The human interleukin 18 gene IL18 maps to 11q22.2-q22.3, closely linked to the DRD2 gene locus and distinct from mapped IDDM loci

OBJECTIVE: To report a laparoscopic technique for placement of a transabdominal cervicoisthmic cerclage. DESIGN: Detailed case report of one of three patients undergoing described procedure. SETTING: University hospital. PATIENT: A 39-year-old infertile patient with a history of cervical adenocarcinoma in situ and two cone biopsies, resulting in an essentially absent exocervix. INTERVENTION(S): Laparoscopic transabdominal cervicoisthmic cerclage placement, as an interval procedure, followed by ET of cryopreserved donor oocyte-derived embryos. MAIN OUTCOME MEASURE(S): Clinical outcome. RESULT(S): Establishment of a pregnancy delivered at 38 1/2 weeks of gestation by elective cesarean section. CONCLUSION(S): Patients believed to require a transabdominal cerclage may undergo a laparoscopic interval procedure, obviating the need for a laparotomy before or during pregnancy.     

Refutational theorem proving for hierarchic first-order theories

We extend previous results on theorem proving for first-order clauses with equality to hierarchic first-order theories. Semantically such theories are confined to conservative extensions of the base models. It is shown that superposition together with variable abstraction and constraint refutation is refutationally complete for theories that are sufficiently complete with respect to simple instances. For the proof we introduce a concept of approximation between theorem proving systems, which makes it possible to reduce the problem to the known case of (flat) first-order theories. These results allow the modular combination of a superposition-based theorem prover with an arbitrary refutational prover for the primitive base theory, whose axiomatic representation in some logic may remain hidden. Furthermore they can be used to eliminate existentially quantified predicate symbols from certain second-order formulae.     

Bounds for the renewal function

Summary Upper and lower bounds are given to the solutionV of a renewal equation by applying a well-known monotonicity argument. The results are applied to the renewal function of an ordinary renewal process.

---

Zusammenfassung Es werden obere und untere Schranken für die LösungV einer Erneuerungsgleichung gegeben durch Anwendung einer bekannten Monotonieeigenschaft des zugehörigen Operators. Die Ergebnisse werden angewandt auf die Erneuerungsfunktion eines gewöhnlichen Erneuerungsprozesses.

     

The pharmacokinetic characteristics of glycolated humanized anti-Tac Fabs are determined by their isoelectric points

To evaluate a method for preventing the nephrotoxicity caused by the high renal accumulation of radiolabeled or toxin-conjugated small immunoproteins used for cancer therapy, we conjugated humanized anti-Tac Fab fragments with various numbers of glycolate molecules [glycolated Fab fragments (glyco-Fabs)] and separated the conjugates by means of ion-exchange columns into three fractions, depending on their isoelectric points (pIs). We evaluated the biodistribution, pharmacokinetics, and catabolism in normal nude mice of nonglycolated Fab (pI > or = 9.3) and three different preparations of glyco-Fab, including strongly anionic glyco-Fab (sa-glyco-Fab: pI < or = 4.5), mildly anionic glyco-Fab (pI = 4.5-7), and mildly cationic glyco-Fab (pI = 7-9.3). In addition, the biodistributions of 125I-labeled sa-glyco-Fab and 131I-labeled nonglycolated Fab were evaluated in normal nude mice coinjected with 50 mg of L-lysine and/or 1 microg of furosemide and in a control group without coinjection. We then evaluated the serial biodistribution of 125I-labeled sa-glyco-Fab (4 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg) in Tac antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice with s.c. tumor xenografts derived from Tac antigen-positive ATAC4 cells and receptor-negative A431 cells. These animals were coinjected with 30 mg of lysine i.v. and 30 mg of lysine i.p. 15 min after the radiolabeled Fab injection. To evaluate the biodistribution data and study scintigraphic imaging, we performed serial scintigraphy on normal and tumor-bearing mice with all four 131I-labeled preparations. 125I-labeled mildly cationic glyco-Fab and 131I-labeled nonglycolated Fab had similar distributions, except in the kidney. However, both 125I-labeled anionic glyco-Fab preparations showed significantly different distributions from both cationic Fabs in the blood, liver, lung, and spleen. Renal accumulation of all four radiolabeled Fab preparations increased significantly as the pI increased (P < 0.01). In addition, the intact fraction of Fab excreted into urine increased as pI decreased. Therefore, the glomerular filtration depended on whether the charge on the Fab was positive or negative. The proportion of Fab reabsorbed by the proximal tubules increased as pI increased. 125I-labeled sa-glyco-Fab and 125I-labeled mildly anionic glyco-Fab showed a similar distribution in the blood and all organs except the kidney. Lysine led to an additional blocking effect on proximal tubular uptake of both sa-glyco-Fab and nonglycolated Fab. Addition of furosemide yielded only a small effect when used with lysine. With lysine, the sa-glyco-Fab:nonglycolated Fab estimated integral radioactivity ratios were 4.7 and 0.7 in the ATAC4 tumor and in the kidney, respectively. The use of anionic fragments, which may be used in conjunction with lysine, represents a promising approach that may help decrease the renal toxicity of other small fragments, the molecular weights of which range from Mr 40,000 to 70,000, and, thereby, allow higher doses of radiation to the tumor.     

Synthesis of GTP-derived Ras ligands

A practical and convenient method for the synthesis of acid- and base-sensitive GTP analogues carrying a further substituent at the terminal phosphate has been developed. Key to the successful synthesis of these potential ligands of the Ras protein is the use of Pd0-sensitive allyl protecting groups in a one-pot synthesis that avoids evaporation steps. Initial biochemical analysis of a representative compound revealed that such GTP analogues can bind to Ras and might open up the possibility of developing small molecules that can act as deactivators of oncogenic Ras.     

Ex-vivo whole blood cultures for predicting cytokine-release syndrome: dependence on target antigen and antibody isotype

Ex-vivo whole blood assays have been evaluated for their ability to accurately predict the risk of a first-dose cytokine reaction developing in vivo following therapeutic antibody infusion. Tumour necrosis factor alpha (TNF alpha) release was rapidly detected in cultures incubated with either anti-CD52 antibodies of the human IgG1 or rat IgG2b isotype, and to a lesser extent with a human IgG4 isotype. Endotoxin contamination of the antibodies was not responsive for cytokine release, since polymixin B failed to inhibit cytokine release using concentrations of this antibiotic which neutralized the enhanced cytokine release seen from LPS-spiked antibody. A rat IgG2b antibody to CD45 and a human IgG1 anti-CD3 also induced significant TNF release, however, an aglycosyl anti-CD3 mutant devoid of adverse side-effects in vivo, did not result in cytokine release in vitro. Since the pattern of cytokine release seen following the clinical use of these antibodies was in good agreement with the findings of the ex-vivo whole cultures, this demonstrates the usefulness of this assay to predict cytokine release in vivo.