Phases of A beta-deposition in the human brain and its relevance for the development of AD

BACKGROUND: The deposition of the amyloid beta protein (Abeta) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Abeta-deposition. OBJECTIVE: To clarify whether there is a hierarchical involvement of the regions of the entire brain as well and whether there are differences in the expansion of Abeta-pathology between clinically proven AD cases and nondemented cases with AD-related pathology, the authors investigated 47 brains from demented and nondemented patients with AD-related pathology covering all phases of beta-amyloidosis in the MTL (AbetaMTL phases) and four control brains without any AD-related pathology. METHODS: Abeta deposits were detected by the use of the Campbell-Switzer silver technique and by immunohistochemistry in sections covering all brain regions and brainstem nuclei. It was analyzed how often distinct regions exhibited Abeta deposits. RESULTS: In the first of five phases in the evolution of beta-amyloidosis Abeta deposits are found exclusively in the neocortex. The second phase is characterized by the additional involvement of allocortical brain regions. In phase 3, diencephalic nuclei, the striatum, and the cholinergic nuclei of the basal forebrain exhibit Abeta deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Abeta-deposition. The 17 clinically proven AD cases exhibit Abeta-phases 3, 4, or 5. The nine nondemented cases with AD-related Abeta pathology show Abeta-phases 1, 2, or 3. CONCLUSIONS: Abeta-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Abeta-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Abeta. There are also indications that clinically proven AD cases with full-blown beta-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Abeta pathology.     

Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer's disease neurofibrillary degeneration

The major component of Alzheimer's disease (AD) neurofibrillary tangles (NFTs) is abnormally hyperphosphorylated tau aggregated as paired helical filaments (PHFs). Cell division cycle (cdc) 2 kinase is one of the main candidate kinases that phosphorylates normal tau in vitro at several sites seen in PHF-tau. Using brains staged according to Braak and Braak criteria, we investigated the role of cdc2 in neurofibrillary changes in the hippocampal formation, and the entorhinal and temporal cortices. Neurons with tangle-like inclusions positive for active cdc2 were found to appear first in the Pre-alpha layer of the entorhinal cortex, and then extend to other brain regions co-incident with the progressive sequence of neurofibrillary changes. This predictable progressive pattern is not associated with amyloid. The intraneuronal accumulation of active cdc2 appeared to precede the deposition of PHF-tau phosphorylated at Ser 202/Thr 205 sites. These data are consistent with the notion that cdc2 might be involved in the abnormal hyperphosphorylation of tau and consequently aggregation of tau into PHF at an early stage and that increased cdc2 activity is not consequent to the deposition of beta-amyloid in AD brain.     

Disarming the mustard oil bomb

Plants are attacked by a broad array of herbivores and pathogens. In response, plants deploy an arsenal of defensive traits. In Brassicaceae, the glucosinolate-myrosinase complex is a sophisticated two-component system to ward off opponents. However, this so-called "mustard oil bomb" is disarmed by a glucosinolate sulfatase of a crucifer specialist insect, diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae). Sulfatase activity of this enzyme largely prevents the formation of toxic hydrolysis products arising from this plant defense system. Importantly, the enzyme acts on all major classes of glucosinolates, thus enabling diamondback moths to use a broad range of cruciferous host plants.     

Dose reduction in CT examination of children by an attenuation-based on-line modulation of tube current (CARE Dose)

In a controlled patient study we investigated the potential of attenuation-based on-line modulation of the tube current to reduce milliampere values (mAs) in CT examinations of children without loss of image quality. mAs can be reduced for non-circular patient cross sections without an increase in noise if tube current is reduced at those angular positions where the patient diameter and, consequently, attenuation are small. We investigated a technical approach with an attenuation-based on-line control for the tube current realised as a work-in-progress implementation. The CT projection data are analysed in real time to determine optimal mAs values for each projection angle. We evaluated mAs reduction for 100 spiral CT examinations with attenuation-based on-line modulation of the tube current in a group of children. Two radiologists evaluated image quality by visual interpretation in consensus. We compared the mAs values read from the CT scanner with preset mAs of a standard protocol. Four different scan regions were examined in spiral technique (neck, thorax, abdomen, thorax and abdomen). We found the mAs product to be reduced typically by 10-60% depending on patient geometry and anatomical regions. The mean reduction was 22.3% (neck 20%, thorax 23%, abdomen 23%, thorax and abdomen 22%). In general, no deterioration of image quality was observed. There was no correlation between the age and the mean mAs reduction in the different anatomical regions. By classifying the children respectively to their weight, there is a positive trend between increasing weight and mAs reduction. We conclude that mAs in spiral CT examinations of children can be reduced substantially by attenuation-based on-line modulation of the tube current without deterioration of image quality. Attenuation-based on-line modulation of tube current is efficient and practical for reducing dose exposure to children.     

Characterization of oxalic acid derivatives as new metabolites of metamizol (dipyrone) in incubated hen's egg and human.

Metamizol (dipyrone, 1), a widely used drug with effective analgesic and antispasmodic properties, shows severe side effects like agranulocytosis and anaphylactic shock reactions, the reasons of which are not known until today. After oral administration 1 is completely metabolized. All hitherto known metabolites have an intact pyrazolinone ring structure like the parent compound and are completely extractable from urine with polar organic solvents. However, only a fractional amount of the applied dosage can be recovered by this procedure. To clarify the reason of this deficit of unknown metabolites we followed the hypothesis of oxidative rupture of the heterocyclic ring during metabolism of 1. On the basis of former in vitro results we now were able to identify in quality three oxalic acid derivatives and one acetic acid phenylhydrazide as new metabolites of metamizol in the allantoic fluid (AF) of incubated hen's eggs as well as in human urine by means of GC-MS analysis and comparison with unequivocally synthesized authentic reference compounds. Whereas the oxamazide 7, the phenylhydrazide 8 and N-methyloxamic acid 9 are only present in trace concentrations and therefore cannot account for the deficit in the balance of metabolites, the oxalic acid monohydrazide 11 seems to be excreted in higher amount. But quantitative determination of this new metabolite would be required to answer the open questions concerning the biotransformation of metamizol and thereby to detect new facts about mode of action and side effects of this drug.     

