Stereotactic radiosurgery for IDH wild type glioblastoma: an international,multicenter study

Journal of Neuro-Oncology - Isocitrate dehydrogenase (IDH) mutation status is recommended used for diagnosis and prognostication of glioblastoma patients. We studied efficacy and safety of...     

Significance of the endothelin ETA receptor in the haemodynamic and inotropic effects of endothelin-1 in rats

The main aim of the present study was to investigate the direct inotropic effects of stimulation of the endothelin (ET) receptor ETA under in vivo conditions. It is well known that ETA receptor stimulation causes pronounced vasoconstriction. The ET-1-induced coronary vasoconstriction may lead to myocardial ischaemia and, consequently, to cardiodepressor effects that may mask the direct positive inotropic effect of ETA receptor stimulation. Thus, in the present study, steps were taken to avoid this possibility. In anaesthetized open-chest rats the haemodynamic and inotropic effects of ETA receptor stimulation were studied by monitoring responses evoked by ET-1 (1 nmol/kg of body weight) after ETB receptor blockade with BQ 788 (0.5 micromol/kg of body weight); these responses were compared with saline controls (after ETB receptor blockade). To avoid vasoconstrictor effects induced by ETA receptor stimulation, additional experiments were performed in the presence of the vasodilator adenosine (2.0 mg.kg(-1) of body weight.min(-1)). Myocardial function was also examined during aortic clamping so as to circumvent the effect of changes in afterload. We studied further the effect of ETA receptor stimulation on myocardial energy metabolism. ETA receptor stimulation reduced cardiac output (-49% compared with control), raised total peripheral resistance (+173%) and reduced myocardial ATP content (-23%). Aortic clamping did not reveal a positive inotropic effect of ETA receptor stimulation. Furthermore, even though adenosine attenuated the decrease in cardiac output (-21%), the increase of total peripheral resistance (+48%) and prevented the fall of myocardial ATP content (+6%), this did not unmask a positive inotropic effect of ETA receptor stimulation. Thus we conclude that ETA receptor stimulation causes vasoconstriction and myocardial ischaemia, but has no positive inotropic effects in rats.     

Increased Dosage of DYRK1A and Brain Volumetric Alterations in a YAC Model of Partial Trisomy 21

A yeast artificial chromosome (YAC) transgenic murine model of partial trisomy 21 overexpressing five human genes—including DYRK1A, which encodes a serine threonine kinase involved in cell cycle control—has been shown to present an increase in brain weight. We analyzed this new phenotype by measuring total and regional brain volumes at different ages, using a 7 Tesla magnetic resonance imaging volumetric approach. Volumetric measurements showed a total volume increase of 13.6% in adult mice. Changes in brain morphogenesis were already visible at a very early postnatal stage (postnatal days 2–7). Region‐specific changes were characterized from postnatal day 15 to 5 months. These results, made it possible to define region‐specific effects of DYRK1A overexpression, with the strongest increase seen in the thalamus–hypothalamus area (24%). Anat Rec, 291:254–262, 2008. © 2008 Wiley‐Liss, Inc.     

Dexamethasone concentration gradients along scala tympani after application to the round window membrane.

