Thrombin Inhibition in discordant xenograft rejection

Abstract: Microvascular thrombosis and the associated platelet and endothelial cell activation are prominent observations in xenograft rejection. This pathological picture could be related to the excessive generation of thrombin in the context of either inflammation or putative inter-species molecular incompatibilities between activated coagulation factors and their natural anticoagulants. Relatively selective thrombin Inhibition with the serine protease inhibitor SDZ MTH 958 (MTH-958) are independent of heparinoids and anti-thrombin III. MTH-958 has been shown to significantly prolong porcine cardiac function during perfusion with human blood in an ex vivo model. The aim of this study was to validate the role of thrombin generation in a rodent model of discordant xenograft rejection in vivo. The effect of thrombin inhibition with MTH-958 was tested in both hyperacute rejection (HAR) and delayed xenograft rejection (DXR) after decomplementation with cobra venom factor (CVF) in normal Lewis (Lew) rats and Intrinsic C6 deficiency In PVG (C6-/PVG) recipient rats. Recipient rats received heterotopic guinea pig cardiac xenografts and were treated with titrated doses of MTH-958 until the time of graft rejection. Plasma samples at selected time points were examined to confirm effective thrombin inhibition, and rejected grafts were analyzed by immunohistology. MTH-958 significantly improved graft survival in HAR albeit the extent of prolongation was not marked, but the agent failed to prolong survival In CVF-treated Lew rats. In C6-/PVG rats receiving MTH-958, a significantly reduced graft survival time was observed when compared with C6-/PVG controls. The grafts from MTH-958-treated animals showed dense deposits of C3, IgM, and IgG with fibrin levels similar to controls. The thrombin antagonist tested could prolong xenograft survival during HAR but had no benefit in DXR. The relative non-specificity of the serine protease inhibitor MTH-958 with the potential activation of alternative pathway of complement via the inhibition of factor I could account for the failure to prolong xenograft survival in DXR. The pathogenetic significance of thrombin generation in this situation remains to be determined by the use of more selective and pharmacologically acceptable I anti-thrombin agents.     

Aktuelle und effektive bildgebende Diagnostik von Sprunggelenk und Fuß

Projection radiographic techniques have been used in a standardized manner for decades for the diagnosis of conditions of the foot and ankle; the indications for them and the pattern of findings useful in the initial diagnosis and monitoring of the course are generally known to clinical radiology staff. Computed tomography has been introduced as an extension of the basic procedures performed for diagnosis in the ankle and the hindfoot. In the case of complex fractures, however, specialist experience is essential. CT is an easily accessible investigative procedure and is meanwhile economical and very powerful. Magnetic resonance imaging supplements the range of investigations in special cases when there are particular problems. Microfractures, findings indicative of inflammation and/or dystrophy and, in particular questions concerning the musculoligamentous support system are the situations in which such investigations are needed. Ultrasound has an additive value vis-à-vis magnetic resonance imaging and is an easily accessible and highly effective examination procedure both for the primary diagnosis and for serial monitoring. Financial constraints in the healthcare sector are increasingly limiting purely medical indications. Regardless of this development, the retention of projection radiography, computer tomography, and magnetic resonance imaging must be demanded for the initial diagnosis in the care of foot and ankle injuries. The earliest possible implementation of all these techniques for the initial diagnosis is the first step towards effective treatment. Cafrefully chosen and, if appropriate, complementary strategies are needed for monitoring of the course and for assessment.     

Anxiety and hippocampus volume in the rat.

In depressed patients as well as healthy controls, a positive relationship between hippocampal volume and trait anxiety has been reported. This study sought to explore the possible inter-relation between hippocampal volume and trait anxiety further. Magnetic resonance imaging at 7 T was used to measure hippocampal volumes in a rat model of extremes in trait anxiety (experiment 1) and in a Wistar population with normal anxiety-related behavior (experiment 2). In addition to anxiety-related behavior, potentially confounding factors (depression-like, exploratory, and locomotor behavior) were assessed. Experiment 1 globally supported the hypothesis of a positive relationship between hippocampus volume and trait anxiety but did not allow for ruling out possible confounds arising from cosegregation of other behavioral traits. Experiment 2 yielded strong evidence for a negative relationship which was specific for trait anxiety. Thus, the relationship between hippocampal volume and anxiety may be more complex than expected. Interestingly, anxiety-related behavior in experiment 2 had a stronger influence on hippocampal volume than depression-like behavior. In the light of hippocampal volume loss in anxiety disorder and frequent comorbidity of anxiety and depression, this finding suggests that further research into the relationship between anxiety and hippocampal volume may be critical for understanding hippocampal contributions to normal and pathological behavior.     

