[Consensus statement "Dementia 2010" of the Austrian Alzheimer Society]. / Konsensusstatement "Demenz 2010" der Osterreichischen Alzheimer Gesellschaft.

The Austrian Alzheimer Society developed evidence-based guidelines based on a systematic literature search and criteria-guided assessment with subsequent transparent determination of grades of clinical recommendation. The authors evaluated currently available therapeutic approaches for the most common forms of dementia and focused on diagnosis and pharmacological intervention, taking into consideration the situation in Austria. The purpose of these guidelines is the rational and cost-effective use of diagnostic and therapeutic measures in dementing illnesses. Users are physicians and all other providers of care for patients with dementia in Austria.

Amelioration of murine colitis by feeding a solution of lysed Escherichia coli.

BACKGROUND: Immune reactivity towards the bacterial intestinal flora plays an important part in the pathogenesis of inflammatory bowel disease. Disease activity can be positively influenced by the administration of living probiotic bacteria. We investigated the effect of soluble bacterial antigens extracted from Escherichia coli (strain Laves) on the disease activity of murine colitis. METHODS: C3H.IL-10-/- and BALB/c mice with dextran sulphate sodium-induced colitis were treated with either a bacterial lysate from E. coli or with a placebo. Mice were monitored and inflammation was assessed by histological scoring, analysis of fecal IL-1beta and measurement of cytokine production by ELISA. T cell proliferation was quantified by 3H-thymidine incorporation. RESULTS: Clinically and histologically, bacterial-lysate-treated mice revealed significantly (P < 0.05) fewer signs of colitis than placebo-treated mice. Fecal IL-1beta and mucosal TNF-alpha and IFN-gamma concentrations were significantly lower (P < 0.05) in verum-treated mice than in the placebo group. Furthermore, lymphocyte proliferation after stimulation with lipopolysaccharide or caecal bacterial antigen was significantly (P < 0.05) reduced in verum-treated mice. CONCLUSION: The use of E. coli lysate is effective in the amelioration of murine colitis. This effect may be due to a decreased Th1 reaction and to an induction of tolerance against bacterial antigens.

Double-blind randomised placebo-controlled phase III study of an E. coli extract plus 5-fluorouracil versus 5-fluorouracil in patients with advanced colorectal cancer.

The primary aim of this study was to evaluate the toxicity (mucositis, diarrhea and leucopenia) of a therapy with 5-fluorouracil (CAS 51-21-8; 5-FU) plus an E. coli extract (LC-Extract, Laves coli extract, Colibiogen inject, cell-free soluble fraction from lysed E. coli, Laves strain) in comparison with 5-FU plus placebo. Secondary endpoints included general toxicity, response rate according to WHO, survival time and quality of life. 164 patients with advanced colorectal cancer were enrolled in this randomised, placebo-controlled, double-blind, multicenter phase III study. The treatment consisted of 0.167 ml/kg/d LC-Extract or placebo followed by 500-750 mg/m2/d 5-FU on five consecutive days, repeated every three weeks for up to six treatment cycles. 158 (77 verum, 81 placebo) patients were evaluable for toxicity, 144 (72 verum, 72 placebo) evaluable for response. The therapy with LC-Extract was well tolerated. Adverse events that occurred during the study were mainly judged as 5-FU- or tumor-related. Toxicity from treatment with 600 mg/m2/d 5-FU in both treatment groups was very low. After treatment with 750 mg/m2/d 5-FU patients in the placebo-group experienced a higher CTC toxicity than in the LC-Extract groups. Remission rate and survival time showed a slight trend in favour of LC-Extract. These results suggest a positive benefit-risk ratio of the additional application of LC-Extract to 5-FU in the treatment of advanced colorectal cancer especially for administration of high doses of 5-FU.

Protein tyrosine phosphatase alpha (PTPalpha) and contactin form a novel neuronal receptor complex linked to the intracellular tyrosine kinase fyn.