HYPOTHESIS: Local application of dexamethasone-21-dihydrogen-phosphate (Dex-P) to the round window (RW) membrane of guinea pigs produces a substantial basal-apical concentration gradient in scala tympani (ST) perilymph. BACKGROUND: In recent years, intratympanically applied glucocorticoids are increasingly being used for the treatment of inner ear disease. Although measurements of intracochlear concentrations after RW application exist, there is limited information on the distribution of these drugs in the inner ear fluids. It has been predicted from computer simulations that substantial concentration gradients will occur after RW application, with lower concentrations expected in apical turns. Concentration gradients of other substances along the cochlea have recently been confirmed using a sequential apical sampling method to obtain perilymph. METHODS: Dexamethasone-21-dihydrogen-phosphate (10 mg/ml) was administered to the RW membrane of guinea pigs (n = 9) in vivo for 2 to 3 hours. Perilymph was then collected using a protocol in which 10 samples, each of approximately 1 mul, were taken sequentially from the cochlear apex into capillary tubes. Dexamethasone-21-dihydrogen-phosphate concentration of the samples was analyzed by high-performance liquid chromatography. Interpretation of sample data using a finite element model allowed the longitudinal gradients of Dex-P in ST to be quantified. RESULTS: The Dex-P content of the first sample in each experiment (dominated by perilymph from apical regions) was substantially lower than that of the third and fourth sample (dominated by basal turn perilymph). These findings qualitatively demonstrated the existence of a concentration gradient along ST. After detailed analysis of the measured sample concentrations using an established finite element computer model, the mean basal-apical concentration gradient was estimated to be 17,000. Both absolute concentrations of Dex-P in ST and the basal-apical gradients were found to vary substantially. CONCLUSION: The existence of substantial basal-apical concentration gradients of Dex-P in ST perilymph were demonstrated experimentally. If the variability in peak concentration and gradient is also present under clinical conditions, this may contribute to the heterogeneity of outcome that is observed after intratympanic application of glucocorticoids for various inner ear diseases.     

Stereotactic radiosurgery versus active surveillance for incidental,convexity meningiomas: a matched cohort analysis from the IMPASSE study

Journal of Neuro-Oncology - The optimal treatment strategy of asymptomatic, convexity meningiomas, remains unclear. The purpose of this study was to define the safety and efficacy of stereotactic...     

A case of apparent trisomy 21 without the Down''s syndrome phenotype.

We describe a case of apparent trisomy 21 that does not fulfill the criteria for the clinical diagnosis of Down's syndrome (DS). Our patient was subjected to karyotype analysis and found to have full, non-mosaic trisomy 21 in both blood lymphocytes and skin fibroblasts, while examination of the term placenta, which was performed earlier in the course of a different study, had shown mosaicism (73%) for trisomy 21. FISH analysis showed no obvious rearrangement of the DS chromosomal region in any of the chromosomes 21. Molecular analysis using polymorphic markers on chromosome 21 verified the existence of trisomy for the entire long arm of the chromosome and showed that the origin of the extra chromosome was maternal and was probably the result of a mitotic error. In contrast with the above, the clinical evaluation using the Jackson checklist of 25 signs failed to establish the diagnosis of DS. We believe that our patient might present mosaicism in other tissues that are not available for analysis and can be regarded as an extreme example in the continuous spectrum of karyotype phenotype associations in mosaic cases.     

Synthesis and degradation of NAD in guinea pig cardiac muscle:

Summary The NAD concentration as well as the¹⁴C-incorporation in NAD and the disappearance of¹⁴C-NAD were studied in spontaneously beating atria of guinea pigs at high and low concentrations of the precursors nicotinamide or nicotinic acid. Atria were incubated in Krebs-Henseleit solution containing 15 mM glucose and the appropriate precursors at 30°C. The control NAD concentration (33 nMol/100 mg w.w.) remained unchanged during a 24-h-incubation time.–20 mM¹⁴C-nicotinamide increased the total NAD about three-fold (90 nMol/100 mg w.w.) after an incubation period of 24 h, with positive effects on the performance. The incorporation rate in¹⁴C-NAD was calculated to be 43.7 nMol/100 mg w.w. –24 h. The ADPR moiety for the NAD synthesis stemmed from an endogenous pool. Between 5 and 20 mM nicotinamide the increase in the NAD concentration followed an apparent Michaelis-Menten kinetics with a K_m of 6.1 mM nicotinamide and a V_max of 70.92 nMol NAD/100 mg w.w. –24 h. This can be explained as a new synthesis of NAD by a high concentration of nicotinamide and also by a decreased degradation of NAD, due to inhibition of the glycohydrolase by the high concentration of nicotinamide. The ratio of incorporation and disappearance of¹⁴C-NAD during the 8th and 16th h incubation period was 2:1. After pre-incubation with 20 mM nicotinamide for an 8-h period the NAD concentration decreased to normal values after incubation for 8 h in a nicotinamide free medium.–20 mM¹⁴C-nicotinic acid did not change the total NAD level and no significant incorporation in¹⁴C-NAD could be detected, whereas negative effects on the performance occurred.–10 M¹⁴C-nicotinamide showed a slight increase in the total NAD concentration (39.7 nMol/100 mg w.w.) and in the¹⁴C-incorporation (4.8 nMol/100 mg w.w.) within 24 h.–10 M¹⁴C-nicotinic acid seemed here to be the better precursor in this concentration. The NAD concentration increased to 49.8 nMol/100 mg w. w. after a 16 h incubation period and the incorporation in¹⁴C-NAD was 12.1 nMol/100 mg w.w. after an incubation time of 24 h.As consequence of the observed different influences of each precursor on NAD turnover and NAD concentration the pathways of NAD synthesis and degradation must be studied. The importance of an increased NAD level for the energy metabolism of the cardiac muscle under aerobic and anaerobic conditions is discussed.

