Richard Sutton

Inhibition of microglial cell RANTES production by IL-10 and TGF-beta.

Using human fetal microglial cell cultures, we found that the gram‐negative bacterial cell wall component lipopolysaccharide (LPS) stimulated RANTES (regulated upon activation of normal T cell expressed and secreted) production through the protein kinase C signaling pathway and that activation of transcription nuclear factor (NF)‐κB was required for this effect. Similarly, the proinflammatory cytokines interleukin (IL)‐1β and tumor necrosis factor‐α dose‐dependently stimulated microglial cell RANTES production via NF‐κB activation. Anti‐inflammatory cytokines, IL‐10, and transforming growth factor (TGF)‐β sequentially inhibited LPS‐ and cytokine‐induced microglial cell NF‐κB activation, RANTES mRNA expression, and protein release. Proinflammatory cytokines but not LPS also stimulated RANTES production by human astrocytes. These findings demonstrate that human microglia synthesize RANTES in response to proinflammatory stimuli, and that the anti‐inflammatory cytokines IL‐10 and TGF‐β down‐regulate the production of this β‐chemokine. These results may have important therapeutic implications for inflammatory diseases of the brain. J. Leukoc. Biol. 65: 815–821; 1999.

Spontaneous and Amphetamine‐Evoked Release of Cerebellar Noradrenaline After Sensorimotor Cortex Contusion: An In Vivo Microdialysis Study in the Awake Rat

Abstract: Microdialysis sampling combined with HPLC was used to assess spontaneous and d‐amphetamine (AMPH)‐evoked release of noradrenaline (NA) in the cerebellum 1 day after probe implantation and 1 day after contusion of the right sensorimotor cortex (SMCX) in rats. In normal controls the mean β SEM basal NA release was 10.08 β 0.97 pg in the left cerebellar hemisphere and 8.21 β 1.17 pg in the right hemisphere 22–24 h after probe implantation. The average β SEM NA release in a 3‐h period after administration of AMPH (2 mg/kg, i.p.) increased to 453 β 47.35 pg in the left and to 402 β 49.95 pg in the right cerebellar hemisphere. NA release (range of 413–951% increase over baseline) was maximal 20–40 min postdrug, returned to basal levels within 5 h, and remained unchanged for the 22–24‐h postdrug measurement period. Animals with a focal SMCX contusion had a marked depression of both spontaneous and AMPH‐evoked NA release. Mean β SEM basal NA release was 4.84 β 1.09 pg in the left and 4.95 β 0.43 pg in the right cerebellar hemisphere from 22 to 24 h postinjury, with NA levels increasing to 259 β 75.44 and 219 β 23.45 pg in the respective hemispheres over a 3‐h period after AMPH. The maximal AMPH‐induced increase in NA release ranged from 522 to 1,088% of basal levels in contused rats, with NA release returning to predrug levels within 5 h and remaining depressed for at least 48 h postinjury. These data indicate that although neocortical injury results in a bilateral reduction of extracellular levels of NA in cerebellum, AMPH‐releasable NA stores are present in the cerebellum. These effects may be related to locomotor impairments and AMPH‐facilitated behavioral” recovery after cortical injury.