Glycosyl phosphatidylinositol (GPI)-linked receptors and receptor protein tyrosine phosphatases (RPTPs), both play key roles in nervous system development, although the molecular mechanisms are largely unknown. Despite lacking a transmembrane domain, GPI receptors can recruit intracellular src family tyrosine kinases to receptor complexes. Few ligands for the extracellular regions of RPTPs are known, relegating most to the status of orphan receptors. We demonstrate that PTPalpha, an RPTP that dephosphorylates and activates src family kinases, forms a novel membrane-spanning complex with the neuronal GPI-anchored receptor contactin. PTPalpha and contactin associate in a lateral (cis) complex mediated through the extracellular region of PTPalpha. This complex is stable to isolation from brain lysates or transfected cells through immunoprecipitation and to antibody-induced coclustering of PTPalpha and contactin within cells. This is the first demonstration of a receptor PTP in a cis configuration with another cell surface receptor, suggesting an additional mode for regulation of a PTP. The transmembrane and catalytic nature of PTPalpha indicate that it likely forms the transducing element of the complex, and we postulate that the role of contactin is to assemble a phosphorylation-competent system at the cell surface, conferring a dynamic signal transduction capability to the recognition element.

Attenuated expression of the serum responsive T1 gene in ras transformed fibroblasts due to the inhibition of c-fos gene activity.

The T1 gene encodes a protein, which shares homology with the IL-1 receptors. In fibroblasts, T1 is induced by growth factors and in response to the onset of oncogene expression. The c-fos gene is transiently activated in these situations and was shown to be the major mediator of T1 gene induction. In contrast, the sustained expression of a ras oncogene in NIH3T3 cells resulted in the downregulation of basal T1 gene activity and the attenuation of T1 gene induction in response to mitogenic signals. Likewise, the immediate early genes encoding c-Fos, FosB, and Fra-2 are repressed in these cells. T1 gene repression could be overcome by the forced expression of c-fos in ras transformed fibroblasts. Thus, the lack of c-fos gene expression is the likely cause for ras mediated T1 gene repression. Fra-1, in contrast to the other three members of the Fos family, is permanently synthesized in high amounts in ras transformed NIH3T3 fibroblasts. We show that AP-1, which is abundant in these cells throughout the whole cell cycle, consists predominantly of Fra-1/c-Jun and Fra1/JunD heterodimers. We provide evidence that Fra1/c-Jun heterodimers are responsible for the repression of c-fos gene induction following serum stimulation. The introduction of a dominant negative version of c-Jun into ras transformed fibroblasts was able to rescue c-fos gene induction in response to serum stimulation, further demonstrating that AP-1 is indeed involved in c-fos gene repression. We conclude that oncogenic ras mediates the activation of the fra-1 gene which results in elevated AP-1 activity throughout the cell cycle. Fra-1 containing AP-1 complexes repress the c-fos and possibly other immediate early genes thereby preventing the induction of certain delayed early genes such as the T1 gene in response to mitogenic stimulation.

Cooperative interactions of AP-1 and basic helix-loop-helix transcription factors regulate T1 gene expression.

The T1 gene is a murine, delayed early serum-responsive gene that encodes glycoproteins of the interleukin-1 receptor (IL-1R) family. Transcription of the T1 gene leads to production of two mRNAs that encode a transmembrane protein, which is highly similar to the type-1 IL-1R, and a secreted protein, which consists solely of the extracellular part. Fibroblasts, in contrast to mast cells, express predominantly the shorter form of the protein, and several mitogens cause strong, transient induction of the T1 gene in these cells. Here we describe the identification of a 148 bp enhancer element that is positioned 3.6 kb upstream of the transcription initiation site. A TPA-responsive element (TRE) and three identical E-boxes are located within this sequence. Introduced point mutations confirmed the necessity of these sites for full T1 promoter activity. The TRE and the distal E-box are absolutely indispensable for promoter function, whereas the two proximal E-boxes contribute less to promoter strength. In vitro the three E-boxes are bound by different protein complexes.

Kinetic analysis of two closely related receptor-like protein-tyrosine-phosphatases, PTP alpha and PTP epsilon.

