Precise Measurement of the D

We report a measurement of the D^{0} and D^{+} lifetimes using D^{0}→K^{-}π^{+} and D^{+}→K^{-}π^{+}π^{+} decays reconstructed in e^{+}e^{-}→cc[over ¯] data recorded by the Belle II experiment at the SuperKEKB asymmetric-energy e^{+}e^{-} collider. The data, collected at center-of-mass energies at or near the ϒ(4S) resonance, correspond to an integrated luminosity of 72 fb^{-1}. The results, τ(D^{0})=410.5±1.1(stat)±0.8(syst) fs and τ(D^{+})=1030.4±4.7(stat)±3.1(syst) fs, are the most precise to date and are consistent with previous determinations.

[Overcoming of radiation resistances]. / Strahlenresistenzen und ihre Überwindung.

Despite good achievements in prevention and control, cancer is still a leading cause of death worldwide. The development of resistances against conventional treatment modalities is one of the main causes of failure in the treatment of cancer. Radio- and chemotherapies fail frequently due to intrinsic or acquired resistances in apoptotic signalling pathways or alterations in DNA-repair processes. Targeted radiotherapies employing α-particle-emitting radionuclides and Auger-emitting electrons are a promising approach in cancer treatment to break radio- and chemoresistance by overcoming DNA-repair mechanisms and reversing deficient activation of apoptotic pathways in cancer cells.

I kappa B-independent control of NF-kappa B activity by modulatory phosphorylations.

Activation of the transcription factor nuclear factor kappa B (NF-kappa B) requires its release from inhibitor of NF-kappa B (I kappa B) proteins in the cytoplasm. Much work has focussed on the identification of pathways regulating this cytosolic rate-limiting step of NF-kappa B activation. However, there is increasing evidence for another complex level of NF-kappa B activation, which involves modulatory phosphorylations of the DNA-binding subunits. These phosphorylations can control several functions of NF-kappa B, including DNA binding and transactivation properties, as well as interactions between the transcription factor and regulatory proteins. Although their overall impact on NF-kappa B function has yet to be determined, modifications of this factor will very probably provide a mechanism to fine tune NF-kappa B function.

Insect-Transmitted Urediniospores of the Rust Puccinia punctiformis Cause Systemic Infections in Established Cirsium arvense Plants.

ABSTRACT The rust fungus Puccinia punctiformis has potential as a biological control agent for creeping thistle Cirsium arvense, because systemically infected shoots usually die before flowering. The mechanism of rust transfer as well as the spore type responsible for systemic infections have been a source of controversy. One possibility of successful transmission is the use of the weevil Ceratapion onopordi as a vector. Our results from a garden experiment show that urediniospores transmitted by the weevil are able to induce systemic infections in established thistle clones. Furthermore, the weevil origin and the date of rust treatment significantly influenced the number of rust-infected shoots. The earlier a shoot was treated, the higher the probability of rust transmission. These results challenge the current belief that teliospores passing through the soil and infecting root buds are the major cause of systemic infections in the field. Further research on biological control of creeping thistle should therefore concentrate on the application of urediniospores to enhance systemic rust infections.

Angiotensin-induced hypertension in conscious dogs: biochemical parameters and baroreceptor reflex.

