Activation of tyrosine receptor kinase plays a role in expression of long-term potentiation in the rat dentate gyrus

Long-term potentiation (LTP) in perforant path-granule cell synapses has been shown to be accompanied by an increase in glutamate release. The objective of this study was to examine the possibility that nerve growth factor (NGF), by activating tyrosine kinase, modulates glutamate release and, therefore, contributes to expression of LTP in dentate gyrus. The data indicate that NGF, in the presence of trans-1-aminocyclopentyl-1,3-dicarboxylate (ACPD), enhanced KCI-stimulated release and KCI-stimulated calcium influx in vitro and that these effects were blocked by the tyrosine receptor kinase (trk) inhibitor tyrphostin AG879. The data also indicate that NGF increased phosphorylation of trkA and the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) in dentate gyrus in vitro. In addition to its effects in vitro, tyrphostin AG879 inhibited the expression of LTP in perforant path-granule cell synapses and the accompanying increase in transmitter release. Analysis of phosphorylation of the two tyrosine kinase substrates trkA and ERK in synaptosomes prepared from untetanized and tetanized dentate gyrus revealed that LTP was associated with increased phosphorylation of both proteins; no evidence of such a change was observed in either tetanized or untetanized tissue prepared from tyrphostin-pretreated rats. These findings are consistent with the hypothesis that NGF, by interacting with trkA, triggers a sequence of tyrosine kinase-dependent phosphorylation steps that modulate glutamate release and calcium influx and impact on expression of LTP in dentate gyrus.     

Sibutramine treatment in obesity: initial eating behaviour in relation to weight loss results and changes in mood.

The aim of the study was to study the role of initial eating behaviour for subsequent weight loss in treatment with sibutramine (Reductil, Meridia) an anti-obesity drug enhancing satiety, and also to assess changes in mood during the treatment. The participants were 36 obese patients with a mean BMI of 39 kg m(-2). Eating behaviour was assessed with the three factor eating questionnaire (TFEQ), and depressive features with the comprehensive psychopathological rating scale (CPRS). Sibutramine (15 mg) was administered daily. The TFEQ restraint scale was negatively related to 6 months weight loss. In particular, strategic dieting behaviour and a more controlled attitude towards self-regulation were negatively related to weight loss. A positive non-placebo controlled change in mood was found already after 2 months treatment. The changes in mood were not related to the weight loss. Patients with more unrestrained eating seem to have reduced their amount of food intake more radically with enhanced satiety, manifested by greater weight loss. Physiologically enhanced satiety could have the greatest weight loss effect for patients whose eating is more governed by hunger drives and appetite rather that by conscious efforts and cognitive control.     

The association between peri‐operative acute risk change (ARC) and long‐term survival after cardiac surgery

Acute risk change has been described as the difference in calculated mortality risk between the pre‐operative and postoperative periods of cardiac surgery. We aimed to assess whether this was associated with long‐term survival after cardiac surgery. We retrospectively analysed 22,570 cardiac surgical patients, with minimum and maximum follow‐up of 1.0 and 6.7 years. Acute risk change was calculated as the arithmetic difference between pre‐ and postoperative mortality risk. ‘Rising risk’ represented an increase in risk from pre‐ to postoperative phase. The primary outcome was one‐year mortality. Secondary outcomes included mortality at 3 and 5 years and time to death. Univariable and multivariable analyses were undertaken to examine the relationship between acute risk change and outcomes. Rising risk was associated with higher mortality (5.6% vs. 3.5%, p < 0.001). After adjusting for baseline risk, rising risk was independently associated with increased 1‐year mortality (OR 2.6, 95%CI 2.2–3.0, p < 0.001). The association of rising risk with long‐term survival was greatest in patients with highest baseline risk. Cox regression confirmed rising risk was associated with shorter time to death (HR 1.86, 1.68–2.05, p < 0.001). Acute risk change may represent peri‐operative clinical events in combination with unmeasured patient risk and noise. Measuring risk change could potentially identify patterns of events that may be amenable to investigation and intervention. Further work with case review, and risk scoring with shared variables, may identify mechanisms, including the interaction between miscalibration of risk and true differences in peri‐operative care.     

