Impact of aging: sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer's disease

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells.     

Blockade of long-term potentiation in the dendate gyrus of freely moving rats by the glutamic acid antagonist GDEE

In 34 male Wistar rats chronically implanted with ‘chemitrodes’ in the dorsal hippocampus and stimulating electrodes in the medial entorhinal cortex the effect of an intrahippocampal injection of the glutamic acid antagonist glutamic acid diethylester (GDEE) on the monosynaptically evoked field potentials in the dentate gyrus and the development of long-term potentiation was studied. The injection of 150 μg GDEE resulted in a marked depression of both the slope function of the EPSP component and the amplitude of the population spike of the extracellular field potential for about 120 min, thus indicating glutamatergic blockade in the stimulated pathway. Furthermore, the development of long-term potentiation after tetanic stimulation was markedly impaired when tested 120 min after tetanization. The result seems to indicate the involvement of transmitter-mediated postsynaptic processes in the development of hippocampal long-term potentiation.     

Die Aktivität der Creatinkinase und anderer Enzyme des Kohlenhydrat- und Proteinstoffwechsels in benignen und malignen Tumoren des Menschen

Zusammenfassung Erstmalig wird in benignen (Myomen) und malignen (Myosarkom, Spindelzellsarkom, Magen-, Portio-, Rectum- und Bronchialcarcinom) Tumoren des Menschen die Aktivität der Creatinkinase (CK) im Vergleich zu Enzymaktivitäten des Kohlenhydrat- (ALD, LDH, MDH, SDH) und Proteinstoffwechsels (GOT, GPT, GLDH) bestimmt. In Myomen besteht eine Korrelation zwischen Cytoplasmareichtum sowie Zahl der glatten Muskelzellen und der CK-Aktivität. Im Myosarkom, Magen-und Protiocarcinom ist die CK-Aktivität erniedrigt, im Rectum- und Bronchialcarcinom erhöht im Vergleich zu gesunden Geweben. In allen untersuchten Carcinomen (Ausnahme Magenkrebs) und im Myosarkom ist die LDH-Aktivität im Vergleich zu gesunden Geweben bzw. benignen Veränderungen erhöht, die MDH-Aktivität im Myosarkom, Spindelzellsarkom und Magencarcinom erniedrigt, im Rectum-, Portio- und Bronchialcarcinom erhöht. Die Aktivitäten der Transaminasen, ALD und SDH verhalten sich unterschiedlich, diejenigen der GLDH sind erniedrigt. In den untersuchten Tumoren besteht eine Korrelation zwischen Höhe der ALD- und SDH-Aktivität. Die Ergebnisse werden im Hinblick auf den gestörten Energiestoffwechsel der Krebszelle diskutiert.Die in Carcinomen des Magens und der Portio sowie im Myosarkom gegenüber gesunder Magenschleimhaut, Portioerosion und Myomen zum Teil signifikant erniedrigte CK-Aktivität zeigt eine neue Möglichkeit der enzymatischen Carcinomdiagnose, zumal viele der getesteten Enzyme des Kohlenhydratstoffwechsels sich als relativ unspezifisch erwiesen haben.

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Summary For the first time the activity of Creatine Kinase (CK) and activities of enzymes of the carbohydrate and protein metabolism were determined in benign and malignant tumors of the human body. In myomas the activity of Creatine Kinase is in correlation with the quantity of cytoplasm and the number of smooth muscle cells. As compared with normal healthy tissues the activity of this enzyme is smaller in carcinomas of the stomach and the uterine cervix, also in a sarcoma of the myometrium, but it is higher in rectal and bronchial carcinomas. The activity of the Lactic Dehydrogenase was higher in all examined carcinomas (exception: gastric carcinoma) and the activity of the Malic Dehydrogenase was smaller (ecxeption: rectal, bronchial, cervical carcinoma) than those of normal healthy tissues, whilst the activities of transaminases, FDP-Aldolase and Sorbit Dehydrogenase were higher or smaller and the activity of Glutamat Dehydrogenase was low. In the examined tumors the activity of FDP-Aldolase was in correlation with the activity of Sorbit Dehydrogenase. The results give some new aspects how to diagnose carcinomas by the activity of enzymes.Die Zellfraktionierung wurde in der biochemischen Abteilung des chemischen Instituts der Universität Heidelberg durchgeführt. Herrn Priv.-Doz. Dr.Knappe aus obigem Institut und Herrn Prof. Dr.B. Hess, Medizinische Klinik der Universität Heidelberg, danke ich für Anregung und liebenswürdige Unterstützung, ebenso der Fa. C. F. Boehringer & Soehne, Mannheim, für Überlassung der Testsubstanzen.

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Mit Unterstützung der Fa. C. F. Boehringer & Soehne, Mannheim.     