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Synthese und Abbau von NAD im Herzmuskel von Meerschweinchen:I. Abhängigkeit von der extrazellulären Konzentration von Nicotinsäureamid und Nicotinsäure

Zusammenfassung In spontanschlagenden Herzvorhöfen von Meerschweinchen wurden bei hohen und niederen Konzentrationen der Precursors Nicotinsäureamid und Nicotinsäure die NAD-Konzentration, die¹⁴C-Einbaurate in NAD und die Verschwindensrate von¹⁴C-NAD untersucht. Die Vorhöfe wurden in Krebs-Henseleit-Lösung mit 15 mM Glukose und der entsprechenden Precursorkonzentration bei 30°C inkubiert. In den Kontrollversuchen blieb die NAD-Konzentration (33 nMol/100 mg FG) während einer Inkubationszeit von 24 Stunden unverändert.20 mM¹⁴C-Nicotinsäureamid führte nach einer 24stündigen Inkubation bei gleichzeitiger positiver Wirkung auf die Leistung zu einer dreifachen Erhöhung des NAD-Gehalts (90 nMol/100 mg FG). Für die Einbaurate in¹⁴C-NAD wurde ein Wert von 43,7 nMol/100 mg FG berechnet. Der ADPR-Anteil für die NAD-Synthese stammt aus einem endogenen Pool. Zwischen einer Konzentration von 5 und 20 mM Nicotinsäureamid folgte der Anstieg der NAD-Konzentration einer scheinbaren Michaelis-Menten-Kinetik mit einem K_m von 6,1 mM Nicotinsäureamid und einem V_max von 70,92 nMol NAD/100 mg FG nach 24 Stunden. Dies kann einerseits erklärt werden durch eine Neusynthese von NAD aus Nicotinsäureamid und andererseits durch einen verminderten Abbau von NAD infolge einer Hemmung der Glykohydrolase durch hohe Nicotinsäureamidkonzentrationen. Das Verhältnis von Einbaurate und Verschwindensrate von¹⁴C-NAD betrug zwischen der 8. und 16. Stunde der Inkubationsperiode 2:1. Nach einer Vorinkubation von 8 Stunden mit 20 mM Nicotinsäureamid fiel nach einer weiteren 8stündigen Inkubation in einem nicotissäureamidfreien Medium die erhöhte NAD-Konzentration bis auf den normalen NAD-Wert ab.20 mM¹⁴C-Nicotinsäure zeigte keine Erhöhung des NAD-Gehalts, und es wurde auch kein signifikanter Einbau in¹⁴C-NAD beobachtet, wohingegen eine negative Wirkung auf die Leistung sichtbar wurde.10 M¹⁴C-Nicotinsäureamid zeigte nach 24 Stunden einen leichten Anstieg der gesamten NAD-Konzentration (39,7 nMol/100 mg FG) und ebenfalls des¹⁴C-Einbaus (4,8 nMol/100 mg FG).10 M¹⁴C-Nicotinsäure war in dieser Konzentration der bessere Precursor. Die NAD-Konzentration erhöhte sich nach 16 Stunden auf 49,8 nMol/100 mg FG und der Einbau in¹⁴C-NAD betrug nach 24 Stunden Inkubation 12,1 nMol/100 mg FG. Zur Erklärung der beobachteten unterschiedlichen Einflüsse beider Precursors auf den NAD-Umsatz und die NAD-Konzentration wie auch die Kontraktionsleistung erscheint es notwendig, die verschiedenen Wege der NAD-Synthese und des NAD-Abbaus im einzelnen zu untersuchen. Die mögliche Bedeutung eines erhöhten NAD-Gehalts für den Energiestoffwechsel des Herzmuskels unter aeroben und anaeroben Bedingungen wird diskutiert.