The effects of a continuous iv infusion (osmotic minipumps) of angiotensin II (80 ng . kg-1 . min-1) and isoprenaline (10 ng . kg-1 . min-1) lasting 28 days were studied in six normotensive, conscious dogs. The parameters measured were systolic and diastolic blood pressure, heart rate, levels of angiotensin II, renin activity, aldosterone and antidiuretic hormone in plasma, baroreceptor reflex sensitivity and body weight. The treatment resulted in an approximately sevenfold increase in plasma angiotensin II level from 62.9 +/- 24.5 pg . ml-1 to 455.3 +/- 95.6 pg . ml-1. Systolic and diastolic blood pressure, measured for the first time 2 days after implanting the minipumps, were markedly increased throughout the infusion period (pretreatment value: 123.8 +/- 5.3/68.3 +/- 3.8 mmHg; after 2 days: 159.8 +/- 12.0/100.5 +/- 9.8 mmHg; after 28 days: 159.8 +/- 7.1/98.3 +/- 6.4 mmHg, whereas the heart rate remained unchanged due to the combined effects of angiotensin II and the concomitantly given isoprenaline. A high correlation was found between angiotensin II level in plasma and mean arterial blood pressure (r = 0.846; p less than 0.001). Furthermore, plasma renin activity was markedly suppressed by the treatment, and aldosterone levels rose. Plasma antidiuretic hormone levels were found to be unchanged at the chosen sampling time. A decrease in baroreceptor reflex sensitivity accompanied the development of the hypertensive state. There was also a loss of body weight during the infusion of angiotensin II and isoprenaline. The data provide evidence for the usefulness of the presented experimental protocol as an alternative model of arterial hypertension in chronically instrumented, conscious dogs.

Blood pressure response and renin release following 4 days of treatment with dihydralazine and urapidil in conscious dogs.

The magnitude and the persistence of blood pressure reduction by dihydralazine and urapidil were investigated following treatment over a period of 4 days. The experiments were performed on six normotensive dogs, trained to submit to puncture of the femoral artery and to stand quietly in a special frame. The first-dose effects of orally administered dihydralazine (1.42, 7.1 mg X kg-1) and urapidil (2.0, 10.0 mg X kg-1) on heart rate, arterial blood pressure and plasma renin activity (PRA) were compared with the effects of the substances after 4 days of treatment. Both compounds caused a dose-dependent decrease in blood pressure but in contrast to urapidil the effect of dihydralazine was accompanied by large increases in heart rate and PRA. Dose-dependent tolerance to dihydralazine but not to urapidil was observed after treatment over only 4 days. However, basal blood pressure was significantly lowered after 4 days of treatment with urapidil at the high dosage and no further reduction was achieved on the fifth day. The importance of persistent counterregulation in the development of tolerance to the antihypertensive effect of dihydralazine is discussed.

In vivo clearance of antibody-sensitized human drug carrier erythrocytes.

Antibody coating of resealed drug carrier erythrocytes may be useful for drug targeting to the reticuloendothelial system. We have investigated the survival in the circulation of anti-Rh antibody (IgG anti-D)-coated autologous erythrocytes loaded with gentamicin by hypoosmotic dialysis. Five subjects were injected with 15.2 +/- 0.4 ml and five additional subjects with 62.8 +/- 1.5 ml carrier cells. Survival of the cells was monitored by intraerythrocytic gentamicin concentration in blood. In the first subject group initial t1/2 was 0.21 +/- 0.06 hours and terminal t1/2 was 1.71 +/- 0.36 hours. In the second group initial t1/2 was 0.59 +/- 0.21 hours followed by a slow phase with a t1/2 of 89 +/- 28 hours. Results indicate that rapid drug delivery to the reticuloendothelial system by antibody-sensitized carrier erythrocytes is possible, but small volumes of erythrocytes seem more efficient.

The Drosophila proteins Pelle and Tube induce JNK/AP-1 activity in mammalian cells.

The mammalian interleukin-1 (IL-1) signal transduction pathways display remarkable homology to the Toll signaling cascade in Drosophila. To address the question whether members of the Drosophila Toll pathway are functional in mammalian cells, inactive and constitutively active versions of the protein kinase Pelle and its regulator Tube were expressed in HeLa cells and tested for their impact on IL-1-dependent signaling events. The Drosophila proteins failed to induce the IL-1-responsive transcription factor, nuclear factor-kappaB, but selectively activated the IL-1-regulated kinase, c-Jun N-terminal kinase (JNK), thus resulting in elevated AP-1 activity. Activation of JNK/AP-1 activity was seen upon expression of a Pelle mutant lacking its C-terminal half or by a membrane-bound and multimerised Tube protein, showing the functionality of the Drosophila proteins in mammalian cells.

Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-kappaB-dependent transcription.

Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-kappaB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound RU486 efficiently reduced NF-kappaB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IkappaB-alpha expression, but impaired the tumor necrosis factor (TNF)-alpha-induced degradation of IkappaB-alpha without affecting DNA binding of NF-kappaB. The structural requirements for the various functions of glucocorticoids are discussed.

The effects of NECA (adenosine-5'N-ethylcarboxamide) and of adenosine on glucagon and insulin release from the in situ isolated blood-perfused pancreas in anesthetized dogs.

The effect of adenosine-5'-N-ethylcarboxamide, (NECA), a long-lasting adenosine derivative with pronounced vasoactivity was investigated on glucagon and insulin release from the in situ isolated blood perfused pancreas in the anesthetized dog: NECA (10(-9) to 10(-5) mol/l) led to a dose-dependent glucagon release. Insulin release was inhibited by NECA at low concentrations, but significantly increased at higher concentrations of the adenosine analogue. Similar effects were observed with infusion of adenosine at 10(-7) and 10(-6) mol/l. Aminophylline (10(-4) mol/l) produced a 10-fold attenuation of the actions of NECA. The preponderance of glucagon release at low concentrations of NECA and adenosine in contrast to that of insulin release at high concentrations may represent a local pancreatic regulatory mechanism of adenosine in glucose homeostasis.

Plasma insulin levels and beta-adrenoceptor antagonists. The effects of cardioselective and non-cardioselective beta-adrenoceptor antagonists with and without intrinsic sympathomimetic activity on basal insulin level and insulin level after glucose stimulation in normoglycemic dogs.

The effect of beta-adrenoceptor antagonists on the intravenous glucose tolerance test was investigated in conscious dogs. dl-Celiprolol (cardioselective with ISA = intrinsic sympathomimetic activity) 200 and 1000 microgram/kg i.v., dl-metoprolol (cardio-selective without ISA) 200 and 1000 microgram/kg i.v., dl-pindolol (non-selective with ISA) 5 and 25 microgram i.v. and l-bupranolol (non-selective without ISA) 10 and 50 microgram/kg i.v. were used in the study. The influence of beta-adrenoceptor antagonists on the plasma glucose and immunoreactive insulin following intravenous glucose tolerance test were evaluated by calculating the respective areas under the plasma curve. The present investigation clearly demonstrates the marked difference between the various beta-adrenoceptor antagonists on heart rate and, especially on metabolic parameters. dl-Metoprolol, a beta-adrenoceptor antagonist with cardioselectivity and without ISA can be assumed not to alter plasma insulin level and glucose assimilation. l-Bupranolol, a non-selective beta-adrenoceptor antagonist without ISA reduces plasma insulin level and probably enhances peripheral glucose uptake, resulting in an "unchanged" glucose tolerance. dl-Celiprolol or dl-pindolol, beta-adrenoceptor antagonists with ISA, but cardioselective or non-selective enhance both, basal insulin level and insulin level after glucose stimulation but must be assumed to decrease peripheral glucose uptake since here too glucose tolerance was unchanged.

Plasma insulin levels and beta-adrenoceptor antagonists. Relevance of the steric configuration of beta-adrenoceptor antagonists to their effect on glucose tolerance.

The relevance of the steric configuration to the effects of two non-selective beta-adrenoceptor antagonists without intrinsic sympathomimetic activity (+)- and (--)-bupranolol (10 and 50 micrograms/kg i.v.) and (4)- and (--)-propranolol (100 and 500 micrograms/kg i.v.) on the i.v. glucose tolerance test (IVGTT) were investigated in conscious, normoglycemic dogs. The effects of the beta-adrenoceptor antagonists on plasma glucose, and insulin levels and insulin-glucagon ratio following IVGTT were evaluated by calculating the respective areas under the curve (AUC). The AUC values for plasma glucose were significantly increased by the (--)-configuration of both beta-adrenoceptor increased by the (--)-configuration of both beta-adrenoceptor antagonists. In the (+)-configuration only propranolol (500 micrograms/kg i.v.) increased the AUC value for plasma glucose significantly. The AUC values for plasma insulin and also for the plasma insulin-glucagon ratio were significantly increased by (--)-propranolol (500 micrograms/kg i.v.) and by (--)-bupranolol (10 and 50 micrograms/kg i.v.). Thus the impairment of glucose tolerance, due to suppression of the plasma insulin level, depends mainly on the beta-adrenoceptor antagonistic activity of the (--)-configuration.