Effekt einer neuen Oberfl?chenbehandlung von Intraokularlinsen aus Silikon durch ein Fluoralkylsilan auf das Adh?renzverhalten Endophthalmitis-relevanter Bakterien in vitro

ZusammenfassungEinleitungDynasilan ^® ist ein Fluoralkylsilan, das an aktive OH-Molekülgruppen der Linsenoberfläche gebunden werden kann und somit eine neue Möglichkeit der Oberflächenmodifikation von Intraokularlinsen (IOL) aus Silikon bietet. In der vorliegenden Untersuchung wurde der Effekt dieser neuen Oberflächenbehandlung an Silikon-IOL auf das Adhärenzverhalten zweier Endophthalmitis-relevanter Keime, Staphylococcus epidermidis und Propionibacterium acnes, in vitro überprüft.Material und MethodenIn 2 Versuchsreihen wurden jeweils 14 Silikonlinsen entweder mit 10 ⁸ KBE/ml Staphylococcus epidermidis oder Propionibacterium acnes für 24 h bei 37°C in Brain-Heart-Infusion inkubiert. Die Hälfte, also 7 IOL jeder Versuchsreihe, wurde vorher durch 1-stündige Tauchbehandlung und Trocknung bei Raumtemperatur mit Dynasilan ^® behandelt, die andere Hälfte unbehandelt gelassen. Anschließend wurden die adhärenten Keime durch 2-maliges Waschen und eine Ultraschallbehandlung (35 KHz, 3-mal 45 s) resuspendiert und mit Hilfe einer Verdünnungsreihe quantifiziert.ErgebnisseAuf unbeschichteten mit Staphylococcus epidermidis inkubierten IOL waren die mittleren Keimzahlen 3,6·10 ⁷/ml, bei den Dynasilan ^®-behandelten IOL 1,09·10 ⁷/ml. Bei Propionibacterium acnes betrugen die mittleren Keimzahlen auf unbehandelten IOL 4,75·10 ⁴/ml, auf den Dynasilan ^®-behandelten IOL 2,94·10 ⁴/ml.SchlussfolgerungDie Oberflächenmodifikation von IOL mittels Dynasilan ^® scheint die Adhärenz zweier Endophthalmitis-relevanter Keime auf Silikonlinsen zu senken. Weitere Versuche zur Stabilität der Oberflächenmodifikation, ihrer Biokompatibilität und ihres Einflusses auf die Adhäsion von Linsenepithelzellen werden zurzeit durchgeführt.     

The correlation between immunohistochemically-detected markers of angiogenesis and serum vascular endothelial growth factor in patients with breast cancer

BACKGROUND: As angiogenesis is known to be a crucial factor in breast cancer growth, numerous studies have examined angiogenic markers in breast cancer. Their definite role, however, has not been fully elucidated. MATERIALS AND METHODS: We investigated intratumoral microvessel density (MVD), Vascular Endothelial Growth Factor (VEGF) and its receptor flk-1, and serum VEGF in 46 patients with breast cancer prior to surgery. RESULTS: Median serum VEGF in patients with breast cancer was 257.5 pg/mL (range, 21.9 to 899.6). Serum VEGF showed a significant correlation with tumor stage, but not with lymph node involvement, histological grade, estrogen and progesterone receptor status. Increased MVD was associated with advanced tumor stage (p=0.05) and high tumor grade (p<0.001). A linear significant correlation between elevated serum VEGF and increased MVD was ascertained (p=0.02). CONCLUSION: Our results suggested that angiogenesis as reflected by immunohistochemically-detected MVD and serum VEGF, is involved in breast cancer growth and lymphatic spread.     

Improvement of albuminuria after renal denervation

Objectives

The primary objective of this study was the effect of renal denervation (RDN) on elevated urinary albumin-to-creatinine ratio (UACR) in treatment-resistant hypertensive patients. In addition, patients were stratified according their UACR at baseline into micro- (30–300 mg/g, n = 37) and macroalbuminuria (≥ 300 mg/g, < 2200 mg/g, n = 22).

Background

Increased albuminuria indicates cardiovascular and renal damage in hypertension. RDN emerged as an innovative interventional approach to reduce blood pressure (BP) and may thus reduce albumin urinary excretion.

Methods

Fifty-nine treatment-resistant hypertensive patients with elevated UACR at baseline underwent catheter-based RDN using the Symplicity Flex™ catheter (Medtronic Inc., Santa Rosa, CA).

Results

In the whole and pre-specified subgroups both office and 24-h ambulatory BP were significantly reduced 6 months after RDN. In parallel, a significant reduction in UACR occurred in all patients (160 (65–496) versus 89 (29–319) mg/g creatinine, p < 0.001) and in both subgroups (microalbuminuria: 83 (49–153) versus 58 (17–113) mg/g creatinine, p = 0.001; macroalbuminuria: (536 (434–1483) versus 478 (109–1080) mg/g creatinine, p < 0.001). In accordance, the prevalence of micro- and macroalbuminuria decreased significantly. Regression analysis revealed a modest positive relationship between the decrease of UACR and the fall of systolic BP (β = 0.340, p = 0.039) independent of renal function. Renal function remained unchanged after RDN.

Conclusions

In summary, following RDN, the magnitude of albuminuria as well as the prevalence of micro- and macroalbuminuria decreased in treatment-resistant hypertensive patients. Since albuminuria is an independent renal and cardiovascular risk factor, our findings suggest a reduction of renal and cardiovascular risk in these patients.     

Naturally Occurring Genetic Variants of Human Caspase‐1 Differ Considerably in Structure and the Ability to Activate Interleukin‐1β

Caspase‐1 (Interleukin‐1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)‐1β and IL‐18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase‐1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL‐1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase‐1 is compatible with normal life and does not prevent moderate and severe autoinflammation.