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Byline: A. Jacolot (1), P. Incagnoli (1), A. R. Edouard (1), M. Tod (2), O. Petitjean (2), K. Samii (1), O. Mimoz (1) Keywords: Key words Cefpirome; Ciprofloxacin; Pharmacokinetics; Systemic inflammatory response syndrome; Trauma Abstract: Objective: To determine the pharmacokinetic parameters of cefpirome, a new so-called fourth-generation cephalosporin, in previously healthy trauma patients with posttraumatic systemic inflammatory response syndrome (SIRS) and to compare them to parameters obtained in matched, healthy volunteers. Design: A prospective study. Setting: 12-bed surgical intensive care unit in a university hospital. Patients: 9 severe [Injury Severity Score, median (range) 29 (16--50)] trauma patients on mechanical ventilation with proven or suspected cefpirome-susceptible nosocomial infection, with no renal or hepatic failure, and healthy volunteers matched for age ( +- 5 years), sex, and body surface area ( +- 10 %) were enrolled. All were men. Interventions: Cefpirome (2 g twice daily) was continuously infused over a 0.5 h period alone or concomitantly with ciprofloxacin (400 mg over 1 h, twice daily). Measurements and main results: Antibiotic concentrations in plasma were measured by high-performance liquid chromatography their pharmacokinetic parameters were evaluated at 12 time points after the first drug administration using a noncompartmental model. Cefpirome pharmacokinetic parameters for the two groups were similar despite a wider variation for trauma patients. Specifically, the median (range) time during which the cefpirome concentration in plasma remained over 4 mg/l (corresponding to the French lower cutoff determining cefpirome susceptibility) was 9.5 (7-- > 12) and 9 (8--12) h for trauma patients and healthy volunteers, respectively. In the group of five patients receiving combined antibiotic therapy, the interindividual variability of pharmacokinetics was wider for ciprofloxacin than for cefpirome. Conclusion: No major pharmacokinetic modification was noted when cefpirome was given to trauma patients with posttraumatic SIRS without significant organ failure, indicating that no dosage adjustment seems required in this population. However, larger studies including determination of antibiotic levels in tissues are warranted to confirm these results. Author Affiliation: (1) Service d'Anesthesie-Reanimation, Hopital Bicetre, F-94 270 Le Kremlin Bicetre, France, FR (2) Centre de Recherche en Pathologie Infectieuse et Tropicale (Crepit 93), F-93 009 Bobigny, France, FR Article note: Received: 3 September 1998 Final revision received: 18 January 1999 Accepted: 25 February 1999

Nuclear LIM domains interact with a family of coregulators referred to as Clim/Ldb/Nli. Although one family member, Clim-2/Ldb-1/Nli, is highly expressed in epidermal keratinocytes, no nuclear LIM domain factor is known to be expressed in epidermis. Therefore, we used the conserved LIM-interaction domain of Clim coregulators to screen for LIM domain factors in adult and embryonic mouse skin expression libraries and isolated a factor that is highly homologous to the previously described LIM-only proteins LMO-1, -2, and -3. This factor, referred to as LMO-4, is expressed in overlapping manner with Clim-2 in epidermis and in several other regions, including epithelial cells of the gastrointestinal, respiratory and genitourinary tracts, developing cartilage, pituitary gland, and discrete regions of the central and peripheral nervous system. Like LMO-2, LMO-4 interacts strongly with Clim factors via its LIM domain. Because LMO/Clim complexes are thought to regulate gene expression by associating with DNA-binding proteins, we used LMO-4 as a bait to screen for such DNA-binding proteins in epidermis and isolated the mouse homologue of Drosophila Deformed epidermal autoregulatory factor 1 (DEAF-1), a DNA-binding protein that interacts with regulatory sequences first described in the Deformed epidermal autoregulatory element. The interaction between LMO-4 and mouse DEAF-1 maps to a proline-rich C-terminal domain of mouse DEAF-1, distinct from the helix-loop-helix and GATA domains previously shown to interact with LMOs, thus defining an additional LIM-interacting domain.

