Suspensions of coated superparamagnetic particles (magnetic fluids, MF) in AC magnetic fields have a pronounced specific absorption rate (SAR) per mass compared to multidomain particles. The aim of the present study was to investigate cellular uptake and the biological effects of AC magnetic field excited bio-compatible magnetic fluids on human carcinoma cells in vitro. One of the fluids tested was a dextran magnetite, which has a very low cyto-toxicity with survival fractions (SF) between 0.8 and 0.9 at concentrations of up to 5 mg ferrite per ml. Human carcinoma cells intracellularly accumulate up to 1 pg ferrite/cell which has been demonstrated by electron microscopy (TEM), X-ray spectroscopy and measurements of intracellular iron. It has been shown that the ferrite core is not altered intracellularly, but many of the dextran shells are degraded which yields particle chains and other aggregates observed in TEM. Semi-solid pellets of the tumour cells were treated with AC magnetic fields (520 kHz, 4-12.5 kA/m) or waterbath hyperthermia at 43 and 45 degrees C, in presence of extracellular and/or intracellular magnetic fluid particles. Although MF heating is produced from individual particles, the survival fractions of MF heated and water bath heated cells are equal. In fact, the extracellular MF particle distribution is homogeneous enough to obtain similar inactivation. In contrast to earlier reports intracellular dextran magnetite particles in AC magnetic fields did not induce cell inactivation. Since the amount of intracellular ferrite should be indeed large enough for cell inactivation, the loss of dextran shells is most probably the main cause of limited effectiveness of the intracellular magnetite particles. The present work has demonstrated that: (1) MFH is able to inactivate tumour cells in vitro to at least the same extent as water bath hyperthermia; and (2) that there is a sensitizer effect of ferrofluids at 43 degrees C probably caused by free ferric ions which induce oxidative stress; and (3) that there is no cytotoxic effect of intracellular dextran magnetite particles 30-180 min excited with AC magnetic fields used in this study. For the new method the term 'magnetic fluid hyperthermia (MFH)' is proposed.

In the present study, we investigated the levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in post-mortem brain tissue of Alzheimer's disease (AD) patients, and we observed a significant increase of BDNF concentration in hippocampus and parietal cortex of AD patients, as well as a negative correlation between NT-3 levels and age in hippocampus and putamen of control subjects, and for BDNF in frontal cortex. A defining feature of AD is the post-mortem identification of neuritic plaques and neurofibrillary tangles in the brain, however, a more significant neuropathological finding is the degeneration of cholinergic neurones of the basal forebrain, critically involved in memory and cognition. Neurotrophic factors are partly responsible for the maintenance of neuronal function and structural integrity in the adult brain. Our results provide, therefore, evidence that, under conditions of progressive neurodegeneration the brain stimulates the over expression of certain neurotrophic factors as a possible mechanisms of compensation, and that during senescence the expression of these molecules is regulated.

Brain mast cells were studied in mice, rats, rabbits, hamsters, guinea pigs, cats, cows, monkeys, and humans with use of a variety of techniques. They were localized by staining with Astrablau or by toluidine blue-induced metachromasia and characterized by their ultrastructural appearance and by the presence of histochemically demonstrable histamine (o-phthaldiadehyde fluorescence method). The identity of the fluorophore was secured by microspectrofluorometry. Mast cells in brain usually had a perivascular localization but were also found scattered in the parenchyma. The regional variations in the number of mast cells agreed with the histamine concentration as measured fluorometrically. The variation was in the order leptomeninges greater than hypothalamus greater than cerebral cortex = mesencephalon greater than cerebellum = brain stem. In addition to histamine, murine mast cells stored serotonin, whereas bovine mast cells contained dopamine, visualized histochemically by the formaldehyde technique.

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✓ The microgravimetric technique and the drying-weighing method for the determination of brain water content are analyzed and compared. A new method has been devised for the automatic production of the gradient column. For gravimetry, tissue samples weighing more than 30 mg have proven adequate for measurement. Specific gravity (SG) should be determined as early as 1 minute after tissue is inserted into the gradient column. Calculations of cerebral blood volume (CBV) from changes in SG of both brain tissue and intravascular perfusate have shown that the SG of brain tissue is considerably influenced by changes in CBV. This is because the SG of blood is higher than that of brain tissue, and may lead to a decrease of SG of about 0.002 in anemic cortex and of 0.001 in anemic white matter, which will simulate a false increase in tissue volume as water of 4% and 2%, respectively. This methodological error may be relevant when the early stages of ischemic brain edema development are studied. Water content of brain tissue can also be determined with acceptable accuracy by vacuum freeze-drying samples of brain tissue weighing about 100 mg. In contrast to cortex, white matter shows a wide range of individual and regional differences in water content. Thus, conclusions on the presence of brain edema drawn from tissue water determinations should always be subjected to cautious analysis and criticism.