Among transmembrane protein-tyrosine-phosphatases, the membrane distal catalytic domain (D2) of protein-tyrosine-phosphatase alpha (PTP alpha) is unusual in having low but detectable activity in the absence of the membrane proximal catalytic domain (D1). To investigate the catalytic properties of PTP alpha D2 in association with D1, kinetic parameters of activity were established for PTP alpha D1D2 proteins containing an inactivating point mutation in D1 and/or D2. In this context, D2 activity was unchanged by the presence (N-terminal or C-terminal) or absence of inactive D1, and the presence or absence of inactive D2 affected the velocity but not the Km of D1 catalysis. While D1 appears to be the major catalytic contributor to PTP alpha activity, D2 possesses a significantly higher substrate-specific activity relative to wild-type D1D2 than the D2 domains of other protein-tyrosine-phosphatases. Also, PTP alpha D2 is an active phosphatase with comparable or better efficiency, on the basis of k(cat)/Km criteria, to some of the dual specificity phosphatases. Kinetic parameters of a closely related receptor-like protein-tyrosine-phosphatase, PTP epsilon, were determined. PTP epsilon D1 is the major, if not the only, catalytic moiety of PTP epsilon, and has much higher turnover numbers than D1 of PTP alpha. The PTP epsilon D2 activity is insignificant compared to that of PTP epsilon-D1D2, with lower turnover numbers than PTP alpha D2. Thus, the intrinsic activity of PTP alpha D2 is high compared to other D2 domains and, more outstandingly, its activity relative to D1 appears unique. These are also apparent upon in vitro assay of full-length PTP alpha catalytic mutants expressed in mammalian cells. Together. these results suggest potential catalytic and regulatory roles for PTP alpha D2, and that PTP alpha may be an optimal model transmembrane protein-tyrosine-phosphatase for investigating the former within the cell.

Growth factor-mediated induction of the delayed early gene T1 depends on a 12-O-tetradecanoylphorbol 13-acetate-responsive element located 3.6 kb upstream of the transcription initiation site.

The T1 gene is a delayed early serum-responsive gene which encodes a secreted glycoprotein of the immunoglobulin superfamily. We have addressed the question of what promoter elements are needed to allow for growth factor-mediated T1 gene expression. By deletion analysis we have identified a 448-bp DNA region 3.5-4.0 kb upstream of the transcription start site which can confer serum inducibility onto a foreign minimal promoter. Within this sequence there is a 12-O-tetradecanoylphorbol 13-acetate (TPA)-responsive element (TRE) which is essential for T1 promoter induction in response to the forced expression of the transcription factor AP-1 in NIH 3T3 fibroblasts and F9 teratocarcinoma cells. This TRE is crucial for growth factor-mediated T1 gene expression. A point mutation within this TRE attenuated serum inducibility. Two E boxes are positioned 6 and 40 bp downstream of the TRE. Point mutations within these sequence motifs reduced basal T1 promoter activity and serum inducibility. Additional, as-yet-unidentified, promoter elements within the 448-bp serum-responsive region are required for T1 gene activation in response to growth stimulation.

T1 is a c-Fos- and FosB-responsive gene which is induced by growth factors through multiple signal transduction pathways.

Stimulation of quiescent cells with growth factors triggers changes in gene expression through multiple signal transduction pathways. One of these changes in Swiss 3T3 cells is the strong accumulation of T1 mRNA which encodes a secreted glycoprotein of the immunoglobulin superfamily. Proliferating cells continued to express T1 mRNA at a lower level, whereas growth arrest induced either by serum deprivation or by contact inhibition was paralleled by the disappearance of the T1 mRNA. T1 mRNA synthesis in response to serum and platelet-derived growth factor stimulation is mediated through protein kinase C-dependent and protein kinase C-independent pathways. Activation of protein kinase A also led to T1 gene expression. Ongoing protein synthesis is a prerequisite for T1 gene induction by growth factors which defines T1 as a delayed early serum-responsive gene. The ability of the immediate early transcription factors c-Fos and FosB to directly induce the T1 gene was demonstrated in a conditional expression system in the absence of protein synthesis. Furthermore, all known inducers of the T1 gene also lead to c-fos gene activation. Thus we show that the T1 gene is regulated by signals which are transduced through multiple pathways and provide evidence that the Fos proteins play an important role in the integration of these pathways.