Approximate Entropy as an Electroencephalographic Measure of Anesthetic Drug Effect during Desflurane Anesthesia

Background: The authors hypothesized that the electroencephalogram (EEG) during higher anesthetic concentrations would show more "order" and less "randomness" than at lower anesthetic concentrations. "Approximate entropy" is a new statistical parameter derived from the Kolmogorov-Sinai entropy formula which quantifies the amount of regularity in data. The approximate entropy quantifies the predictability of subsequent amplitude values of the EEG based on the knowledge of the previous amplitude values. The authors investigated the dose-response relation of the EEG approximate entropy during desflurane anesthesia in comparison with spectral edge frequency 95, median frequency, and bispectral index.

Methods: Twelve female patients were studied during gynecologic laparotomies. Between opening and closure of the peritoneum, end-tidal desflurane concentrations were varied between 0.5 and 1.6 minimum alveolar concentration (MAC). The EEG approximate entropy, median EEG frequency, spectral edge frequency 95, and bispectral index were determined and the performance of each to predict the desflurane effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modeling, was compared.

Results: Electroencephalogram approximate entropy decreased continuously over the observed concentration range of desflurane. The performance of the approximate entropy (prediction probability PK = 0.86 +/- 0.06) as an indicator for desflurane concentrations is similar to spectral edge frequency 95 (PK = 0.86 +/- 0.06) and bispectral index (PK = 0.82 +/- 0.06) and is statistically significantly better than median frequency (PK = 0.78 +/- 0.06).     

Changes of pressure and humidity affect olfactory function

The present study aimed at investigating the question whether olfactory function changes in relation to barometric pressure and humidity. Using climate chambers, odor threshold and discrimination for butanol were tested in 75 healthy volunteers under hypobaric and hyperbaric, and different humidity conditions. Among other effects, olfactory sensitivity at threshold level, but not suprathreshold odor discrimination, was impaired in a hypobaric compared to a hyperbaric milieu, and thresholds were lower in humid, compared to relatively dry conditions. In conclusion, environmental conditions modulate the sense of smell, and may, consecutively, influence results from olfactory tests.     

Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings

The majority of patients showing neuronal migration disorders in cortical structures suffer from pharmaco-resistant epilepsy. In order to study the molecular and cellular mechanisms underlying this pronounced hyperexcitability, we used an animal model of focal cortical dysplasia demonstrating structural malformations which resemble the human pathology of microgyria. Neocortical slices prepared from adult rats, which at the day of birth received a cortical freeze lesion, were analysed in vitro with an array of eight extracellular recording electrodes to investigate the pattern and pharmacology of propagating epileptiform activity in microgyric cortex. In cortical slices exhibiting neuronal migration disorders, orthodromic synaptic stimulation elicited late recurrent activity and early epileptiform responses that spread with 0.06 m/s over ≥ 3.5 mm across the cortex. Application of a N-methyl-d -aspartate (NMDA) antagonist blocked the late recurrent activity, but not the propagation of the early epileptiform responses. The latter were blocked by an (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist, indicating that the spread of this activity was predominantly mediated by activation of AMPA receptors. A very similar response pattern could be observed in neocortical slices obtained from untreated age-matched control rats, when the slice was partially disinhibited by bath-application of 5 μm bicuculline methiodide. Stimulus-evoked epileptiform signals recorded in disinhibited slices propagated with 0.08 m/s across the cortex and showed the same sensitivity to ionotropic glutamate antagonists as in dysplastic cortex. Our results indicate that widespread structural and/or functional modifications of the AMPA receptor and possibly also of the γ-amino-butyric acid type A receptor contribute to the pronounced hyperexcitability in dysplastic cortex.     

c-erbB2 and topoisomerase IIalpha protein expression independently predict poor survival in primary human breast cancer: a retrospective study

Introduction

c-erbB2 (also known as HER-2/neu) and topoisomerase IIα are frequently overexpressed in breast cancer. The aim of the study was to analyze retrospectively whether the expression of c-erbB2 and topoisomerase IIα protein influences the long-term outcome of patients with primary breast cancer.

Methods

In this study c-erbB2 and topoisomerase IIα protein were evaluated by immunohistochemistry in formalin-fixed paraffin-embedded tissue from 225 samples of primary breast cancer, obtained between 1986 and 1998. The prognostic value of these markers was analyzed.

Results

Of 225 primary breast tumor samples, 78 (34.7%) showed overexpression of either c-erbB2 (9.8%) or topoisomerase IIα protein (24.9%), whereas in 21 tumors (9.3%) both proteins were found to be overexpressed. Patients lacking both c-erbB2 and topoisomerase IIα overexpression had the best long-term survival. Overexpression of either c-erbB2 or topoisomerase IIα was associated with shortened survival, whereas patients overexpressing both c-erbB2 and topoisomerase IIα showed the worst disease outcome (P < 0.0001). Treatment with anthracyclines was not capable of reversing the negative prognostic impact of topoisomerase IIα or c-erbB2 overexpression.

Conclusion

The results of this exploratory study suggest that protein expression of c-erbB2 and topoisomerase IIα in primary breast cancer tissues are independent prognostic factors and are not exclusively predictive factors for anthracycline response in patients with primary breast cancer.