The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways

Initiation factor eIF4E binds to the 5'-cap of eukaryotic mRNAs and plays a key role in the mechanism and regulation of translation. It may be regulated through its own phosphorylation and through inhibitory binding proteins (4E-BPs), which modulate its availability for initiation complex assembly. eIF4E phosphorylation is enhanced by phorbol esters. We show, using specific inhibitors, that this involves both the p38 mitogen-activated protein (MAP) kinase and Erk signaling pathways. Cell stresses such as arsenite and anisomycin and the cytokines tumor necrosis factor-alpha and interleukin-1beta also cause increased phosphorylation of eIF4E, which is abolished by the specific p38 MAP kinase inhibitor, SB203580. These changes in eIF4E phosphorylation parallel the activity of the eIF4E kinase, Mnk1. However other stresses such as heat shock, sorbitol, and H2O2, which also stimulate p38 MAP kinase and increase Mnk1 activity, do not increase phosphorylation of eIF4E. The latter stresses increase the binding of eIF4E to 4E-BP1, and we show that this blocks the phosphorylation of eIF4E by Mnk1 in vitro, which may explain the absence of an increase in eIF4E phosphorylation under these conditions.     

Survivorship analysis of the Kinematic Stabilizer total knee replacement: a 10- to 14-year follow-up

The Kinematic Stabilizer is a posterior-cruciate-substituting design of total knee replacement. We have reviewed 109 primary total knee replacements in 95 patients at a mean follow-up time of 12.7 years (10 to 14). We used survival analysis with failure defined as revision of the implant. This gave a cumulative survival rate of 95% (95% CI +/- 5%) at ten years and (87% +/- 10%) at 13 years. These results from an independent centre confirm the value of an established design of cemented total knee replacement and question the wisdom of the introduction of modifications and new designs without properly controlled trials.     

SDZ 216-525, a selective 5-HT1A receptor antagonist, reverts zinc-induced inhibition of water intake in dehydrated rats

Zinc is found in many brain regions where it participates in important processes such as neurotransmission and neuromodulation. We previously demonstrated that acute third ventricle injection of zinc inhibits water intake in dehydrated rats. The present study was undertaken to explore a possible link between zinc-induced inhibition of water intake in dehydrated rats and serotonergic systems in the brain. Adult, male Wistar rats had the third ventricle cannulated a week before the experiments. After an overnight period of water deprivation, the animals (N = 12 per group) received acute intracerebroventricular injections (2 microliters) of Zn(Ac)2 (6.7, 67.1 and 671.6 ng/rat). Control animals (N = 12) received NaAc (671.6 ng/rat). Zinc-treated animals displayed a significant, dose-dependent reduction in water intake. Water intake after 120 min was 7.70 +/- 0.50 ml in control (NaAc-treated) dehydrated rats while animals treated with the highest dose of Zn(Ac)2 drank 2.63 +/- 0.73 ml. Third ventricle injections of SDZ 216-525, a selective 5-HT1A receptor antagonist, 45 min before zinc administration, generated a dose-dependent reversal of zinc-induced thirst blockade in water-deprived rats. At the highest dose used (10 micrograms/rat), the water intake of the animals after 120 min was 7.30 +/- 0.23 ml, a value equal to that of control animals. These data suggest that zinc may decrease water intake in dehydrated rats by activation of a 5-HT1A receptor-related mechanism.     

Synthesis and structure-activity data of some new epibatidine analogues

The high-pressure Diels-Alder reaction of N-carbomethyoxypyrroles and phenyl vinyl sulfone affords versatile intermediates for the palladium-catalyzed preparation of new epibatidine analogues. Structure-activity relationships of new epibatidine analogues are presented. High affinities of Ki = 0.81 and 2.6 nM for the [3H]-cytisine rat brain nicotinic acetylcholine binding sites were found for the 5-pyrimidinyl and the 5-(2-amino)-pyrimidinyl epibatidine analogues, respectively.     

Motility in the Hunt-Lawrence pouch after total gastrectomy

PURPOSE: The aim of this study was to evaluate motility patterns of the Hunt-Lawrence pouch and the jejunal limb of patients reconstructed with a pouch after total gastrectomy, and to compare the findings in symptomatic patients to those without symptoms after the operation. PATIENTS AND METHODS: Thirty-three patients who had undergone post-gastrectomy pouch reconstruction were studied using a water-perfused motility system. In 21, the pouch was connected by a Roux-en-Y, and, in 12, by a jejunal interposition. Twenty-eight patients were asymptomatic, including 17 connected by a Roux-en-Y and 11 by a jejunal interposition. Five patients were by a jejunal interposition. Five patients were symptomatic, including 4 connected by Roux-en-Y Y and 1 by jejunal interposition. A control group consisted of 5 healthy volunteers who had not undergone operation. RESULTS: The motility phases in the pouch and jejunal limb of asymptomatic patients were of shorter duration than those of controls, and they followed a random sequence instead of a normal progression from phase I to II to III. Motility features were similar in the pouch and the jejunal limb. Orthograde propagation of phase III-like activity was reduced and may contribute to the pouch storage function. Four of the 5 symptomatic patients showed highly abnormal motility with hypomotile or obstructive patterns. The technique of connecting the pouch--jejunal interposition of Roux-en-Y--did not affect the motility findings. CONCLUSIONS: The altered motility occurs after a Hunt-Lawrence pouch reconstruction in asymptomatic patients. Symptoms after gastrectomy are associated with further disturbed motility that can be differentiated from the motility changes in asymptomatic patients.     