[Effects of a long-acting adenosine analogue on insulin and glucagon release (author's transl)]. / Beeinflussung der Insulin- und Glukagonsekretion durch ein lang wirksames Adenosinanalog.

The adenosine analogue 765-21 (10 micrograms/kg intravenously), substituted at the 5'-position, caused a sustained increase in plasma glucose and a decrease in plasma free fatty acid concentrations in conscious dogs. Concomitantly, plasma glucagon levels rose threefold. Changes in plasma insulin concentration were relatively small and of no statistical significance. A simultaneous fall in arterial blood pressure was also observed. Aminophylline, an adenosine antagonist, inhibited the haemodynamic as well as the metabolic responses evoked by the adenosine analogue. - In collagenase-isolated rat islets of Langerhans 765-21 inhibited glucose-induced insulin release in a dose-dependent manner (concentration range 10(-8) to 10(-5) M). In contrast to the data obtained on conscious dogs, 765-21 did not promote glucagon release from the pancreatic islets. Since stimulation of glucagon secretion was also not observed on decreasing the glucagon concentration in the incubation medium, the collagenase technique of isolation may be responsible for the insensitivity of the islets to glucagon-releasing stimuli. - The results are indicative of a specific inhibition of glucose-induced insulin release by 765-21. The data obtained in vivo additionally suggest a glucagon-releasing activity of the adenosine analogue investigated.

[Studies of biological availability. A critical assessment based on a study of spironolactone preparations]. / Zur Problematik der Bioverfügbarkeits-untersuchungen. Eine kritische Betrachtung anhand einer Studie über Spironolactonpräparate.

Investigations have been performed to determine the relative bioavailability of canrenone from an improved spironolactone preparation, Deverol drgs., in comparison with canrenone from a spironolactone standard preparation on the Austrian market (Osiren drgs.). This was carried out by comparing the areas under the serumconcentration-time-curves under conditions of steady-state after oral application of both preparations. Additionally the contents of spironolactone in the two preparations tested were determined. By intraindividual comparison of the areas under the serum-concentration-time-curves of canrenone a relative bioavailability of 99.37% of canrenone from Deverol drgs. could be calculated versus canrenone from the standard. However a remarkable different content of spironolactone in the preparations was found: in 50 mg of Deverol drgs. 50.5 mg spironolactone and in 100 mg of Osiren drgs. 109.6 mg spironolactone were found. Determination of drug contents in products appears to be necessary to determine their relative bioavailability correctly, because the usual range of +/- 5% may be overshot as demonstrated in our investigation.

Pharmacokinetics and bioavailability of isosorbide-5-mononitrate in humans.

The relative bioavailability of isosorbide-5-mononitrate from two different formulations (MONOCLAIR, ISMO) was investigated in a double-blind randomized cross-over study in 8 healthy human subjects. After single orale doses of 40 mg the plasma concentration and the urinary excretion of isosorbide-5-mononitrate were measured over 24 hours. The comparison of the results obtained over the whole experimental period showed a significantly higher plasma concentration with a higher renal excretion after MONOCLAIR, the latter changes being insignificant as compared with those after ISMO, the reference drug. Thus the two formulations are judged to be at least equivalent with regard to their drug bioavailability.

Substrate vibrations elicit defensive behaviour in leafminer pupae.

