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In vivo cell-death imaging is still a challenging issue. Until now, only (99m)Tc-labeled HYNIC-rh-annexin A5 has been extensively studied in clinical trials. In the ongoing search for an alternative imaging agent, we synthesized a series of fluorescent zinc-cyclen complexes as annexin A5 mimics and studied structural variations on the uptake behavior of cells undergoing apoptosis/necrosis. The number of cyclen chelators was varied and the spacer separating cyclen from the central scaffold was modified. Five zinc-cyclen complexes were labeled with fluorescein for flow cytometric studies and one was labeled with (18)F for in vivo applications. Jurkat cells were treated with staurosporine to induce apoptosis/necrosis, incubated with the fluorescein-labeled zinc complexes and analyzed them by flow cytometry. Fluorescent annexin A5 and propidium iodide were applied as reference dyes. Flow cytometry revealed greater accumulation of zinc-cyclen complexes in staurosporine treated cells. The uptake was contingent on the presence of zinc and the fluorescence intensity was dependent on the number of zinc-cyclen groups. Confocal laser scanning microscopy showed the {bis[Zn(cyclen)]}(4+) complex distributed throughout the cytosol different to annexin A5. Owing to the structural similarity of the bis-cyclen ligands with CXCR4 binding bis-cyclam derivatives the zinc-cyclen complex uptake was challenged with the meta derivative of AMD3100. Lack of uptake depletion in staurosporine treated cells ruled out measurable CXCR4 interaction. PET imaging using the (18)F labeled zinc-cyclen complex revealed significantly higher uptake in an irradiated Dunning R3327-AT1 prostate tumor as compared to the contralateral control tumor. PET imaging of a HelaMatu tumor model additionally showed an increased uptake after taxol treatment. It could be demonstrated that the fluorescent zinc-cyclen complexes offer potential as new agents for flow cytometry and microscopic imaging of cell death. In addition, the (18)F labeled analogue holds promise for in vivo applications providing informations about cell death after radiation therapy and cytostatic drug treatment.

Unlabelled: Peptides involving the RGD motive (arginine-glycine-aspartic acid) recognize members of the integrin receptor family. Since the receptors are located mainly on the surface of endothelial cells, structural modifications including multimers of c(RGDfE) were recently found to improve the binding avidity for α(v)β(3) integrin significantly. The multivalent RGD peptides exhibited rather loose linkages partly including oligo(ethylene glycol) spacers (EG(n)) with different chain lengths. Therefore, the dependence of multivalent RGD systems with and without EG(n) linkers were investigated on their binding properties to cultured α(v)β(3) integrin-expressing U87MG cells., Methods: We synthesized a series of di-, tri- and tetravalent rigid scaffolds (terephthalic acid, trimesic acid and adamantane-1,3,5,7-tetracarboxylic acid) conjugated to c(RGDyK) ligands, which were linked contiguously or separated by the oligo(ethylene glycol) spacers. The inhibition constants of these c(RGDyK) derivatives were determined by competition assays with (125)I-labeled echistatin., Results: While c(RGDyK) function is a relative weak competitor against [(125)I]echistatin (K(i), 329 ± 18 nM) for α(v)β(3) integrin-expressing U87MG cells, RGD dimers improved the competition potency considerably (K(i), 64 ± 23 nM). This effect was even more pronounced with the RGD trimers (K(i), 40 ± 7 nM) and tetramers (K(i), 26±9 nM). The introduction of EG(n) spacers and the increase of linker lengths proved to be detrimental since more competitors were needed to compete with [(125)I]echistatin. The EG(6) group, for example, reduced the inhibition constants by 29% (dimer), 57% (trimer) and 97% (tetramer)., Conclusion: The binding experiments performed with the three forms of multivalent RGD ligands indicate the weakening of competitive potency against [(125)I]echistatin with the introduction of EG(n) spacers. This effect may be related to the decrease of the effective RGD molarity, which becomes most prominent within the tetravalent series., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We report the first known case of a device-related bloodstream infection involving Staphylococcus lugdunensis small-colony variants. Recurrent pacemaker-related bloodstream infection within a period of 10 months illustrates the poor clinical and microbiologic response even to prolonged antimicrobial drug therapy in a patient infected with this staphylococcal subpopulation.