Tilt-Table Testing in the Evaluation of Syncope

The vasovagal or “common” faint is both the most frequent of all forms of syncope and by far the predominant cause of fainting in otherwise healthy individuals.1,2 Establishing a diagnosis of vasovagal syncope is usually possible by careful review of the patient’s medical history, with particular attention being directed to the history of events immediately surrounding the loss of consciousness spells. Specifically, the physician must address the clinical circumstances associated with the onset of loss of consciousness, as well as symptoms both accompanying the faint itself and occurring during the recovery period. The “classic” vasovagal faint is often triggered by identifiable circumstances (e.g., unpleasant sights, emotional upset, pain, prolonged upright posture, hot crowded environments), and after recovery the victim frequently complains of a persistent sense of feeling fatigued. Additionally, eye-witness observations should be sought by the physician in order to help to complete the clinical picture of the symptomatic events. The bystander may report the vasovagal fainter to have been pale and “clammy,” or to have complained of feeling nauseated or generally unwell. However, in many cases (and especially in older individuals) the “classic” markers of vasovagal syncope are absent, and historical features alone are inadequate to establish a confident diagnosis. In such cases, even the experienced clinician may desire additional diagnostic evidence in order to feel comfortable. Moreover, the fainter may develop a greater sense of confidence in the physician’s diagnosis if additional evaluation is obtained, particularly if that evaluation permits reproduction of the patient’s symptoms at a time when these symptoms can be witnessed by the medical practitioner. At present, head-up tilt (HUT) table testing is the only clinical laboratory technique recommended for unmasking susceptibility to the vasovagal faint in patients with unexplained syncope.1,2 As such, it should be available in all centers offering “expert” management for syncope and “falls” victims. However, like any other medical laboratory procedure, HUT is not without potential for inaccurate results and misinterpretation of observations. The most important rule is to consider the possibility of life-threatening causes of syn-

Effects of unilateral entorhinal cortex lesion and ganglioside GM1 treatment on performance in a novel water maze task.

Transient deficits have been reported after unilateral entorhinal cortex (EC) lesion. To determine whether there is a more persistent deficit, adult male Sprague-Dawley rats with electrolytic or sham lesions of the left entorhinal cortex were examined on acquisition of a modified working memory task in the Morris water maze. This delayed matching-to-sample task, with a 1-h intertrial interval, reveals a significant deficit in total distance to platform in both presentation (Trial 1) and matching (Trial 2) in the rats with entorhinal lesions. We have also found that this test can be used to assess significant deficits in perseveration (repeated nonproductive movement) in rats with entorhinal lesions. The deficits can be seen up to 16 days postinjury. Administration of ganglioside GM1 resulted in a moderate improvement in performance in both water maze measures analyzed. All groups (sham operated, lesion with saline treatment, and lesion with ganglioside GM1 treatment) were given three other tests, which were used to evaluate possible contributing factors to deficient water maze performance. A one-trial test for exploration of novel objects revealed no significant, simple working memory deficit in any group. Plus maze testing, to assess possible differences in levels of anxiety or increased activity as a component of water maze performance, also revealed no differences in the three groups. All groups were also similar in motor activity, shown by monitoring of activity levels. The worsened water maze performance observed in rats with EC lesion may be related to deficits in working memory ability within the framework of acquisition of a more complex spatial learning task.

Hyperosmosis of cerebral injury.

Changes in tissue osmolarity or cerebrospinal fluid osmolarity after cerebral injury have received little attention in the literature, but osmosis may be an important cause of early cerebral edema. This paper reviews concepts and terms relating to osmosis, and reviews the few papers in the literature which have studied osmolarity after cerebral injury. In studies of both traumatic brain injury and ischemia, tissue osmolarity is elevated. Osmolarity of cerebrospinal fluid has also been shown to increase with injury. There have been no human studies examining osmolarity of tissue or cerebrospinal fluid after cerebral injury. Theoretical implications of the osmotic gradient are discussed.

Dispatcher-directed bystander initiated cardiopulmonary resuscitation: A safe step, but only a first step, in an integrated approach to improving sudden cardiac arrest survival

Approximately 330 000 out-of-hospital cardiac arrests (OHCAs) occur annually in the United States; in essence, there are nearly 1000 OHCA events each day.1 However, despite the presence of extensive emergency medical response systems (especially in heavily populated regions) and aggressive steps by both professional organizations and private industry to enhance public awareness of the magnitude of the problem and the need for cardiopulmonary resuscitation (CPR) training,1,2 overall OHCA survival rates generally remain dismal and highly variable from location to location. On average, only ≈5% of OHCA victims leave the hospital.3–6 Article see p 91 Improving OHCA survival should be a healthcare priority, but effecting substantial improvement is complex. Experience suggests that altering current outcomes requires a well-organized, multifaceted treatment strategy. It is unlikely that introduction of any single intervention, no matter how novel, will do the trick. In fact, as the course of events that followed the introduction of portable automatic external defibrillators (AEDs) illustrates, excessive reliance on any single innovative technology might be detrimental. In that case, AED availability was initially accompanied by a seemingly paradoxical decline in resuscitation success.7 Only later did it become evident that failure to initiate basic CPR while waiting for an AED to arrive undermined patient viability. Thus, although early defibrillation is now advocated if available quickly after a witnessed OHCA event, in most cases, CPR should be initiated first to “prime” the pump with oxygenated blood and increase the chances for a successful defibrillation.1,2,7 That prompt initiation of CPR in OHCA victims has a positive impact on survival is well established. In one of the earliest reports to emphasize the value of early CPR, Cummins et al8 examined survival outcomes in 1297 OHCA events; 579 cases received bystander CPR, whereas CPR was delayed until paramedics arrived in …