The axonally secreted cell adhesion molecule, axonin-1. Primary structure, immunoglobulin-like and fibronectin-type-III-like domains and glycosyl-phosphatidylinositol anchorage.

Axonin-1 is an axon-associated cell adhesion molecule (AxCAM) of the chicken, which promotes neurite outgrowth by interaction with the AxCAM L1(G4) of the neuritic membrane. Here we report the cloning and sequence determination of a cDNA encoding axonin-1. Peptides generated by enzymatic cleavage showed similarity to the AxCAM F11. Degenerated polymerase chain reaction (PCR) primers were designed and an axonin-1 fragment was amplified from mRNA of embryonic retina. Screening of a cDNA library from embryonic brain resulted in the isolation of a 4.0-kb cDNA insert with an open reading frame of 3108 nucleotides. The deduced polypeptide of 1036 amino acids includes a putative hydrophobic N-terminal signal sequence of 23 or 25 amino acids and a C-terminal hydrophobic sequence of 29 amino acids which is suggestive of sequences serving as signal for the attachment of a glycosyl-phosphatidylinositol (glycosyl-PtdIns) anchor. The putative mature form of axonin-1 comprises six immunoglobulin-like repeats, followed by four fibronectin-type III repeats. Axonin-1 exhibits 75% amino acid identity with the AxCAM TAG-1 of the rat, suggesting that it is the chicken homologue of TAG-1. Like TAG-1, axonin-1 is glycosyl-PtdIns-anchored to the neuronal membrane; in contrast to TAG-1, it does not exhibit an Arg-Gly-Asp sequence.

[Gerontopsychiatric patients in psychiatric facilities]. / Gerontopsychiatrische Patienten in psychiatrischen Einrichtungen.

The population of Vienna is relatively old. The structure of care and support for aged patients is described. The relative share of aged patients in all admissions to the large mental hospital is smaller than their share in total population. Reduction in the number of in-patients also included the group of patients over 65 years. The task force "Ubergangspflege" (i.e.: transitional nursing) prepares and supports the deinstitutionalization of recently admitted and of long-stay patients. Utilization of a regionalized out-patients psychiatric department shows differences between the age group 60-80 years and the group over 80 years.

Correlative pathology of subdural hematoma with computerized tomography.

Subdural hematoma (SDH) develops as a result of bleeding in the subdural space. According to nowadays accepted division, three groups of subdural hematomas can be differentiated: acute, subacute and chronic. The time elapsed from the moment of the occurrence of the hematoma to the moment when it was diagnosed is the main factor for determining the stage of SDH. However, for the above-mentioned types of SDH, this time differs depending on the author reporting it. Subdural hematoma is most often diagnosed by means of computerized tomography (CT). This method is safe and reliable, giving the exact diagnosis in more than 90% of cases. According to the basic principle of the concept of "living pathology", the knowledge of histological appearance of an investigated lesion is essential for the diagnostic interpretation of this lesion in neuroimaging methods. Very few authors studied the histological picture of subdural hematoma. The only structure which was histologically examined in details was the subdural neomembrane. Studies correlating histological picture of SDH and its appearance on CT scans have not been carried out until now. In this work such a correlation was made, and some regularities connecting these two methods were pointed out. Hyperdense picture of SDH on CT scans represents a hematoma containing almost only erythrocytes and erythrocyte-fibrin component being formed. Hypodense picture of SDH on CT scans represents a hematoma containing fibrin and inflammatory cells. Hematomas of mixed density on CT scan in all cases contained a neomembrane. Obvious histological differences between the mentioned types of subdural hematoma have led to the conclusion that chronic subdural hematoma is not the last stage of an "old" acute SDH. Chronic and acute subdural hematomas are different entities, considering their etiopathogenetic and clinical picture, and especially their CT and histopathological appearances.