Clinical results of meniscus repair in patients 40 years and older

The critical role that the meniscus plays in the knee along with the advantages of preserving as much of the meniscus as possible have both been well documented. Whenever possible, meniscus repair has become the procedure of choice for treatment of meniscal tears. However, some researchers have reported less favorable results in older patients. To determine the results of meniscus repair in older patients, patients 40 years and older who underwent arthroscopically assisted meniscus repair were prospectively followed up. Thirty-seven patients were included in the study, all of which had a minimum 2-year follow-up (average, 26.5 months). The average age of the patients at the time of the repair was 44.2 years (range, 40 to 52 years); 26 were males and 11 were females. There were 19 left knees and 18 right knees included in the study. Twenty-two patients had associated anterior cruciate ligament reconstructions. Physical examination at follow-up included swelling, joint line tenderness, locking, and McMurray testing and radiographs. Five of 37 menisci repaired (13.5%) were symptomatic at latest follow-up. All of these patients had joint line tenderness and two had a positive McMurray test. Three of these patients had repeat arthroscopy confirming that the meniscus had not healed. Because of the small number of patients with symptoms at follow-up, the authors feel that meniscus repair in patients 40 years and older is an effective treatment for peripherally located meniscus tears. With 86.5% of the patients having good clinical results, these findings are comparable with other studies with a younger population and signify that repair of peripheral tears is indicated in this age group especially in conjunction with anterior cruciate ligament reconstruction. The findings suggest that the location and meniscal tear, rather than the age of the patient, determine the potential for successful repair.     

Preservation with 8-bromo-cyclic GMP improves pulmonary function after prolonged ischemia

BACKGROUND: Cyclic guanosine monophosphate (cGMP) is a potent second messenger for the nitric oxide pathway in the pulmonary vasculature. Increased cytosolic cGMP levels elicit pulmonary vasodilatation resulting in decreased pulmonary vascular resistance and maximized pulmonary function after ischemia-reperfusion injury. We hypothesized that the addition of a membrane-permeable cGMP analogue (8-bromo-cGMP) to a Euro-Collins (EC) preservation solution would ameliorate pulmonary reperfusion injury better than prostaglandin E1 injection alone after prolonged hypothermic ischemia. METHODS: All lungs from New Zealand White rabbits (weight, 3 to 3.5 kg) were harvested en bloc, flushed with EC solution, and reperfused with whole blood for 30 minutes. Group 1 lungs (immediate control) were immediately reperfused. Group 2 lungs (control) were stored inflated at 4 degrees C for 18 hours before reperfusion. Groups 3 and 4 lungs were flushed with EC solution containing 200 micromol/L 8-bromo-cGMP and stored at 4 degrees C for 18 and 30 hours, respectively. Fresh, nonrecirculated venous blood was used to determine single-pass pulmonary venous-arterial oxygen gradients at 10-minute intervals. Assays for cGMP, cyclic adenosine monophosphate, nitric oxide synthase activity, and myeloperoxidase were performed on all lung tissue samples. Wet to dry weight ratios were determined after 2 weeks of passive desiccation. RESULTS: Oxygenation (venous-arterial oxygen gradient), pulmonary artery pressure, pulmonary vascular resistance, and edema formation were significantly improved in groups 3 and 4 (addition of 8-bromo-cGMP to EC plus 18 or 30 hours of hypothermic ischemia). Hypothermic storage (groups 2, 3, and 4) decreased both nitric oxide synthase activity and myeloperoxidase levels compared with immediate reperfusion (group 1). CONCLUSIONS: These results suggest that the addition of a membrane-permeable cGMP analogue to an EC pulmonary flush solution improves pulmonary function after prolonged storage compared with EC and prostaglandin (E1) preservation alone. The finding of myeloperoxidase reduced levels after hypothermic storage and subsequent reperfusion may suggest a more important role for pulmonary hemodynamic control in mitigating pulmonary reperfusion injury.     

Mechanical properties and 95 ° aging characteristics of zircon-reinforced Zn-4AI-3Cu alloy

A process for preparing zinc alloy castings containing dispersions of zircon particles is described. Composites were prepared by stirring zircon particles in Zn-4Al-3Cu (ZAS) alloy melts and subsequently casting these melts in permanent molds. It was found that additions of zircon resulted in an increase in the sliding wear resistance and in the proportional limit in compression. The aging characteristics of the ZAS alloy have also been investigated by hardness tests, dilatometry technique, and transmission electron microscopy observations. There are two kinds of precipitates that occur during the aging process. The α-phase precipitates from the ŋ phase in the early stage of aging and the copper-rich ɛ-phase precipitates from the ŋ phase in the later stage of aging. Therefore, there are two peaks in the hardening curve caused by both a-phase and ŋ-phase precipitation. The a-phase precipitation induces the dimensional shrinkage, and the copper-rich ŋ phase precipitation results in dimensional expansion. Zircon particles existing in ZAS alloy reduce the maximum shrinkage from 353 × 10^-6 for the monolith to 167 × 10^-6 for the composite. Two groups of parallel a-phase plates had formed within the ŋ dendrite during aging at 95 °. The orientation relationship between the a phase and matrix was determined as [άcr1l01]_ŋ//[lάrc10]_a, (1120)ŋ/(lll)α.