Understanding Neurology - A Problem-Orientated Approach

History taking and Physical Examination Neurological Investigations The Problems: Blackouts Acute Confusional States Forgetfulness (memory) Speech and Language Problems Loss of Vision and Double Vision Dizziness and Vertigo Weakness Tremor and Other Involuntary Movements Poor Coordination Headache Neck Pain and Back Ache Numbness and Tingling MCQs Index

BEHAVIORAL AND MORPHOLOGICAL CONSEQUENCES OF PRIMARY ASTROCYTES TRANSPLANTED INTO THE RAT CORTEX IMMEDIATELY AFTER NUCLEUS BASALIS IBOTENIC LESION

Adult male rats received transplants of dissociated 30-day old cultured cortical astrocytes into the ipsilateral frontal and parietal cortex immediately after unilateral ibotenic acid lesion of the NBM or after sham injury. We hypothesized that transplants of astrocytes into the acetylcholine-deprived cortex might provide trophic support to terminals arising from damaged NBM neurons. Twenty four hours after transplantation and every other day for 11 days post surgery, the animals were tested for locomotion and habituation in an open field. NBM lesion reduced vertical movements on ly as compared to no lesion and no transplant counterparts. Nine days after surgery rats with NBM lesion and astrocyte-transplants into the cortex were as impaired in the acquisition of a passive avoidance (PA) task as untreated counterparts. Animals with no lesions and transplants into the cortex also had significant PA acquisition deficits. All rats with ibotenic lesion were significantly impaired on PA retention as compared to rats with no lesions. Astrocyte-transplants survived up to 2 months after cortical implantation but these transplants produced severe laminar disruption and gliosis. This effect was greater in rats with NBM lesion than in intact animals with transplants into the cortex. These data show that astrocyte-transplants do not promote functional recovery after NBM lesion and suggest an immune rejection of the astrocyte transplants by the host brain.

Clinical Cardiac Electrophysiology: An Overview of Its Evolution

Clinical cardiac electrophysiology represents a convergence of five key medical sciences, each with a unique (albeit occasionally overlapping) evolutionary history. Without any one of the following five elements, the modern clinical cardiac electrophysiologist would be less well equipped to address many common problems as effectively as currently expected: (1) electrocardiographic assessment; (2) device therapy including pacing, defibrillation, and monitoring; (3) intracardiac recordings, stimulation, and/or autonomic assessments; (4) mapping (both epicardial and endocardial) with associated imaging and/or navigation; and (5) pharmacologic therapies such as antiarrhythmic and anticoagulation drugs. This chapter is designed to provide readers with a brief overview of the evolution of each of these aspects of modern clinical cardiac electrophysiology practice, and also to illustrate how they interact to facilitate our understanding and treatment of common clinical conditions. Inevitably, space and time preclude a comprehensive review of each subject. Such a review would span more than 100 years, encompass contributions from throughout the world, and emanate from the effort and insight of scientists, engineers, clinicians, and often volunteers and patients too numerous to mention. Furthermore, in many cases the origin of seminal work remains controversial. As a result, some readers may differ with our interpretation of some of the cited events. Nevertheless, our primary goal is to provide an appropriate perspective that will enhance appreciation of the more detailed and focused chapters to follow.