The effectiveness of air bags, drivers-side and passenger-side, as an additional passive safety system in motor vehicles was tested in a collective study in which 47 trauma centers in Germany participated. The inquiry was answered by 80% of 181 hospitals. The evaluation of a total of 119 air bag-protected patients involved in accidents, who were treated in German trauma centers in the year 1993 shows predominant minor injuries on the head-, cervical- and thorax-region. Some patients had superficial injuries caused by air bag in their face and chest area, such as abrasions and contusions. It is notable, that a large number of patients continue to suffer severe injuries (AIS 3+) in their lower extremities. The trend of the industry to equip more and more vehicles with air bags must be sustained. According to manufacturer statements, in 1994 already more than 60% of all mass produced vehicles in Germany will be provided with this modern passive safety system.

It has been proposed that prophylactic administration of lidocaine i.m. can prevent ventricular arrhythmias during myocardial infarction. Thus we studied the pharmacokinetics of lidocaine after i.m. injection of 300 mg in the deltoid muscle and subsequent infusion to maintain antiarrhythmically effective plasma levels. The mean duration for exceeding a threshold concentration of 1.5 mg/l after 300 mg lidocaine i.m. was about 2 h; maximum concentrations were reached after 10 min and amounted to 3.2 mg/l (n = 10). By varying the infusion onset after i.m. injection (1 or 2 h later) and the infusion rates from 0.029-0.039 mg/kg X min, steady-state plasma levels of lidocaine were found to be in the therapeutic range (1.5-6 mg/l) for 5 h of observation. Long-lasting infusions (greater than 10 h) may result in increased plasma concentrations of lidocaine due to reduced body clearance.

A new enzymatic method for simultaneous estimation of radioactivity of 1-14C-glucose and 1-14C-fructose is described. It is based on the isomerisation of 1-14C-fructose to 1-14C-glucose by phosphoglucoseisomerase (EC 5.3.1.9) and on its enzymatic removal as ribulose-5-phosphate and 14CO2. The method is specific, reproducible, and gives over 97% recoveries of glucose and fructose concentrations up to 11 mmol/1 in aquos and biological solutions.

0,8 mg nitroglycerin administered sublingually to 10 patients with asthma bronchiale and chronic obstructive pulmonary disease effects a reduction of airway resistance up to 21% in the second and fifth minute. Even one hour after application the oscillatory resistance (Ros) is 15% lower than at the beginning. In the same patients 0,4 mg inhaled fenoterol has a stronger effect (-30%). After intravenous administration of nitroglycerin (2,5 mg/h) over 15 minutes there is a significant decrease of the plethysmographic measured resistance (Rt) (-23%), an increase of the vital capacity and a decrease of the residual volume. Side effects are a small reduction of pO2 and blood pressure and an increase of heart rate. Orthostatic disturbances may occur. The venous lactate concentration does not change. The investigation shows that patients with obstructive airway disease may benefit from the application of nitroglycerin.

Antipyrine-clearance calculated from a single 24 hrs blood sample following i. v. injection of 1 g was determined in insulin dependent diabetics (n = 20), patients with liver cirrhosis (n = 8), with fatty liver + hepatitis (n = 5) and alcoholics with normal liver morphology (n = 3). Antipyrine-clearance values in normal subjects amounted to 58,7 +/- 4,8 ml/min (means +/- s), in cirrhotics to 11,8 +/- 10,1 ml/min (p less than 0.01), in patients with fatty liver to 43,3 +/- 10,1 ml/min (p less than 0.01), and in alcoholics to 62,5 +/- 18,6 ml/min. In diabetics, diseased for many years, also a decrease in the clearance values was seen (41 +/- 17,5 ml/min; p less than 0.05). 15 out of them were below the 2 s range of normal subjects. Thus, the drug-metabolizing capacity in diabetics seems to be markedly reduced, and drug dosage might have to take account of this fact.

In a double blind study performed in cooperation with 69 emergency doctors and general practitioners in the catchment areas of the university and of the city hospital in Lübeck the action of intramuscular lidocaine on mortality and on the incidence of arrhythmias was investigated in patients with acute myocardial infarction aged less than 70 years. The mortality in the lidocaine group was significantly lower than in the placebo group. The incidence of ventricular arrhythmias up to 120 minutes after the lidocaine injection was also lower than in the placebo group. However, the only case of primary ventricular fibrillation was in the lidocaine group. As the difference in mortality between the two groups appeared at a time when an antifibrillatory action of lidocaine can no longer be assumed one must question whether the positively beneficial effect was real or whether the lower mortality was in fact due to primarily milder disease in the lidocaine group.