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There is increasing evidence that in Alzheimers disease nerve growth factor (NGF)protein and NGF mRNA content in post‐mortem cortex is not decreased, but may evenbe elevated although the NGF‐sensitive cholinergic basal forebrain neurons are preferentiallyaffected. However, only little is known about the early pathophysiological events leading toAlzheimers disease. We therefore measured the post‐mortem NGF concentrations intemporal and frontal cortex of Alzheimers disease patients, non‐demented controls withoutAlzheimers disease‐related pathology, as well as non‐demented patients with βA4plaques who might be classified as preclinical cases. In the Alzheimers disease group we found upto 43% increase in NGF concentrations in the frontal and temporal cortex as compared to the twoother groups. In a subgroup analysis of the non‐demented patients with plaques, NGFconcentrations were lower in the frontal cortex when βA4 plaques were present (46% ofthe control temporal area) than in patients without evidence of frontal plaques (81% of the controltemporal area). This NGF decrease was paralleled to a similar decrease of cholineacetyltransferase activity, which is regulated by NGF in the cholinergic basal forebrain. Thesefindings support the hypothesis of lower cortical NGF content at the onset of plaque formationand of elevated NGF levels in the clinically manifest and neuropathologically advanced stage ofthe disease.

Summary:Galanthamine, physostigmine and 9-amino-l,2,3,4-tetrahydroacridine (tacrine) were evaluated s inhibitors of human acetylcholinesterase activity from samples of postmortem human brain, fresh brain cortex biopsies and human erythrocytes. Acetylcholinesterase activity was most effectively inhibited in all tissues by physostigmine, followed by tacrine and galanthamine. The respective inhibitor concentrations exerting a half maximal effect (IC 50 ) on acetylcholinesterase in postmortem human brain frontal cortex were 14nmol/l, 1.0 μιηοΐ/ΐ and 3.2 μηιόΐ/ΐ versus 15 nmol/1, 1.1 μτηοΐ/ΐ and 2.8 μιηοΐ/ΐ in the hippocampus region. In addition, the Inhibition of acetylcholinesterase by galanthamine was similar in postmortem brain and brain cortical biopsies from patients submitted to brain-tumour removal, indicating that postmortem changes up to 28 h after death probably did not influence the measurement of acetylcholinesterase Inhibition. While physostigmine and tacrine acted equally on acetylcholinesterase from different sources, galanthamine was 10-fold less potent in inhibiting the enzyme activity from human brain than from human erythrocytes. Comparison with issues from mice revealed that galanthamine was selectively more potent in suppressing acetylcholinesterase in human erythrocytes. The results are discussed in the light of pharmacokinetic data, and conclusions are drawn for further clinical studies.in Alzheimer's disease were determined: the frontal Reversible cholinesterase inhibitors are currently used cortex and the hippocampus. Since measurement of for symptomatic treatment of cognitive deficits and red-cell acetylcholinesterase Inhibition ex vivo may memory impairment in Alzheimer's disease. One pos-predict enzyme Inhibition in the brain (6, 7), it seemed tulated mechanism is restoration of the cholinergic useful to perform additional in vitro experiments with deficit at synaptic sites in the brain by inhibition of erythrocytes. Postmortem acetylcholinesterase activacetylcholine metabolisipti (1), b t severalother mech^ ity has been shown to be stable (8) for at least 31 h. anisms have also been discussed (2 -5). It was the It has also been reported, however, that the 4S and purpose of this study to measure the inhibition of 10S molecular forms in the brain are extremely labile acetylcholinesterase 1 ) from various sources by galan-and that freezing of either subcellular or intact tissue thamine, physostigmine and tacrine. A series of con-causes dramatic shifts in the level of the molecular centration response trials was performed using human forms (9), although the molecular shift was not asbrain tissue; and, prior to further specified analysis soeiated with any change of total acetylcholinesterase currently in progress, two separate regions of interest activity. To identify possible alterations in postmortem tissue, the inhibition of acetylcholinesterase by 1 ) Enzymes: Acetyl holinesterase, EC 3.1.1.7 galanthamine in fresh human brain cortex samplesEur.