Preclinical Assessment of Adjunctive tPA and DNase for Peritoneal Dialysis Associated Peritonitis

A major complication of peritoneal dialysis is the development of peritonitis, which is associated with reduced technique and patient survival. The inflammatory response elicited by infection results in a fibrin and debris-rich environment within the peritoneal cavity, which may reduce the effectiveness of antimicrobial agents and predispose to recurrence or relapse of infection. Strategies to enhance responses to antimicrobial agents therefore have the potential to improve patient outcomes. This study presents pre-clinical data describing the compatibility of tPA and DNase in combination with antimicrobial agents used for the treatment of PD peritonitis. tPA and DNase were stable in standard dialysate solution and in the presence of antimicrobial agents, and were safe when given intraperitoneally in a mouse model with no evidence of local or systemic toxicity. Adjunctive tPA and DNase may have a role in the management of patients presenting with PD peritonitis.     

Characterization of Dahl salt-sensitive rats with genetic disruption of the A2B adenosine receptor gene: implications for A2B adenosine receptor signaling during hypertension

The A_2B adenosine receptor (AR) has emerged as a unique member of the AR family with contrasting roles during acute and chronic disease states. We utilized zinc-finger nuclease technology to create A_2BAR gene (Adora2b)-disrupted rats on the Dahl salt-sensitive (SS) genetic background. This strategy yielded a rat strain (SS-Adora2b mutant rats) with a 162-base pair in-frame deletion of Adora2b that included the start codon. Disruption of A_2BAR function in SS-Adora2b mutant rats was confirmed by loss of agonist (BAY 60-6583 or NECA)-induced cAMP accumulation and loss of interleukin-6 release from isolated fibroblasts. In addition, BAY 60-6583 produced a dose-dependent increase in glucose mobilization that was absent in SS-Adora2b mutants. Upon initial characterization, SS-Adora2b mutant rats were found to exhibit increased body weight, a transient delay in glucose clearance, and reduced proinflammatory cytokine production following challenge with lipopolysaccharide (LPS). In addition, blood pressure was elevated to a greater extent (∼15–20 mmHg) in SS-Adora2b mutants as they aged from 7 to 21 weeks. In contrast, hypertension augmented by Ang II infusion was attenuated in SS-Adora2b mutant rats. Despite differences in blood pressure, indices of renal and cardiac injury were similar in SS-Adora2b mutants during Ang II-augmented hypertension. We have successfully created and validated a new animal model that will be valuable for investigating the biology of the A_2BAR. Our data indicate varying roles for A_2BAR signaling in regulating blood pressure in SS rats, playing both anti- and prohypertensive roles depending on the pathogenic mechanisms that contribute to blood pressure elevation.     

Prostaglandins involvement in the formation of luteinized unrupted follicles in the cyclic female rat

The purpose of this investigation was to study the role played by prostaglandins in advanced ovulation and in the formation of luteinized unrupted follicles (LUF) in cyclic female rats. Dose related effects on ovulation were observed in rats given LH on diestrus 2 at 16.30. A significant positive correlation was observed between the number of postovulatory corpura lutea (POCL) and the increasing doses of LH. By contrast the number of LUF was negatively correlated with LH. Indomethacin treatment by 6h30 after administration of an ovulatory LH dose significantly increased the occurence of LUF at the expense of POCL. Conversely PGF_2α when admiststered by 6h30 after a subovulatory LH stimulation enhanced in a dose dependent manner the number of POCL with respect to the LH treated controls. Under a similar treatment with a subovulatory dose of LH, PGE₂ remained without ovulatory effects. The mechanisms of the formation of LUF are discussed on the basis of these results.     

Lichtbedingte Wachstumsschwingungen beiHelianthus annuus

Ohne ZusammenfassungHerrn Prof. Dr. W.Ruhland zum 80. Geburtstag gewidmet.     

An NMR Study of the Conformations of N-terminal Substance P Fragments and Antagonists

Abstract

Three N-terminal fragments of the neurotransmitter Substance P as well as two antagonist heptapeptides containing D-amino-acid residues were studied using different ID and 2D NMR techniques. Total nonexchangeable ¹H-NMR assignments were carried out in D₂O and the NH protons were assigned in H₂O by means of COSY experiments. The spectral data indicates that there are no preferred conformations for the backbone. The N-terminal tetrapeptide SP_1–4-OH exists as a mixture of cis/trans isomers and this effect was studied as a function of pH.     

Bifidobacteria-mediated immune system imprinting early in life

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