Continuous intrathecal glyceryl trinitrate prevents delayed cerebral vasospasm in the single-SAH rabbit model in vivo

Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of high morbidity and mortality. The reduced availability of nitric oxide (NO) in blood and cerebrospinal fluid (CSF) is well established as a key mechanism of vasospasm. Systemic administration of glyceryl trinitrate (GTN), an NO donor also known as nitroglycerin, has failed to be established in clinical settings to prevent vasospasm because of its adverse effects, particularly hypotension. The purpose of this study was to analyze the effect of intrathecally administered GTN on vasospasm after experimental SAH in the rabbit basilar artery.

Bombesin antagonist-based radioligands for translational nuclear imaging of gastrin-releasing peptide receptor-positive tumors

Bombesin receptors are overexpressed on a variety of human tumors. In particular, the gastrin-releasing peptide receptor (GRPr) has been identified on prostate and breast cancers and on gastrointestinal stromal tumors. The current study aims at developing clinically translatable bombesin antagonist-based radioligands for SPECT and PET of GRPr-positive tumors.

PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference

Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-positive tumors, especially of subtype 2 (sst2). The clinically used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors determining the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four (64)Cu or (68)Ga radioantagonists for PET of sst2-positive tumors.

Comparison of the binding and internalization properties of 12 DOTA-coupled and ¹¹¹In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607

Specific overexpression of cholecystokinin 2 (CCK2)/gastrin receptors has been demonstrated in several tumours of neuroendocrine origin. In some of these cancer types, such as medullary thyroid cancer (MTC), a sensitive diagnostic modality is still unavailable and therapeutic options for inoperable lesions are needed. Peptide receptor radionuclide therapy (PRRT) may be a viable therapeutic strategy in the management of these patients. Several CCK2R-targeted radiopharmaceuticals have been described in recent years. As part of the European Union COST Action BM0607 we studied the in vitro and in vivo characteristics of 12 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R binding peptides. In the present study, we analysed binding and internalization characteristics. Stability, biodistribution and imaging studies have been performed in parallel by other centres involved in the project.

Highly improved metabolic stability and pharmacokinetics of indium-111-DOTA-gastrin conjugates for targeting of the gastrin receptor

The development of metabolically stable radiolabeled gastrin analogues with suitable pharmacokinetics is a topic of recent research activity. These imaging vectors are of interest because the gastrin/CCK2 receptor is highly overexpressed in different tumors such as medullary thyroid cancer, neuroendocrine tumors, and SCLC. The drawback of current targeting agents is either their metabolic instability or their high kidney uptake. We present the synthesis and in vitro and in vivo evaluation of 11 (111)In-labeled DOTA-conjugated peptides that differ by their spacer between the peptide and the chelate. We introduced uncharged but hydrophilic spacers such as oligoethyleneglycol, serine, and glutamine. The affinity of all radiopeptides was high with IC(50) values between 0.5 and 4.8 nM. The improvement of human serum stability is 500-fold within this series of compounds. In addition the kidney uptake could be lowered distinctly and the tumor-to-kidney ratio improved almost 60-fold if compared with radiotracers having charged spacers such as glutamic acid.

Processing and Composition Effects on the Fracture Behavior of Spray-Formed 7XXX Series Al Alloys

The fracture properties of high-strength spray-formed Al alloys were investigated, with consideration of the effects of elemental additions such as zinc,manganese, and chromium and the influence of the addition of SiC particulate. Fracture resistance values between 13.6 and 25.6 MPa (m)1/2 were obtained for the monolithic alloys in the T6 and T7 conditions, respectively. The alloys with SiC particulate compared well and achieved fracture resistance values between 18.7 and 25.6 MPa (m)1/2. The spray-formed materials exhibited a loss in fracture resistance (KI) compared to ingot metallurgy 7075 alloys but had an improvedperformance compared to high-solute powder metallurgy alloys of similar composition. Characterization of the fracture surfaces indicated a predominantly intergranular decohesion, possibly facilitated by the presence of incoherent particles at the grain boundary regions and by the large strength differentialbetween the matrix and precipitate zone. It is believed that at the slip band-grain boundary intersection, particularly in the presence of large dispersoids and/or inclusions, microvoid nucleation would be significantly enhanced. Differences in fracture surfaces between the alloys in the T6 and T7 condition were observed and are attributed to inhomogeneous slip distribution, which results in strain localization at grain boundaries. The best overall combination of fracture resistance properties were obtained for alloys with minimum amounts of chromium and manganese additions.

High-dose intravenous immunoglobulins: A promising therapeutic approach for idiopathic systemic capillary leak syndrome

The systemic capillary leak syndrome (SCLS), also known as Clarkson’s disease, is a life-threatening disorder of unknown cause. It is characterised by recurrent acute episodes of hypotension, weight gain and generalised oedema with haemoconcentration and hypoproteinaemia caused by paroxysmal capillary hyperpermeability with a shift of plasma fluid from the intravascular to the interstitial space. We report the case of a 40-year-old woman with chronic SCLS treated with high-dose intravenous immunoglobulins, after a prophylactic therapy with theophylline and terbutaline was poorly tolerated and failed to decrease the frequency and severity of the attacks sufficiently.

Kidney infarction in Friedreich's ataxia with dilated cardiomyopathy

A 37-year-old man with advanced Friedreich's ataxia was referred to our emergency department with acute exacerbated abdominal pain of unclear aetiology. Laboratory tests showed slightly increased inflammatory parameters, elevated troponin and B-type natriuretic peptide, as well as minimal proteinuria. Transthoracic echocardiography revealed a pre-existing dilated cardiomyopathy. Abdominal sonography showed no pathological alterations. Owing to persistent pain under analgesia, a contrast-enhanced CT-abdomen was performed, which revealed a non-homogeneous perfusion deficit of the right kidney, although neither abdominal vascular alteration, cardiac thrombus, deep vein thrombosis nor a patent foramen ovale could be detected. Taking all clinical and radiological results into consideration, the current incident was diagnosed as a thromboembolic kidney infarction. As a consequence, lifelong oral anticoagulation was initiated.

Opioids trigger alpha 5 beta 1 integrin-mediated monocyte adhesion

Inflammatory reactions involve a network of chemical and molecular signals that initiate and maintain host response. In inflamed tissue, immune system cells generate opioid peptides that contribute to potent analgesia by acting on specific peripheral sensory neurons. In this study, we show that opioids also modulate immune cell function in vitro and in vivo. By binding to its specific receptor, the opioid receptor-specific ligand DPDPE triggers monocyte adhesion. Integrins have a key role in this process, as adhesion is abrogated in cells treated with specific neutralizing anti-alpha5beta1 integrin mAb. We found that DPDPE-triggered monocyte adhesion requires PI3Kgamma activation and involves Src kinases, the guanine nucleotide exchange factor Vav-1, and the small GTPase Rac1. DPDPE also induces adhesion of pertussis toxin-treated cells, indicating involvement of G proteins other than Gi. These data show that opioids have important implications in regulating leukocyte trafficking, adding a new function to their known effects as immune response modulators.