce overall postoperative mortality and stroke morbidity.

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Epileptic seizures occur less during wakefulness or paradoxical sleep, conditions during which hippocampal theta rhythm is seen. This leads to the hypothesis that this rhythm indicates a physiological state of the hippocampal formation which opposes its recruitment into seizures. This was tested by determining the effects of experimental induction or suppression of hippocampal theta activity on seizures. Hippocampal theta activity can be induced by chemical or electrical stimulation of the medial septal nucleus and adjacent nucleus of the diagonal band of Broca. Microinjections of the muscarinic agonist carbachol in the medial septum during pentylenetetrazol (PTZ) induced facial-forelimb seizures stopped behavioral seizures and EEG spiking within five seconds, and caused hippocampal theta activity. Medial septal electrical stimulation at 4-8 Hz had similar effects. Electrolytic medial septal lesions abolished hippocampal theta activity and lowered myoclonic and facial-forelimb PTZ seizure thresholds. Medial septal carbachol injections were also made during electrically kindled limbic status epilepticus. Within ten seconds, ictal behavior stopped and the EEG spike rate decreased by half with a gradual return to the baseline rate over three minutes. These results demonstrate that the hippocampal theta rhythm corresponds to a seizure-resistant condition, providing a possible explanation for the seizure promoting properties of slow wave sleep.

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The cerebellum is electrically and metabolically active during seizures. Numerous studies have also shown that cerebellar electrical stimulation and lesions of the cerebellar cortex or nuclei influence seizure threshold, but there are significant contradictions, with different effects observed even in investigations using the same species and similar seizure types and experimental manipulations. Discrete intracerebral microinjection of neuroactive agents has been used to characterize the way in which other brain regions control seizures, but has not been applied to the cerebellar systems. This approach has advantages because effects are restricted to specific receptors and spare passing axons; experimental variables also can be simply specified and reproduced. We used this method to characterize the role of the cerebellar nuclei in seizures and to determine if observed effects could be reproduced with different agents at different doses. Effects of bilateral control microinjections in the fastigial (medial) cerebellar nucleus were compared with different doses of the GABAA agonist piperidine-4-sulfonic acid and the GABAB agonist (-)baclofen (Bf). Soon after injection, the animals were ataxic. After 4 min, seizures were induced by timed continuous intravenous (i.v.) bicuculline (BIC) infusion. Both GABA agonists produced significant reductions in myoclonic, clonic, and tonic seizure thresholds. Injections just dorsal or anterior to this nucleus and bilateral dentate (lateral) nucleus injections had little effect on seizures. These results demonstrate that the cerebellar system does control seizures, but does not provide support for the early concept that cerebellar stimulation and systemic phenytoin block seizures through inhibition of cerebellar nuclei secondary to Purkinje cell activation.

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This study demonstrated that an ascending pathway from the laterodorsal tegmental nucleus (LDTg) of the pontomesencephalic tegmentum to the thalamic central medial intralaminar nucleus (CeM) controls the thresholds of experimental seizures. Electrolytic and excitotoxic lesions of the CeM and adjacent thalamus facilitated myoclonic, facial-forelimb clonic, and tonic pentylenetetrazol seizures. Microinjections of the GABAB agonist (-)baclofen in the LDTg facilitated myoclonic and facial-forelimb clonic but not tonic seizures. When LDTg injections of (-)baclofen were performed in animals with prior electrolytic lesions of the midline thalamus, the thresholds of myoclonic and facial-forelimb clonic seizures were unchanged compared to similarly lesioned rats with control vehicle LDTg injections. In addition, the lowering of tonic seizure threshold observed with thalamic lesions was reversed by these (-)baclofen injections. Taken together with past studies, these results imply that the LDTg controls myoclonic and facial-forelimb clonic seizures via ascending projections to the CeM and possibly other medial thalamic nuclei. We also postulate that the LDTg affects tonic seizures by two different, opposing pathways. Although the LDTg-CeM pathway is part of the "ascending reticular activating system," lesions of the midline thalamus did not affect spontaneous sleep, implying that the CeM does not have an essential role in sleep regulation.

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This study determined the effects of bilateral discrete partial lesions of cholinergic neurons of the laterodorsal tegmental nucleus (LDTg) of the pontomesencephalic tegmentum on seizures induced by intravenous pentylenetetrazol (PTZ). Relatively selective lesions produced by bilateral 50 nl microinjections of 75 pmol of the cholinergic neurotoxin ethylcholine mustard aziridinium ion (AF64A) resulted in a significant reduction in the threshold of myoclonic and facial-forelimb clonic seizures but not tonic seizures when PTZ was infused 7 days later. This demonstrates that this cholinergic nucleus is a key site of subcortical seizure regulation. We propose that this control is mediated by ascending projections from the LDTg to the central medial intralaminar nucleus of the thalamus.

