A synthetic derivative of the natural product rocaglaol is a potent inhibitor of cytokine-mediated signaling and shows neuroprotective activity in vitro and in animal models of Parkinson's disease and traumatic brain injury.

Many acute and chronic neurodegenerative diseases are characterized by a localized inflammatory response and constitutive activation of the transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) as well as their upstream activating signaling cascades. Ample evidence indicates the implication of these processes in the pathogenesis of several diseases of the central nervous system. In this study, we show that a synthetic derivative of the natural product rocaglaol (compound A) displays potent anti-inflammatory properties in human endothelial and murine glial cells in vitro. Compound A inhibited cytokine- and lipopolysaccharide-induced release of various cytokines/chemokines and of nitric oxide as well as expression of the adhesion molecule endothelial leukocyte adhesion molecule-1 and the inducible enzymes nitric-oxide synthase and cyclooxygenase-2. As shown by immunocytochemistry and immunoblotting, compound A inhibited NF-kappa B and AP-1 activity in mixed glial cultures. Compound A exhibited neuroprotective activity in vitro and in vivo. 1-Methyl-4-phenylpyridinium-induced damage of mesencephalic dopaminergic neurons was significantly decreased, and long-term treatment of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-injected mice with compound A significantly and dose-dependently reduced dopaminergic neuronal cell death. In addition, shortterm application of compound A to rats suffering from traumatic brain injury induced by subdural hematoma resulted in a significant reduction of the cerebral infarct volume. These results suggest that by inhibiting NF-kappa B and AP-1 signaling, compound A is able to reduce tissue inflammation and neuronal cell death, resulting in significant neuroprotection in animal models of neurodegeneration.

Chronic cognitive effects of bilateral subdural haematomas in the rat.

Humans suffering from subdural haematomas often show long-term cognitive dysfunctions. For identifying putative, recovery-enhancing therapeutics, animal models need to be developed in which recovery of function can be measured. For investigating whether and which type of recovery, i.e. spontaneous or training-induced recovery, or continuous partial retardation, is present in the rat model for bilateral subdural haematomas, spatial navigation abilities were assessed in the Morris water escape task in independent groups of rats at 1, 2, 4, 8, or 18 weeks after surgery. Complete spontaneous recovery seemed to occur at 8 weeks after injury. However, at 18 weeks after injury, the subdural haematoma caused a renewed deterioration of water maze performance, which was of a lesser degree than the impairments observed immediately after injury. This second phase performance deterioration was accompanied by an increase in generalised astrocyte reactivity. The rat subdural haematoma model provides an interesting tool for investigating spontaneous recovery processes of spatial navigation (8 weeks after injury), but also for progressive brain dysfunctions, considering the second phase of behavioural impairments seen at 18 weeks after injury.

Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats.

The pathophysiology of traumatic axonal injury (TAI) is only partially understood. In this study, we investigated the inflammatory response as well as the extent of neurological deficit in a rat model of traumatic brain injury (TBI). Forty-two adult rats were subjected to moderate impact-acceleration brain injury and their brains were analyzed immunohistochemically for ICAM-1 expression and neutrophil infiltration from 1 hr up to 14 days after trauma. In addition, the chemotactic factors MIP-2 and MCP-1 were measured in brain homogenates by ELISA. For evaluating the neurological deficit, three sensorimotor tests were applied for the first time in this model. In the first 24 hr after trauma, the number of ICAM-1 positive vessels increased up to 4-fold in cortical and subcortical regions compared with sham operated controls (P < 0.05). Maximal ICAM-1 expression (up to 8-fold increase) was detected after 4 days (P < 0.001 vs. 24 hr), returning to control levels in all brain regions by 7 days after trauma. MCP-1 was elevated between 4 hr and 16 hr post-injury as compared with controls. In contrast, neither neutrophil infiltration nor elevation of MIP-2, both events relevant in focal brain injury, could be detected. In all neurological tests, a significant deficit was observed in traumatized rats as compared with sham operated animals from Day 1 post-injury (grasping reflex of the hindpaws: P < 0.001, vibrissae-evoked forelimb placing: P = 0.002, lateral stepping: P = 0.037). In conclusion, after moderate impact acceleration brain injury ICAM-1 upregulation has been demonstrated in the absence of neutrophil infiltration and is paralleled by a selective induction of chemokines, pointing out that individual and distinct inflammatory events occur after diffuse vs. focal TBI.