Subcaliber discarding sabot airgun projectiles

Medical literature abounds with reports on injuries and fatalities caused by airgun projectiles. While round balls or diabolo pellets have been the standard projectiles for airguns for decades, today, there are a large number of different airgun projectiles available. A very uncommon — and until now unique — discarding sabot airgun projectile (Sussex Sabo Bullet) was introduced into the market in the 1980s. The projectile, available in 0.177 (4.5 mm) and 0.22 (5.5 mm) caliber, consists of a plastic sabot cup surrounding a subcaliber copper-coated lead projectile in typical bullet shape. Following the typical principle of a discarding sabot projectile, the lightweight sabot is supposed to quickly loose velocity and to fall to the ground downrange while the bullet continues on target. These sabot-loaded projectiles are of special forensic interest due to their non-traceability and ballistic parameters. Therefore, it is the aim of this work to investigate the ballistic performance of these sabot airgun projectiles by high-speed video analyses and by measurement of the kinetic parameters of the projectile parts by a transient recording system as well as observing their physical features after being fired. While the sabot principle worked properly in high-energy airguns (E?>?17 J), separation of the core projectile from the sabot cup was also observed when discharged in low-energy airguns (E?<?7.5 J). While the velocity of the discarded Sussex Sabo core projectile was very close to the velocity of a diabolo-type reference projectile (RWS Meisterkugel), energy density was up to 60 % higher. To conclude, this work is the first study to demonstrate the regular function of this uncommon type of airgun projectile.     

The Fra-2 transgenic mouse model of systemic sclerosis

In systemic sclerosis, microvascular injury often precedes the development of fibrosis. Whereas the development of digital ulcers and skin fibrosis causes high morbidity, the affection of internal organs, in particular complications such as interstitial lung disease and pulmonary (arterial) hypertension, account for the high disease-associated mortality of these patients. Vascular animal models of systemic sclerosis are of utmost importance to study pathophysiological aspects, to identify molecular key players, and to perform interventional proof of concept-studies. So far, animal models of systemic sclerosis have mainly reflected the pro-fibrotic features of the human disease. The Fra-2 (Fos-related antigen-2) transgenic mouse model simultaneously displays both pro-fibrotic and vascular characteristics of human systemic sclerosis.     

Going Against the Tide - How Encephalitogenic T Cells Breach the Blood-Brain Barrier

During multiple sclerosis or its animal model, experimental autoimmune encephalomyelitis, circulating immune cells enter the central nervous system (CNS) causing neuroinflammation. Extravasation from the blood circulation across the vessel wall occurs through a multistep process regulated by adhesion and signal transducing molecules on the immune cells and on the endothelium. Since the CNS is shielded by the highly specialized blood-brain barrier (BBB), immune cell extravasation into the CNS requires breaching this particularly tight endothelial border. Consequently, travelling into the CNS demands unique adaptations which account for the extreme tightness of the BBB. Modern imaging tools have shown that after arresting on BBB endothelium, in vivo or in vitro encephalitogenic effector/memory T cells crawl for long distances, possibly exceeding 150 μm along the surface of the BBB endothelium before rapidly crossing the BBB. Interestingly, in addition to the distance of crawling, the preferred direction of crawling against the flow is unique for T cell crawling on the luminal surface of CNS microvessels. In this review, we will summarize the cellular and molecular mechanisms involved in the unique T cell behavior that is obviously required for finding a site permissive for diapedesis across the unique vascular bed of the BBB.     

Eukaryotic and prokaryotic stomatins: the proteolytic link

The 32kD membrane protein stomatin was first studied because it is deficient from the red cell membrane in two forms of the class of haemolytic anaemias known as "hereditary stomatocytosis." The hallmark of these conditions is a plasma membrane leak to the monovalent cations Na+ and K+: the protein is missing only in the most severely leaky of these conditions. No mutation has ever been found in the stomatin gene in these conditions. Stomatin-like proteins have been identified in all three domains of biology, yet their function remains enigmatic. Although the murine knock-out is without phenotype, we have identified a family showing a splicing defect in the stomatin mRNA, in which affected children showed a catastrophic multisystem disease not inconsistent with the now-known wide tissue distribution of stomatin. We report here a study of strongly homologous stomatin-like genes in prokaryotes, which reveals a close connection with a never-studied gene erroneously known as "nfed." This gene codes for a hydrophobic protein with a probable serine protease motif. It is possible that these stomatin-like genes and those which are known as"nfed" form an operon, suggesting that the two protein products are aimed at a common function. The corollary is that stomatin could be a partner protein for a membrane-bound proteolytic process, in both prokaryotes and in eukaryotes generally: this idea is consistent with experimental evidence.