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This study determined the effects of injections of different cholinergic agents in the central medial intralaminar nucleus of the thalamus on seizures induced by intravenous injection of pentylenetetrazol. Injections of the cholinesterase inhibitor, neostigmine bromide, induced a stiff, tremulous state and lowered myoclonic, clonic and tonic seizure thresholds. The nicotinic agonist, tartrate, depressed arousal and facilitated all types of seizure, while its antagonist, d-tubocurarine chloride, heightened arousal and transformed pentylenetetrazol-induced convulsions, with tonic seizures occurring at a very low threshold without preceding myoclonic or clonic seizures or EEG spikes. The muscarinic agonist (+/-)pilocarpine hydrochloride, in very large doses, induced slight hyperactivity and facilitated tonic seizures but did not affect myoclonic or clonic seizures. Its antagonist, (-)scopolamine hydrobromide, slightly depressed arousal and myoclonic and clonic seizure thresholds. Injections of mixtures of agonists and antagonists (d-tubocurarine chloride + nicotine tartrate or (+/-)pilocarpine hydrochloride + (-)scopolamine) had little effect on spontaneous behavior or seizures. These results suggest that the midline thalamus regulates seizures and arousal, under the control of cholinergic neurotransmission. Nicotinic and muscarinic receptors have opposing roles in mediating these functions.

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This study determined the effects of discrete microinjections of GABA agonists in the cholinergic nuclei of the pontomesencephalic tegmentum on spontaneous behavior and seizures induced by intravenous pentylenetetrazol, bicuculline or strychnine, in the rat. Injections of both the GABAA agonist piperidine-4-sulfonic acid and the GABAB agonist (-)baclofen in the laterodorsal tegmental nucleus produced a dose-dependent suppression of behavioral arousal and a reduction in the threshold of myoclonic and clonic but not tonic seizures induced by bicuculline and pentylenetetrazol. There were no significant effects on any type of strychnine seizure. Injections in the surrounding brainstem structures, including the pedunculopontine tegmental nucleus, had little effect on spontaneous behavior and did not significantly alter the thresholds of pentylenetetrazol-induced seizures. We have previously demonstrated that injections of GABA agonists in the central medial intralaminar nucleus of the thalamus have similar effects on behavior and seizures. Since the central medial nucleus receives important direct cholinergic projections from the laterodorsal tegmental nucleus, these two nuclei form a discrete ascending system which regulates seizure threshold.

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This paper presents the use of the expanded myocutaneous flap for the reconstruction of the difficult pressure ulcer. The results of expanded myocutaneous flaps on 10 patients with a variety of locations of pressure ulcers showed few complications. A review of the literature on the use of expanded flaps indicates the potential for this technique to be more frequently used.

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No clear data exist as to the efficacious use of antibiotics during the perioperative period for repair of pressure ulcers. Results of a survey from 50 university departments of plastic surgery and spinal cord injury centers revealed that 58% reported routine use of antibiotics for flap surgery with cephalosporins as the choice at 69% of the centers. Clinical experience with 35 patients perioperatively showed good results with a third generation cephalosporin.

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A prediction of patient volume expected at "mass gatherings" is desirable in order to provide optimal on-site emergency medical care. While several methods of predicting patient loads have been suggested, a reliable technique has not been established. This study examines the frequency of medical emergencies at the Syracuse University Carrier Dome, a 50,500-seat indoor stadium. Patient volume and level of care at collegiate basketball and football games as well as rock concerts, over a 7-year period were examined and tabulated. This information was analyzed using simple regression and nonparametric statistical methods to determine level of correlation between crowd size and patient volume. These analyses demonstrated no statistically significant increase in patient volume for increasing crowd size for basketball and football events. There was a small but statistically significant increase in patient volume for increasing crowd size for concerts. A comparison of similar crowd size for each of the three events showed that patient frequency is greatest for concerts and smallest for basketball. The study suggests that crowd size alone has only a minor influence on patient volume at any given event. Structuring medical services based solely on expected crowd size and not considering other influences such as event type and duration may give poor results.

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The growth in the use of small portable analysers outside hospital laboratories has been a cause of concern to laboratory practitioners. This has been partly because of a perceived threat to laboratory careers and partly because of fears that the quality of testing would be poor, with a consequent danger of patients being placed at risk. The evidence in this paper indicates that the use of equipment outside laboratories is still increasing in many areas. Despite the fears which have been expressed, little attention is being given to operator training, service costs, safety and many other aspects; only rarely has responsibility for the quality of results been accepted.

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