Acute systemic and antiischemic effects of epanolol in patients with coronary artery disease

Summary Antiischemic effects of ₁-blocking agents are based on intrinsic negative inotropic and chronotropic properties. Partial ₁-agonistic activity, although useful in preserving cardiac function, may counteract such antischemic properties by modulating the intrinsic negative cardiac effects of beta-blockade. To investigate the acute hemodynamic and antiischemic profile of epanolol, a cardioselective ₁-antagonist and partial agonist, 20 patients with left coronary artery disease underwent two incremental atrial pacing tests, 45 minutes before (APST I) and 15 minutes after (APST II) 4 mg intravenous epanolol, administered over 5 minutes. Additional measurements were carried out at 1, 3, 5, 10, and 15 minutes after epanolol, at basal and fixed heart rates. Epanolol immediately reduced heart rate with a maximum of 10% at 15 minutes and decreased contractility (Vmax) by 7% (both p<.05), whereas cardiac output fell temporarily by 9% (p<.05). Other hemodynamic parameters did not change, except for a significant 11% reduction in myocardial oxygen demand. Despite comparable pacing conditions, both the double product and contractility decreased significantly less during APST II, resulting in a 17% lower myocardial oxygen consumption (p<.05). Myocardial ischemia was markedly reduced, indicated by normalization of lactate metabolism [lactate extraction 16±7% vs. –7±8% (APST I)], less ST depression (21%), and modulation of LV end-diastolic pressure postpacing (all p<.05 vs. APST I), whereas angina was absent or less in 14 patients. None of the patients reported an adverse effect. Thus, under resting conditions intravenous epanolol induces moderate, short-lasting negative chronotropic and inotropic effects, but does not alter cardiac pump function or vascular resistance, reflecting its additional ₁-agonistic properties. Alternatively, during pacing it still reduces ischemia through negative inotropic effects and diminishes myocardial oxygen demand, reflecting its ₁-antagonistic profile.     

Relationship of amyloid β/A4 protein to the neurofibrillary tangles in Guamanian parkinsonism-dementia

The Chamorro population of the island of Guam is highly susceptible to a disease called lytico-bodig (LB), wich clinically resembles a mixture of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer disease (AD). The disease is characterized by the widespread development of neurofibrillary tangles in the central nervous system. These tangles have an immuno-histochemical profile indistinguishable from that seen in AD. We studied by immunohistochemistry the occurrence of intracellular and extracellular neurofibrillary tangles in LB in the entorhinal cortex, hippocampus and substantia nigra using antibodies to tau protein and ubiquitin. We also studied the relationship of these tangles to amyloid precursor protein (APP) and its -amyloid fragment (BAP), using multiple antibodies to BAP and other APP sequences. In advanced cases of LB, the development of neurofibrillary tangles was far more severe than in advanced cases of AD. Virtually all neurons of CA-1 and the subiculum were lost and only ghost tangles remained. In areas dominated by such extracellular tangles, BAP deposits were frequently observed developing around the fibers of ghost tangles. In some cases, the deposits covered only a few of the fibers, but in others, they seemed to envelope the complete tangle. The deposits were thiolavin S and Congo red positive, indicating that the BAP was in a consolidated form. We describe these entities as tangle-associated amyloid deposits. Such BAP deposits have previously eeen described in some cases of AD, dementia pugilistica and LB. However, we found them in all cases of LB with dementia in the hippocampal-entorhinal areas and in most cases in the substantia nigra. They do not evolve from diffuse BAP deposits since they are remote from them, and they do not trap dystrophic neurites. The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further consideration needs to be given to the ways in which extracellular BAP deposits are formed.     

Neuropsychological profiles of FMR-1 premutation and full-mutation carrier females

The present French-German investigation of fragile-X syndrome (fra-X) was undertaken to disentangle genetic from environmental effects on cognitive performance as assessed with the following measures: Wechsler Adult Intelligence Scale-Revised (WAIS-R), Wisconsin Card Sorting Test, Trail-Making Test, Tower of Hanai, Verbal Fluency Test, Stroop Test, short-term and consolidation memory, and the d2 task. Groups with different genotypes (n = 11 mothers with a full mutation in the FMR-1 gene of fra-X children; n = 65 mothers with a premutation in the FMR-1 gene of fra-X children; n = 18 siblings of these mothers with normal CGG repeats) and with different psychosocial stressors from fra-X families (n = 14 siblings with a premutation but without affected children of their own) were examined. A group of mothers of non-fra-X autistic children (n = 39) formed an external control group. Previous findings were replicated concerning cognitive performance of FMR-1 full-mutation carrier mothers, who were characterized by lower overall IQ and poorer performance than the group of mothers with the FMR-1 premutation in verbal and performance subtests of the WAIS-R, tests of executive-frontal lobe functioning, and tests of sustained attention. Carriers of the FMR-1 premutation, whether they were mothers of affected children or not,performed in a similar way on all neuropsychological tasks to the intrafamilial control group without CGG amplification. On the basis of these results, it is concluded that there is no neuropsychological evidence of reduced cognitive performance of FMR-1 premutation carriers compared with performance of two control groups with normal CGG repeats. Furthermore, the psychosocial burden of raising fra-X children does not exert an environmental effect on neuropsychological test performance.     

Acute inflammatory responses to mechanical lesions in the CNS: differences between brain and spinal cord

Lesion-induced inflammatory responses in both brain and spinal cord have recently become a topic of active investigation. Using C57BL/6J mice, we compared the tissue reaction in these two central nervous system (CNS) compartments with mechanical lesions of similar size involving both grey and white matter. This evaluation included the quantitative assessment of neutrophils, lymphocytes and activated macrophages/microglia, as well as astrocyte activation, upregulation of vascular cell adhesion molecules (ICAM-1, VCAM-1, PECAM) and the extent of blood-brain barrier (BBB) breakdown. Time points analysed post-lesioning included 1, 2, 4 and 7 days (as well as 10 and 14 days for the BBB). We found clear evidence that the acute inflammatory response to traumatic injury is significantly greater in the spinal cord than in the cerebral cortex. The numbers of both neutrophils and macrophages recruited to the lesion site were significantly higher in the spinal cord than in the brain, and the recruitment of these cells into the surrounding parenchyma was also more widespread in the cord. The area of BBB breakdown was substantially larger in the spinal cord and vascular damage persisted for a longer period. In the brain, as in spinal cord, the area to which neutrophils were recruited correlated well with the area of BBB breakdown. It will be of interest to determine the extent to which the infiltration of inflammatory cells contributes, either directly or indirectly, to the vascular permeability and secondary tissue damage or, conversely, to local tissue repair in the brain and the spinal cord.     

Sprouting and regeneration after pyramidotomy and blockade of the myelin-associated neurite growth inhibitors NI 35/250 in adult rats

After a selective unilateral lesion of the corticospinal tract (CST) at the level of the brainstem (pyramidotomy) and neutralization of the myelin associated neurite growth inhibitors NI-35/250 with the monoclonal antibody (mAb) IN-1, we had previously observed a strong behavioural recovery in parallel with an enhanced structural plasticity of the lesioned as well as the unlesioned CST. The present study focuses on the regenerative response of the cut CST axons at the lesion site in these adult rats. The results show a strong enhancement of regenerative sprouting of CST fibres by treatment with the mAb IN-1. Successful elongation of these sprouts through the pyramidal decussation and into the cervical spinal cord was also dependent on the presence of this antibody. In the spinal cord, regenerating fibres were rarely found in the position of the former CST; most of the fibres were distributed seemingly randomly over the entire lateral extent of the spinal cord.