Femoral head size is a risk factor for total hip luxation

On the basis of the Norwegian Arthroplasty Register, which has recorded nearly all primary hip prostheses and revisions in Norway since 1987, we studied risk factors for prosthesis luxation leading to revision. 7 prosthesis brand combinations used in 42,987 primary operations were included from 1987-2000. We found that femoral head size was an important risk factor; 28 mm heads led to revision more often than 32 mm ones (failure rate ratio (FRR) 4.0, 95% confidence interval (CI) 2.2-7.3). Charnley (22 mm head) performed equally well or better than the 28 mm heads. The Exeter stem and cup is the type of prosthesis on the Norwegian market with more than two femoral head sizes (26, 28, 30, 32 mm) and 26 mm heads led to revision due to luxation significantly more often than 30 mm heads (FRR 4.1, 95%CI 2.2-8.1). Old age, preoperative diagnosis, and choice of prosthesis brand combination were also important factors affecting the revision rate due to luxation. A posterior approach increased the risk of revision more than a lateral one (FRR 1.9, 95%CI 1.4-2.5). Gender, trochanteric osteotomy and duration of the operation did not affect the results.     

4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes

4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies, and the series of 4-alkyl-HIBO analogues have been extended in this paper in the search for versatile agents. Pharmacological characterization of five new analogues, branched and unbranched 4-alkyl-HIBO analogues, have been carried out. The present compounds are all weak antagonists at Group I mGluRs (mGluR1 and 5) presenting only small differences in potencies (Ki values ranging from 89 to 670 microM). Affinities were studied at native and cloned iGluRs, and the compounds described show preference for the AMPA receptor subtypes GluR1 and 2 over GluR3 and 4. However, compared to previous 4-alkyl-HIBO analogues, these compounds show a remarkably high affinity for the Kain preferring subtype GluR5. The observed GluR5 affinities were either similar or higher compared to their GluR1 and 2 affinity. Isopropyl-HIBO showed the highest affinity for GluR5 (Ki=0.16 microM), and represents a unique compound with high affinity towards the three subtypes GluR1, 2 and 5. In general, these compounds represent new selectivity profiles compared to previously reported Glu receptor analogues.     

MMP-2 and MMP-9 and their tissue inhibitors in the plasma of preterm and term neonates

Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in a variety of physiologic growth and development and pathophysiologic inflammatory conditions. We hypothesized that 1) MMP-2 and -9 plasma activities and TIMP-1 and -2 plasma concentrations in preterm and term neonates were dependent on the gestational and postnatal age; and 2) the respective MMP and their inhibitors were deranged in the development of bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) in preterm neonates. From 1998 to 1999, blood samples were collected from preterm neonates (25-36 wk gestation) with or without BPD and/or IVH as well as from healthy term (37-40 wk gestation) neonates during the first 28 d of life. MMP-2 and MMP-9 plasma activities were measured by zymography; TIMP-1 and TIMP-2 plasma concentrations were determined by ELISA. In neonates without BPD or IVH (n = 50), MMP-2 and MMP-9 plasma activities both appeared to be gestational age dependent, with the highest levels observed in neonates of 33-36 wk gestation. TIMP-1 plasma concentration was highest in term neonates but no gestational difference was found in TIMP-2. Only MMP-9 showed a 50% decrease after d 1 in the first postnatal month. Twelve preterm infants with BPD and/or IVH had significantly lower MMP-2 but higher MMP-9 activity and higher TIMP-1 concentration than those of corresponding neonates without BPD or IVH. These findings show the gestational age-dependent expression of plasma MMP activities and their inhibitors. MMP and TIMP may be involved in the feto-neonatal development and may contribute to the pathogenesis of BPD and/or IVH in critically ill preterm neonates.     

Local activation of dendritic cells leads to insulitis and development of insulin-dependent diabetes in transgenic mice expressing CD154 on the pancreatic beta-cells

The initial events leading to activation of the immune system in type 1 diabetes are still largely unknown. In vivo, dendritic cells (DCs) are thought to be the only antigen-presenting cells (APCs) capable of activating na?ve T-cells and are therefore important for the initiation of the autoimmune response. To test the effect of activating islet-associated APCs in situ, we generated transgenic mice expressing CD154 (CD40 ligand) under control of the rat insulin promoter (RIP). RIP-CD154 mice developed both insulitis and diabetes, although with different incidence in independent lines. We show that activated DCs could be detected both in the pancreas and in the draining pancreatic lymph nodes. Furthermore, diabetes development was dependent on the presence of T- and B-cells since recombination-activating gene (RAG)-deficient RIP-CD154 mice did not develop diabetes. Finally, we show that the activation of immune cells was confined to the pancreas because transplantation of nontransgenic islets to diabetic recipients restored normoglycemia. Together, these data suggest that expression of CD154 on the beta-cells can lead to activation of islet-associated APCs that will travel to the lymph nodes and activate the immune system, leading to insulitis and diabetes.     