Late instar larvae and pupae of the spotted tentiform leafminer Phyllonorycter malella (Ger.) (Lepidoptera: Gracillariidae) react with defensive behaviour when attacked by one of their parasitoids, the eulophid wasp Sympiesis sericeicornis Nees (Hymenoptera: Eulophidae). Vibrations produced during the insertion of the ovipositor into the mine are known to be important cues by which larvae detect the presence of their enemies. The aim of this study was to investigate which frequency components elicit defensive reactions in leafminer pupae using synthetic vibrations. Sine vibrations and bandlimited noise stimuli were offered to both free pupae and pupae concealed in their leafmines. Using Laser vibrometry we measured the vibrations experienced by pupae inside their mines and assessed the influence of the mine. Pupae were shown to react to substrate vibrations, and do so over a broad range of frequencies. Behavioural reactions to noise stimuli were stronger than to pure sine stimuli. Mine tissue attenuated vibration amplitudes of the input signal from 5.1 to 22.6dB. However, as response thresholds of concealed pupae were only twice as high as thresholds of free pupae (which is adequate to 3dB) pupae inside their mine were more sensitive than expected. This discrepancy is discussed both in terms of the conditions of pupae and in terms of mine structure. The results indicate that broadbandedness of vibrations produced by hunting parasitoids during ovipositor insertion into the mine may be a major criterion used by leafminers to perceive parasitoid presence and to escape ovipositor stings.

The effect of repeated intravenous and oral doses of molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester) on plasma renin activity and plasma catecholamine levels in conscious dogs.

The responses of plasma renin activity (PRA) and plasma catecholamine levels to molsidomine, administered both intravenously and orally, were investigated in conscious trained dogs. Intravenous administration of molsidomine at increasing dosage up to 0.4 mg/kg with a constant dose interval of 4 hours did not lead to a sustained increase in PRA. By contrast, a significant increase in PRA was still present after 4 hours on administration of 0.4 mg/kg molsidomine by the oral route. This longer-lasting increase in PRA following oral administration is discussed in relation to the conversion of molsidomine to an active metabolite in the liver. A reduction of dose interval to 3 hours or less led to a marked cumulative increase in PRA. It appears that substances acting via venous pooling lead to persistent activation of the renin angiotensin aldosterone system (RAA system), which counteracts its primary therapeutic effect. A slight increase in plasma noradrenaline levels was observed in response to repeated oral administration of 0.4 mg/kg molsidomine at a dose interval of 2 hours, indicating participation of the sympathetic nervous system in the counterregulatory process.

The effect of a long-acting adenosine analog on blood flow through various organs in the dog.

Radioactively labeled microspheres were used to investigate the effect of 2',3'-di-O-nitro-5'-(N-ethylcarboxamido)-adenosine (10 micrograms/kg orally), a long-acting adenosine analog, on blood flow through various organs over an experimental period of three hours in conscious dogs. There was a significant increase in myocardial, cerebral, intestinal, and renal cortical blood flow, whereas the flow through skeletal muscle, liver, pancreas, and renal medulla was unaffected. The endocardial/epicardial flow ratio, which was more than one under control conditions, decreased significantly. Arterial blood pressure and heart rate remained virtually unchanged. Since the adenosine analog is rapidly and completely denitrated in vivo, the denitration product 5'-(N-ethylcarboxamide)-adenosine, a highly potent adenosine receptor agonist, must be considered as the vasoactive metabolite.

Characterization of vasodilators by comparison of their effects on blood pressure, counterregulation and myocardial oxygen demand in conscious normotensive dogs.

Vasodilators were characterized on the basis of their first-dose effect on systolic and diastolic blood pressure, heart rate, on the product of heart rate and systolic blood pressure and on plasma renin activity (PRA) in conscious normotensive dogs. The compounds were given orally to the animals and the effects were studied over a period of 4 h. The arterial vasodilators (propyldazine, dihydralazine and labetalol) caused a marked reduction of systolic and diastolic blood pressure with excessive stimulation of the sympathetic nervous system, leading to an increase in myocardial oxygen demand. The blood pressure effect of urapidil and prazosin resembled more the pattern seen with typical venous dilators (molsidomine and nitrates) and was not accompanied by significant increases in heart rate and in PRA. Hence, the magnitude of diastolic blood pressure reduction seems to be an essential determinant of reflex counterregulation. The results prove that some few parameters can give information about the overall pattern of hemodynamic effects of vasodilators.