Effects of subdural haematoma on sensorimotor functioning and spatial learning in rats.

Twenty per cent of all strokes are haemorrhagic in character and are associated with severe disturbances in sensorimotor behaviour and cognition. Although spontaneous recovery of pre-stroke functioning occurs in some cases, the process is demanding, slow, and often incomplete. A first step in the preclinical testing of new putative, neuroprotective and recovery-supporting therapeutics is to validate animal models of brain injury. In a series of four experiments we evaluated the behavioural impairments and the time course of recovery of functional deficits in rats with an experimentally induced subdural haematoma. We found that unilateral subdural haematoma resulted in dysfunction in both simple reflexive (experiment 1) and skilled sensorimotor behaviour (experiment 2). Reflexive behaviour did not recover, or recovered only marginally, and neither did the deficits in skilled forepaw use. Bilateral subdural haematoma impaired the learning and memory performance of adult (experiment 3) and old rats (experiment 4) in the Morris water escape task. Considering the diversity of the deficits found in our experiments, we conclude that different models are needed to cover the broad range of deficits seen in stroke patients.

The effects of subdural haematoma on spatial learning in the rat.

Although memory deficits are one of the most persistent consequences of human subdural haematoma, cognitive functioning has hardly been investigated in the rat subdural haematoma model. In the present study, the effects on spatial learning of right- and left-sided unilateral subdural haematoma and of bilateral subdural haematoma induced above the sensorimotor cortical areas were evaluated. Spatial learning was assessed by standard acquisition in the Morris water escape task (five sessions). Additional issues addressed were sensorimotor functioning (footprint analysis), recovery of cognitive functioning (tested by an overtraining and a reversal training) and replicability of induced cognitive deficits. Following unilateral subdural haematoma surgery, hardly any impairments in the Morris water escape task were observed: rats with a unilateral right-sided subdural haematoma showed very mild, transient deficits, whereas rats with left-sided subdural haematoma were indistinguishable from controls. Bilateral subdural haematoma surgery led to a clear, although transient, performance deficit. We conclude that animals with bilateral subdural haematoma may provide a promising cognitive deficit model for investigating recovery of function.

Brainstem afferents to the lateral mesencephalic tegmental region of the cat.

The lateral mesencephalic tegmental region (LTR) is a part of the midbrain reticular formation characterized by the presence of neurons exhibiting head movement-related discharge modulation. In addition, the LTR contains directionally selective visual units. Possible sources for these vestibular and visual signals were studied by retrograde axonal transport of horseradish peroxidase and three different fluorescent tracers (rhodamine, fast blue, and fluorogold) injected into various parts of the LTR. All injections into the LTR traced afferents from the vestibular nuclei and from the nucleus prepositus hypoglossi. Predominant projections were derived from the ipsilateral nucleus prepositus hypoglossi and the ipsilateral medial vestibular nucleus, whereas the observed inputs from the inferior, lateral, and superior vestibular nuclei were much weaker. Further inputs to the LTR originated in the deep and intermediate layers of the ipsilateral superior colliculus and the ipsilateral periaqueductal gray, the contralateral LTR, and the contralateral marginal nucleus of the brachium conjunctivum. Tracer deposits in medial parts of the tegmentum neighboring the LTR never produced the pattern of afferents observed after injections into the LTR. Our results suggest that afferents from the deeper layers of the superior colliculus are probably the source of visual signals in the LTR and that head movement-related responses are likely to be derived from the nucleus prepositus hypoglossi and the medial vestibular nucleus.

Visual and vestibular signals in the lateral mesencephalic tegmental region of the cat.