Human xenoreactive natural antibodies of the IgM isotype activate pig endothelial cells

Abstract: Preformed, xenoreactive natural antibodies (XNA) and complement (C) are involved in the initiation of vascular rejection of organs transplanted between discordant species, presumably by stimulating donor organ endothelial cells (EC). Although C is known to play a role in the activation of EC, it has not been clear whether the antibodies serve only to anchor the initial components of C, and thus permit the C cascade to proceed, or whether the antibodies themselves deliver a signal to the EC. We have tested affinity-purified human IgM containing XNA (IgM-XNA) for its ability to stimulate in vitro the up-regulation of genes in pig EC. Northern blot analysis shows that IgM, which contains XNA, stimulates mRNA accumulation for certain genes (including IL-8, PAI-1, and ECI-7, a new gene that we have found is associated with EC activation), but not others known to be up-regulated in response to TNF, IL-1 or LPS. Our results show that XNA provide a signal to EC, and thus may themselves participate in activation of EC and consequent vascular rejection.     

Hypothalamic-pituitary-gonadal function in two infants with Smith-Lemli-Opitz syndrome

We report on the hypothalamic-pituitary-gonadal function in 2 male infants with the Smith-Lemli-Opitz (SLO or RSH) syndrome. Both infants had abnormal external genitalia. Basal and LHRH stimulated plasma gonadotropins were normal for age (1 month). Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate were normal for age and sex. Some forms of congenital adrenal hyperplasia (17,20-desmolase deficiency, 17α-hydroxylase deficiency, and 3β-hydroxysteroid dehydrogenase deficiency) were ruled out by hormonal studies. The endocrinological findings indicate a normal hypothalamic-pituitary-gonadal function and a normal adrenal steroid biosynthesis in these 2 patients. A partial androgen receptor defect causing the genital malformations seems possible in one patient. Whether 5α-reductase deficiency is the cause of the male pseudohermaphroditism in SLO syndrome remains the subject of future studies. © 1992 Wiley-Liss, Inc.     

Effect of early and late antibiotic treatment in experimental acute pancreatitis in rats

Background The clinical course in acute necrotizing pancreatitis is mainly determined by bacterial infection of pancreatic and peripancreatic necrosis. The effect of two antibiotic regimens for early and late treatment was investigated in the taurocholate model of necrotizing pancreatitis in the rat. Materials and methods Seventy male Wistar rats were divided into five pancreatitis groups (12 animals each) and a sham-operated group (10 animals). Pancreatitis was induced by intraductal infusion of 3% taurocholate under sterile conditions. Animals received two different antibiotic regimes (20 mg/kg imipenem or 20 mg/kg ciprofloxacin plus 20 mg/kg metronidazole) early at 2, 12, 20, and 28 h after induction of pancreatitis or late at 16 and 24 h after induction of pancreatitis or no antibiotics (control). Animals were examined after 30 h for pancreatic and extrapancreatic infection. Results Early and late antibiotic treatment with both regimes could significantly reduce pancreatic infection from 58 to 8–25%. However, extrapancreatic infection was only reduced by early antibiotic therapy. While quinolones also reduced bacterial counts in small and large bowel, imipenem did not. Conclusions In our animal model of necrotizing pancreatitis, early and late treatment with ciprofloxacin/metronidazole and imipenem reduce bacterial infection of the pancreas. Extrapancreatic infection, however, is reduced significantly only by early antibiotic treatment. The effectivity of early antibiotic treatment in the clinical setting should be subject to further investigation with improved study design and sufficient patient numbers.     

Release of vasopressin from supraoptic neurons within the median eminence in vivo. A combined microdialysis and push-pull perfusion study in the rat

The present study was designed to investigate whether or not arginine vasopressin (AVP) is released from magnocellular neurons within the median eminence (ME) in vivo. Urethane-anesthetized adult male Wistar rats were equipped with a microdialysis probe aimed at the supraoptic (SON) or paraventricular nucleus (PVN), a push-pull perfusion probe resting in the ME, and a blood microdialysis probe within the jugular vein. Dialysis of the SON (but not the PVN) with Ringer's solution containing 56 mmol l⁻¹ K⁺ resulted in an increase in AVP release within the ME (to 492 ± 192% of release during basal conditions,P < 0.05) and into blood (to 138 ± 9%,P < 0.01) whereby the release probably occurred from axonal swellings and nerve terminals of supraoptic neurons which project through the internal zone of the ME to the posterior pituitary. The calculated amount of AVP released into the extracellular fluid of the ME was high enough (approximately 1 pg/μ1) to hypothesize that the neuropeptide could enter the portal blood capillaries in physiologically relevant concentrations. Taken together, the present study indicates that activation of magnocellular neurons is accompanied by release of AVP within the median eminence. We assume that AVP released in this way might mediate a communication between the hypothalamic-neurohypophysial system and the hypothalamic-pituitary-adrenal axis in response to selected stressful stimuli.