Danish obstetricians' personal preference and general attitude to elective cesarean section on maternal request: a nation-wide postal survey

OBJECTIVE: To assess Danish obstetricians' and gynecologists' personal preference and general attitude towards elective cesarean section on maternal request in uncomplicated single cephalic pregnancies at term. DESIGN: Nation-wide anonymous postal questionnaire. POPULATION: Four hundred and fifty-five obstetricians and gynecologists identified in the records of the Danish Society of Obstetrics and Gynecology from January 2000. MAIN OUTCOME MEASURES: Personal preference on the mode of delivery and general attitude towards elective cesarean section on maternal request in an uncomplicated single cephalic pregnancies at term. RESULTS: Of Danish specialists in obstetrics and gynecology, 1.1% would prefer an elective cesarean section in an uncomplicated pregnancy at 37 weeks of gestation with fetal weight estimation of 3.0 kg. This rose to 22.5% when the fetal weight estimation was 4.5 kg at 37 weeks. The main reasons given for preferring abdominal deliveries was the risk to the fetus, risks of perineal injury, and urinary and anal incontinence. Of Danish specialists in obstetrics and gynecology, 37.6% agreed with a woman's right to have an elective cesarean section on maternal request without any medical indication. Obstetricians and gynecologists who had experienced a noninstrumental vaginal delivery themselves or practiced as a private gynecologist only, were less likely to agree with the woman's right to elective cesarean section on maternal request. CONCLUSION: The vast majority of Danish obstetricians and gynecologists would personally prefer vaginal delivery in uncomplicated pregnancies, but nearly 40% agree with the woman's right to request a cesarean section.     

The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

We have determined the pharmacological activity of N-hydroxypyrazole analogues (3a and 4a) of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA), as well as substituted derivatives of these two compounds. The pharmacological profile of 3a is closer to that of thioibotenic acid rather than ibotenic acid, while 4a is a selective N-methyl-D-aspartic acid (NMDA) receptor agonist. Ring substitution of 3a and 4a leads to NMDA receptor antagonists. Whereas efficacy of 3a derivatives at mglu2 receptor decreases from agonism via partial agonism to antagonism with increasing substituent size, substitution abolishes affinity for mglu1 and mglu4 receptors. Ligand- and receptor-based modelling approaches assist in explaining these pharmacological trends among the metabotropic receptors and suggest a mechanism of partial agonism at mglu2 receptor similar to that proposed for the GluR2 glutamate receptor.     

Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors

In this study, we have determined and compared the pharmacological profiles of ibotenic acid and its isothiazole analogue thioibotenic acid at native rat ionotropic glutamate (iGlu) receptors and at recombinant rat metabotropic glutamate (mGlu) receptors expressed in mammalian cell lines. Thioibotenic acid has a distinct pharmacological profile at group III mGlu receptors compared with the closely structurally related ibotenic acid; the former is a potent (low microm) agonist, whereas the latter is inactive. By comparing the conformational energy profiles of ibotenic and thioibotenic acid with the conformations preferred by the ligands upon docking to mGlu1 and models of the other mGlu subtypes, we propose that unlike other subtypes, group III mGlu receptor binding sites require a ligand conformation at an energy level which is prohibitively expensive for ibotenic acid, but not for thioibotenic acid. These studies demonstrate how subtle differences in chemical structures can result in profound differences in pharmacological activity.     

Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site

Inhibition of glycogen phosphorylase (GP) has attracted considerable attention during the last five to 10 years as a means of treating the elevated hepatic glucose production seen in patients with type 2 diabetes. Several different GP inhibitors binding to various binding sites of the GP enzyme have been reported in the literature. In this paper we report on a novel class of compounds that have been identified as potent GP inhibitors. Their synthesis, mode of binding to the allosteric AMP site as well as in vitro data on GP inhibition are shown. The most potent inhibitor was found to be 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid (4j) with an IC(50) value of 74 nM. This compound together with a closely related analogue was further characterized by enzyme kinetics and in primary rat hepatocytes.     

Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential

Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone currently under investigation for use as a novel therapeutic agent in the treatment of type 2 diabetes. One of several important effects of GLP-1 is on nutrient-induced pancreatic hormone release and is mediated by binding to a specific G-protein coupled receptor resulting in the activation of adenylate cyclase and an increase in cAMP generation. In the beta-cell, cAMP binds and modulates activities of both protein kinase A and cAMP-regulated guanine nucleotide exchange factor II, thereby enhancing glucose-dependent insulin secretion. The stimulatory action of GLP-1 on insulin secretion involves interaction with a plethora of signal transduction processes including ion channel activity, intracellular Ca(2+) handling and exocytosis of the insulin-containing granules. In this review we focus principally on recent advances in our understanding on the cellular mechanisms proposed to underlie GLP-1's insulinotropic effect and attempt to incorporate this knowledge into a working model for the control of insulin secretion. Lastly, this review discusses the applicability of GLP-1 as a therapeutic agent for the treatment of type 2 diabetes.