Byline: O. Mimoz (1), V. Binter (2), A. Jacolot (2), A. Edouard (1), M. Tod (2), O. Petitjean (2), K. Samii (1) Keywords: Key words Intensive care unit; Ciprofloxacin; Bioavailability; Pharmacokinetics; Enteral nutrition Abstract: Objective: To determine the pharmacokinetics and absolute bioavailability of ciprofloxacin in 12 critically ill patients receiving continuous enteral feeding. Design: a prospective, cross-over study. Setting: 12-bed surgical intensive care unit in a University Hospital. Patients: 12 stable critically ill patients on mechanical ventilation and receiving continuous enteral feeding (Normoreal fibres) without diarrhea or excessive residual gastric contents ( &lt 200 ml/4 h). None had gastro-intestinal disease, renal insufficiency (estimated creatinine clearance aY= 50 ml/min) or was receiving medications that could interfere with ciprofloxacin absorption or metabolism. Measurements and main results: The study was carried out after the fourth (steady state) b. i. d. intravenous (i. v.) 1-h infusion of 400 mg and the second b. i. d. nasogastric (NG) dose of 750 mg (crushed tablet in suspension). Plasma concentrations were measured by high-performance liquid chromatography. The median (range) peak concentration after i. v. infusion was 4.1 (1.5--7.4) mg/l, and that after NG administration was 2.3 (0.7--5.8) mg/l, occurring 1.25 (0.75--3.33) h after dosing. The median [range] areas under plasma concentration-time curves were similar for the two administration routes (10.3 [3.3--34.6] and 8.4 [3.6--53.4] for i. v. infusion and NG administration, respectively). Ciprofloxacin bioavailability ranges from 31 to 82 % (median, 44 %). Conclusions: In tube-fed critically ill patients, a switch to the NG ciprofloxacin after initial i. v. therapy to simplify the treatment of severe infections is restricted to those for whom serial assessments of ciprofloxacin levels are routinely available. Author Affiliation: (1) Service d'Anesthesie-Reanimation Chirurgicale, Hopital Bicetre, F-94 275 Le Kremlin-Bicetre, France Tel.: 33 1 45 21 34 41 Fax: 33 1 45 21 28 75 email: darkb@imaginet.fr, FR (2) Centre de Recherche en Pathologie Infectieuse et Tropicale (CREPIT 93), Hopital Avicenne, F-93 009 Bobigny, France, FR Article note: Received: 7 November 1997 Accepted: 8 July 1998

The interaction of glutamine aspartate (i, i + 4) with the H-bond results in the stabilization of the peptide helices. These type of interactions are prevalent in protein helices. When aspartate is charged, the Gibbs energy of the interaction is - 1.0 kcal/mol and when it is protonated the charge is - 0.4(sub 4) kcal/mol. The specific interaction of aspartate carboxylate group with the trans amide proton of glutamine is revealed by magnetic proton experiments. This interaction is observed when the glutamine is N-terminal to the aspartate and the spacing is (i, i + 4).

The study demonstrates the principle of therapeutic RNA editing and reports the use of a synthetic complimentary RNA oligonucleotide in the treatment of a premature stop codon mutation in dystrophin RNA. The synthetic RNA was hybridized to a premature stop codon and then treated with nuclear extracts having cellular enzyme double-stranded RNA adenosine deaminase. Upon in vitro translation of treated RNA, a dramatic increase in expression of a downstream luciferase coding region was noticed.

Certain purine methylphosphonate oligodeoxyribonucleotides (MPOs) bind complementary single-stranded RNA targets to form triple-stranded complexes. At submicromolar concentrations, cell-free protein synthesis is inhibited by these MPOs. These MPOs also inhibit reverse transcription in their complementary polypyrimidine target sites in a sequence-specific manner.

A statistical weight was assigned to the amino acid that preceded helical residues to include N-capping effects in the Lifson-Roig theory for the helix-coil transition. The Lifson-Roig theory predicts the negligible influence of N-terminus substitution in an unacetylated peptide on alpha-helix stability.

Researchers analyzed the localization of the mRNAs encoding the activin betaA and betaB subunits in Xenopus embryos to identify the source of activin protein for initial mesoderm induction, and to discover whether activins could further influence embryonic development for the induction. Activin betaA and betaB mRNAs were discovered in the follicle cells around oocytes but not in oocytes themselves or fertilized eggs.

A study was done to determine antisense oligonucleotide sensitivity to intended target RNA. Xenopus oocytes were injected with perfect and partially matched antisense oligonucleotides afterwhich target RNA degradation was measured. Results show that the oocyte model cannot provide specific cleavage of an intended target RNA without causing partial destruction of many nontargeted RNAs. These conclusions were based on the extent to which antisense nucleotides cause cleavage of RNAs at imperfectly matched target sites.