The dose-dependent haemodynamic effects and pharmacokinetics and parenteral prenalterol (0.5-10 microgram/kg/min), a new cardioselective beta-1-adrenoceptor agonist, have been studied in 10 healthy volunteers by computed echocardiography. Prenalterol induced a dose-dependent strong and persistent increase in contractility (FV 46%, VCF70 64%, STI 12%), heart index (46%) and heart rate (27%) and a moderate not significant decrease in VED (14%). Afterload and mean arterial blood pressure was nearly unaltered. The hemodynamically effective threshold concentration of prenalterol in plasma was 20-30 nmol/l, the mean value of maximum concentration 493 nmol/l; 1 hour after stopping the infusion prenalterol plasma level was about 90 nmol/l. A strong linear correlation between the haemodynamic alterations and the logarithm of prenalterol plasma concentrations was not apparent.

The kinetics of lidocaine after i.m. injection (M. deltoideus) of 300 mg were studied in patients with acute myocardial infarction in the course of 4 hrs.; another patient received this i.m. dose after being pretreated with 100 mg lidocaine i.v. The antiarrhythmically effective threshold concentration in plasma (1.5 mg/l) was reached after an average time of 5.5 min by 9 out of 10 patients. The mean value of maximum concentration after 30 min was 3.6 mg/l in 10 patients and the mean duration for exceeding the threshold (1.5 mg/l) was about 2 hrs. The elimination half-life for lidocaine valued 1.77 hrs. The toxic threshold concentration of 6 mg/l was exceeded for a short time by 3 patients without any side effects; in three other patients suffering from side-effects no relation to high plasma levels of lidocaine was observed.

In 11 normal subjects (NS) and 12 patients with liver cirrhosis (LC) the utilisation of 14C-glucose and 14C-fructose infusions (0.75 g/kg/h for 4 h) was compared. There were nor relevant side effects. Lactate and pyruvate were in both groups during fructose infusion slightly increased compared to glucose infusion. The free fatty acids were significantly decreased. The serum glucose level rose more in LC than in NS when given fructose infusion. During glucose and fructose infusion in LC higher insulin concentrations were calculated than in NS. 15 min after infusion of 14C-fructose 20% of the total serum activity was 14C-glucose, after 2 to 4 h the level was 30%. Differences between NS and LC were not found to be significant. The specific activity of 14CO2 was the same in both the 14C-glucose infusion and the 14C-fructose infusion. The glucose oxidation was impaired in LC, but not the 14CO2-exhalation during infusion of 14C-fructose. Unimpaired 14CO2-exhalation, and normal utilisation and conversion to glucose are arguments for the use of fructose in infusion treatment of cirrhotics.

The effect of fructose infusions (1.0 g/kg/g) on serum glucose, insulin, lactate, free fatty acids, glucose production and glucose oxidation was investigated with 14C-glucose in 10 normals and 11 patients with liver cirrhosis. Elevation of glucose and insulin were small and only slightly higher in cases of cirrhosis. Decrease of free fatty acids and rise of lactate were approximately the same in both groups. During infusion of fructose glucose turnover increased up to 196 +/- 41% in the normals and up to 279 +/- 78% in the patients with cirrhosis. No influence on the specific activity of 14CO2 was observed. It was therefore suggested, that approximately the same amount of glucose leaving the liver in excess during infusion of fructose was taken up by the liver at the same time. This behaviour of glucose supply to the blood stream and removal from it would explain, why high rates of conversion of fructose to glucose were measured with 14C-fructose, while only small amounts of glucose production were estimated from hepatic arteriovenous differences.

Male Holtzman albino and Long-Evans hooded rats were administered one microgram of arginine vasopressin (AVP) or a placebo each day after the acquisition trials of a visual white-black discrimination. Animals were then trained in the reversal of the discrimination. Performance was assessed by the number of trials to criterion during acquisition and reversal. Treatment with AVP resulted in significantly fewer trials to criterion during reversal learning in Holtzman albino rats, but did not influence reversal learning in Long-Evans hooded rats. These results provide evidence that AVP may have differential actions on memory processes in different strains of rats.