Single unit recordings from two alert cats were used in an attempt to further elucidate the function of the lateral mesencephalic tegmental region (LTR), a part of the mesencephalon forming a link between the superior colliculus and the lower brain stem. A total of 155 units recorded from the LTR were tested with visual, vestibular and acoustic stimuli. Of these, 54 cells (36%) were characterized as either visually (n = 33) or vestibularly (n = 21) responsive and an additional 13 cells were driven by complex acoustic stimuli. Visually responsive cells typically were directionally selective with large, mainly contralateral receptive fields. Vestibularly responsive cells were modulated by stimulation of either the horizontal canals (yaw stimulation; n = 16) or of both pairs of vertical canals (pitch stimulation; n = 5). About half of the cells with activity modulated by rotation about the yaw axis increased discharge during ipsiversive (Type I), the other half during contraversive rotation (Type II). Of the 5 cells with activity modulated by pitch stimulation, 4 preferred the nose-down and only 1 the nose-up direction. Although the discharge of units responsive to yaw stimulation was roughly in phase with head velocity (mean phase lag with respect to head velocity: 10.6 deg), none of the vestibular cells had activity correlated with eye position, eye velocity or movement of visual stimuli. Our observations suggest that the LTR might introduce visual and vestibular signals into the tecto- facial pathway which may be used to adjust the size of pinna movements with respect to the size of ongoing head- or body movements.

[Opinion of mothers on continuous peridural obstetrical anesthesia]. / Beurteilung der geburtshilflichen kontinuierlichen Periduralanaesthesie durch die Mutter.

The general opinion on epidural anesthesia in obstetrics may be adversely affected by recent public controversies about the mother's situation during childbirth in hospital, which nowadays is often considered to be a highly technological, impersonal, or "unnatural" procedure. This assumption led us to conduct an inquiry on maternal assessment of obstetric epidural anesthesia and its relation to the clinical and social history. The study included 113 parturients, who received epidural anesthesia (on-demand epidural injections of bupivacaine 0.25%) for vaginal delivery. Mothers were asked to answer certain questions about this regimen (e.g. analgetic efficacy; difficulties in deciding on this method; recommendations to other parturients; opinion of the role of epidural anesthesia in obstetrics; choice of analgesic regimen for future childbirth) 1 day after delivery and 2 months later. Additional social and historical factors (e.g. education; profession; family status; preceding pregnancy, childbirth or abortion; complications during pregnancy or childbirth; duration of parturition) were used to reveal relevant statistical correlations. Sixty-five percent of the patients considered pain relief by epidural anesthesia as "good" or even "very good" during the first inquiry immediately after childbirth. Women who had undergone prior interruptions of pregnancy were less satisfied, probably because of their rather ambiguous attitude towards motherhood. With regard to the choice of analgesic regimen for future childbirth (50% of the patients had made a definite decision to have epidural anesthesia under this condition), those women were especially reserved who had suffered from complications during pregnancy and disapproved of it in the future.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnostic and prognostic significance of hemodynamic and respiratory parameters in venous air embolism]. / Diagnostische und prognostische Bedeutung hämodynamischer und respiratorischer Parameter bei venöser Luftembolie.

In 25 patients undergoing neurosurgical operations in the sitting position we investigated the reliability of different continuously monitored haemodynamic and respiratory data for hypoxia, which is the most important alteration for the prognosis of air embolism. Simply referring to characteristic changes of end-tidal carbon dioxide (pCO2E) we were able to establish the diagnosis of venous air emboli in 12 of these patients. Besides a decrease in pCO2E, only the reduction of arterial oxygen concentration was statistically significant. Using a simple regression-test, however, no sufficient correlation between the two parameters could be found. Including pCO2E and haemodynamic data in our statistical comparison, multiple regression revealed an optimal correlation with the decrease in arterial pO2. Pathophysiological effects of air embolism are due to a transient accumulation of air in the pulmonary arterioles. Continuous monitoring of pCO2E is the most direct and therefore most reliable method for detection of pulmonary air emboli. Hypoxia, prognostically the most decisive alteration, develops parallel to the decrease in pCO2E and, being of multifactorial aetiology, is also influenced by haemodynamic effects of air embolism.

Immunoreactive parathyroid hormone in early and advanced renal failure.

Immunoreactive parathyroid hormone (iPTH) was measured in the serum of 20 patients with early renal failure (ERF) using three assays with different specificity. Half of these patients had elevated iPTH in one or more assays, up to twice the upper limit of normal. In contrast, 36 patients with a creatinine clearance below less than 20 ml/min had an 80% elevated iPTH, up to 5 times the upper limit of normal. The patients with ERF and elevated iPTH had a lower serum calcium but no higher serum phosphate than those with normal iPTH. The differences in iPTH in early and end-stage renal failure can be explained by known differences in metabolism of different PTH forms in uremia.