Principal advantages of CNS diagnostics by magnetic resonance imaging.

In this paper the authors present the principal advantages and values of CNS diagnostics by magnetic resonance imaging (MRI), on the basis of the data from the available literature as well as on the 3-year experience of the MRI Institute in Innsbruck. Also, qualitative advantages of MR 1.5 T over other, less powerful machines, have been emphasized. So far, the experience has proved that, for the moment, the 1.5 MR machine offers optimal characteristics for the diagnostics of the CNS diseases.

Correlative tissue pathology of intracranial neurinomas with computed tomography scans.

On computed tomography (CT) layers through the tumor the quality of picture depends upon the tumoral tissue structure, i.e., upon its histological appearance. In the formation of this histological appearance to a greater or lesser extent a series of various elements are involved, which are responsible for the density on CT scan, e.g., blood vessels, fatty tissue, calcium, connective tissue, collagen, etc. For some tumors the most important characteristic is specific organization of tissues in the volume, which can be clearly seen on high-quality CT scan. Possible limitations are due to technical capabilities of a CT apparatus. In our study we have obtained the most valuable results by analyzing the quality of picture of neurinomas on the so-called native CT scans, and by evaluating the way in which the picture of the tumoral tissue changed by opacification after an intravenous injection of contrast medium. Our study included 23 intracranial neurinomas. Twenty of them were neurinomas of the statoacoustic nerve, 1 of the orbit, 1 of the Gasser's gaglion and 1 was in the parasagittal region. For each particular tumor on histological specimens Antoni A and Antoni B types of tissue were semiquantitatively identified. In our study we have chosen only those cases for which we had a plenty of tumoral tissue suitable for semiserial analysis. The results of the histological analysis were compared with the results of the CT assessment of the tumoral tissue. Larger necrotic areas and cystic formations within tumoral tissue, which we could not analyze on our histological specimens, were excluded from the evaluation of CT scans of these tumors. Our results indicate a positive correlation between the histological appearance of neurinomas and their CT scans. This correlation between the histological properties of the tumoral tissue and the CT scan was almost 100% in those cases in which one histological type of neurinomas significantly prevailed. The prevalence of one type of neurinoma tissue was found in 74% of cases. In almost 61% of neurinomas in the histological appearance Antoni A type of tissue prevailed, what was clearly seen on CT in the form of hyperdense areas of the tumor. Antoni B type of tissue was histologically found in about 13% of neurinomas. These tumors had a marked hypodense picture of the tumoral tissue. The rest of neurinomas had mixed types of tissue. In this group of tumors we could not use the CT findings as an indicator in preoperative analysis of histopathological tissue characteristics.

[Neurocutaneous melanosis and melanoma of the brain]. / Neurokutana melanoza i melanomi mozga.

A case of neuro-cutaneous melanoma, in the course of which a bifocal melanoma of the cerebral hemisphere had developed, was used as a natural model for the study of the relation between tumorous and non-tumorous elements. The need is pointed out for the definition of such a cutaneous-meningeal syndrome before the development of a neoplasm. As tumours develop from the cells defining leptomeningeal melanosis, the possibility of a neuroradiological diagnosis of this process is accentuated, primarily by a minute examination of the sites characteristic of the disease. A premorbid detection of all such cases is imperative in order to introduce an early anti-tumour treatment.

[Subacute encephalitis caused by herpes simplex virus]. / Subakutni tok encefalitisa uzrokovanog virusom herpes simpleks.

The authors present a case of herpes-simplex encephalitis in a 58-year-old woman. The disease had a biphasic course and lasted 87 days. The clinical picture, laboratory data and the pathologic-anatomical changes of the disease are discussed. The authors also emphasize the importance of the encephalitic process in the brain stem, which can make the clinical picture even more complicated because of the appearance of respiratory disturbances.