Attempts to improve tissue survival during ex vivo storage

Ex vivo hypothermic perfusion has been shown to enhance short-term survival of organs before transplantation. The effects of perfusion, control of media pH, and systemic drug treatment were studied utilizing superficial epigastric free flaps in Sprague-Dawley rats. Viability of the flaps could be reliably maintained (9/10, 90%) for 72 hours using simple storage in phosphate-buffered Ringer's (pH 7.8) at 4 degrees C. Pretreatment with prostaglandin E1 was of slight benefit. Flap perfusion with or without pharmacologic agents was not beneficial.     

Synthesis and antibacterial activity of new C-10 quinolonyl-cephem esters

A series of cephalosporins derived from cephalothin containing an ester-linked quinolonyl substituent at the C-10 position (C-10 quinolonyl-cephem esters) has been prepared and evaluated for in vitro antibacterial activity. The C-10 quinolonyl-cephem esters exhibited a broadened spectrum of activity when compared with cephalothin and the corresponding quinolones, including activity against beta-lactamase-producing bacteria.     

Excitability of auditory neurons in the dorsal and ventral cochlear nuclei of and mice

Extracellular response properties were studied in neurons of the dorsal and ventral divisions of the cochlear nucleus (DCN and VCN, respectively) of (DBA) and (C57) mice. Mice of the former inbred strain show susceptibility to audiogenic seizures and have severe high frequency hearing loss when young; mice of the latter strain do not. Whereas afterdischarges had been readily observed in the inferior colliculus of DBA mice in a previous study, they were never observed in the cochlear nucleus. The incidence of nonmonotonic intensity functions, the slopes of intensity functions, and the incidence of inhibition in response areas indicated that inhibition was diminished in the DCN of DBA mice. However, in the VCN, these response properties did not differ between the two strains. There appeared to be an “amplification” of excitability (i.e., attenuation of inhibition) from VCN to DCN to inferior colliculus in DBA mice.     

Effects of dipeptidyl peptidase IV on the satiety actions of peptide YY

Aims/hypothesis Dipeptidyl peptidase IV (DP IV) inhibitors are currently being developed to prolong the biological activity of insulinotropic peptides as a novel approach in the treatment of diabetes. We hypothesised that DP IV inhibition could attenuate the satiety actions of peptide YY (PYY) by altering the conversion of PYY(1–36) to PYY(3–36).Materials and methods The effects of PYY delivered by osmotic mini-pumps were assessed in rats treated with a DP IV inhibitor and in a rat model deficient in DP IV.Results Pharmacological levels of total PYY were found in the circulation after the exogenous administration of PYY(3–36). While both PYY(1–36) and PYY(3–36) reduced food intake in normal rats, PYY(1–36) was ineffective in rats deficient in DP IV. When re-fed after a 24-h fast, DP IV-deficient rats exhibited higher food intake and weight gain than normal rats. Moreover, unlike controls, there was no postprandial increase in PYY levels in DP IV-deficient rats. Despite these findings, administration of a DP IV inhibitor, Pro-boroPro, did not alter the acute anorectic effects of exogenous PYY(1–36) in normal rats. This could be the result of the protection of other appetite regulatory peptides or the generation of PYY(3–36) by remaining DP IV activity or other dipeptidyl peptidases.Conclusions/interpretation Although DP IV inhibition with Pro-boroPro attenuated the generation of PYY(3–36), our results indicate that short-term DP IV inhibition does not eliminate the satiety actions of exogenously administered PYY(1–36) at the doses tested.     

Interaction of Porphyromonas gingivalis with oral streptococci requires a motif that resembles the eukaryotic nuclear receptor box protein-protein interaction domain

Porphyromonas gingivalis initially colonizes the oral cavity by interacting with organisms in supragingival plaque, such as the oralis group of oral streptococci. This interaction involves the association of the streptococcal antigen I/II with the minor fimbrial antigen (Mfa1) of P. gingivalis. Our previous studies showed that a peptide (BAR) derived from antigen I/II inhibits P. gingivalis adherence and subsequent biofilm formation on streptococcal substrates. In addition, screening a combinatorial peptide library identified select amino acid substitutions in the NITVK active region of BAR that increased the adherence of P. gingivalis to streptococci. Here we report that incorporating these residues in a synthetic peptide results in more-potent inhibition of P. gingivalis adherence and biofilm formation (I(50) [50% inhibition] at 0.52 microM versus I(50) at 1.25 microM for BAR). In addition, a second structural motif in BAR, comprised of the amino acids KKVQDLLKK, was shown to contribute to P. gingivalis adherence to streptococci. Consistent with this, the KKVQDLLKK and NITVK motifs are conserved only in antigen I/II proteins expressed by the oralis group of streptococci, which interact with P. gingivalis. Interestingly, the primary and secondary structures and the functional characteristics of the amphipathic VQDLL core alpha-helix resemble the consensus nuclear receptor (NR) box protein-protein interacting domain sequence (LXXLL) of eukaryotes. BAR peptides containing amino acid substitutions with the potential to disrupt the secondary structure of VQDLL were less-effective inhibitors of P. gingivalis adherence and biofilm formation, suggesting that the alpha-helical character of VQDLL is important. Furthermore, replacing the lysines that flank VQDLL with acidic amino acids also reduced inhibitory activity, suggesting that the association of VQDLL with Mfa1 may be stabilized by a charge clamp. These results indicate that the Mfa1-interacting interface of streptococcal antigen I/II encompasses both the KKVQDLLKK and NITVK motif and suggest that the adherence of P. gingivalis to streptococci is driven by a protein-protein interaction domain that resembles the eukaryotic NR box. Thus, both motifs must be taken into account in designing potential peptidomimetics that target P. gingivalis adherence and biofilm formation.     

Cardiopulmonary Side‐Effects and Pharmacokinetics of an Emulsion of Propofol (Disoprivan®) in Comparison to Propofol Solved in Polysorbate 80 in Goats

The aim of this study was to determine whether any pharmacokinetic or pharmacodynamic differences exist in goats between propofol in its currently licensed form (Disoprivan®) and a new 1 % solution of propofol (NSP) containing polysorbate 80. Nine goats received, on two different occasions in a randomized double‐blinded order, 4 mg/kg propofol intravenously (i.v.; Disoprivan® or NSP). To detect differences in cardiopulmonary effects and pharmacokinetics, the Wilcoxon signed rank test for paired data was used. In the NSP group the duration of initial apnoea was significantly longer, and 6 and 12 min after drug application p_AO₂ levels were significantly lower than in the Disoprivan® group. Mean cardiovascular parameters did not differ significantly between the groups but in the NSP group in six goats marked changes in blood pressure occurred: systolic arterial pressures fell to a minimum of 40–60 mmHg within the first 10 min. This was followed by a marked increase in blood pressure,with maxima exceeding 300 mmHg. In the NSP group the half‐life of propofol was significantly longer, the clearance rate was smaller and the areas under the drug concentration‐time curves were larger than in the Disoprivan® group. The cardiopulmonary side‐effects of NSP suggest that propofol dissolved in polysorbate 80 is not a suitable alternative to the current formulation of propofol.