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With 7 figures and 2 tablesWith 7 figures and 2 tablesThis study was supported by grants from the Deutsche Forschungsgemeinschaft, Bad Godesberg, W. Germany.     

The influence of various precursors on the concentration of energy-rich phosphates and pyridine nucleotides in cardiac tissue and its possible meaning for anoxic survival

Summary A special anoxia test was developed with isolated guinea pig atria to test influences on the anoxic energy balance. Adenine, ribose, nicotinic acid or nicotinamide added as precursors to nutrition solutions inhibit the loss of cardiac adenine and pyridine nucleotides during anoxia and improve the energy balance under aerobic and anaerobic conditions in the myocardium.

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Der Einfluß verschiedener Prekursoren auf die Konzentration von Pyridinnukleotiden und energiereichen Phosphaten im Herzmuskel und seine mögliche Bedeutung für das Überleben in Anoxie

Zusammenfassung Ein besonderer Anoxie-Test wurde mit isolierten Meerschweinchen-Herzvorhöfen entwickelt, um Einflüsse auf das anoxische Energiegleichgewicht zu prüfen. Adenin, Ribose, Nikotinsäure oder Nikotinamid—als Prekursoren der Nährlösung zugegeben—verhindern den Verlust der kardialen Adenin- und Pyridinnukleotide während Anoxie und verbessern das Energiegleichgewicht im Herzmuskel unter aeroben und anaeroben Bedingungen.

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Paper, presented at the Erwin Riesch Symposium, Tübingen, April 3–7, 1979

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With 1 figure and 1 table     

Simple and sensitive binding assay for measurement of adenosine using reduced S-adenosylhomocysteine hydrolase

BACKGROUND: Adenosine has been suggested to play an important role in the regulation of renal function. We developed a simple and sensitive binding assay for the detection of adenosine based on the displacement of [(3)H]adenosine from S-adenosylhomocysteine (SAH) hydrolase in its reduced form. METHODS: SAH hydrolase was purified to apparent homogeneity from bovine kidney by standard chromatographic methods. SAH hydrolase was converted in its reduced form, which had the advantage that the SAH hydrolase is enzymatically inactive. This reduced enzyme retains its ability to bind adenosine with high affinity. To determine adenosine in urine or tissues, samples must be deproteinized (e.g., with 10 g/L sulfosalicylic acid or 0.6 mol/L perchloric acid). RESULTS: The reduced SAH hydrolase bound adenosine with a dissociation constant of 33.0 +/- 2 nmol/L. Displacement of adenosine binding by the adenine 5'-nucleotides, adenine and hypoxanthine, required >1000-fold higher concentrations than adenosine itself. The intra- and interassay imprecision (CV) was <3.9% and 7.8%, respectively, and the values obtained showed acceptable correlation with those by HPLC. CONCLUSIONS: The highly sensitive adenosine-binding protein assay is a simple test that allows detection of adenosine in samples with small volumes without purification, and is in this respect superior to HPLC.