A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

Efficiency improvements in US office equipment: Expected policy impacts and uncertainties

We create a business as usual scenario for office equipment electricity use from industry forecasts of equipment sales, surveys of equipment densities by building type, measured data on wattage and usage by equipment type and projected lifetimes for equipment. We then calculate electricity used by building type and equipment type for Energy Star and advanced scenarios and explore the sensitivity of these results to variations in key input parameters. According to our analysis, the Energy Star programme will save the US almost US$1 billion annually starting in the year 2000, with minimal expenditure of public funds.     

Bacterial attachment to oropharyngeal epithelial cells in breastfed newborns

Dopaminergic agents and carbidopa/levodopa have become the preferred treatment for both the restless legs (RL) syndrome and for periodic limb movements in sleep (PLMS). For once-nightly treatments with carbidopa/ levodopa, a problem with morning end-of-dose rebound increases in leg movements has been reported to occur in the about one-fourth of the patients. In our clinical studies a previously unreported but far more significant problem of markedly augmented RL symptoms occurred in the afternoon and the evening prior to taking the next nightly dose. A systematic prospective evaluation of this augmentation in 46 consecutive patients treated with carbidopa/ levodopa for RL syndrome or PLMS disorder found this augmentation to be the major adverse effect of treatment. Augmentation occurred for 31% of PLMS patients and 82% of all RL patients. It was greater for subjects with more severe RL symptoms and for patients on higher doses (> or = 50/200 mg carbidopa/levodopa) but was unrelated to gender, age or baseline severity of PLMS. This augmentation was severe enough to require medication change for 50% of the RL patients and 13% of PLMS patients. Augmentation resolved with cessation of the medication and could be minimized by keeping the dose low.     

Recurrent erosion after photorefractive keratectomy

Recurrent erosion of the corneal epithelium has been treated successfully by phototherapeutic keratectomy when convention therapy has failed. We present a case of recurrent corneal erosion occurring 1 year after photorefractive keratectomy in a 55-year-old myopic woman. No corneal abnormalities were previously identified in either the affected or the fellow eye. This case demonstrates the potential for ineffective healing of the corneal epithelial basement membrane complex after excimer laser photorefractive keratectomy.     

Improvements in the silver-staining technique for nucleolar organizer regions (AgNOR)

The silver-staining technique for nucleolar organizer regions (AgNOR) of Ploton et al., as popularized by Crocker, is being widely used for evaluation of nucleolar function, especially in neoplasia. It suffers from limited reliability, background staining, precipitates, and fading of the sections. Factors were identified that affect these problems. The oxidation-reduction level and gelatin used are particularly important. An improved procedure is presented which incorporates pre-reduction of the sections, selection of an optimal gelatin, and post-treatment of the sections to produce a permanent preparation. It is compatible with many fixatives and with other stains used before or after the silver stain.     

Late complication of laparoscopic salpingoophorectomy: retained foreign body presenting as an acute abdomen

The technique of immunocytochemistry was used to identify myoglobin in kidney, confirming a diagnosis of neuroleptic malignant syndrome following an otherwise obscure autopsy in a decomposed body. The features of neuroleptic malignant syndrome are reviewed with a differential diagnosis of myoglobin renal casts. The report emphasizes a thorough and detailed assessment of deaths which occur during treatment with neuroleptic drugs.     

An in vitro model of traumatic neuronal injury: loading rate-dependent changes in acute cytosolic calcium and lactate dehydrogenase release

We developed a new in vitro model of neuronal injury using NT2-N cells to examine the effects of hydrodynamic loading rate on intraneuronal calcium dynamics and lactate dehydrogenase (LDH) release. Our apparatus consisted of a parallel disk viscometer which induced fluid shear stress with well-defined magnitudes and loading rates to cultured cells. We found that the deformation response of the cells was dependent on the severity of the insult, with increased cellular strains generated for higher shear stresses at a constant loading rate. Peak intracellular free calcium concentration correlated with strain, suggesting that mechanical deformation may regulate calcium response. Slowly applied fluid shear stress elicited no response, whereas high loading rates resulted in peak calcium increases 2.9 to 3.6 times baseline values as injury severity was increased. LDH release measured within 5 min after the insult correlated with loading rate. In addition, LDH release continued to increase out to 24 h following high loading rate conditions, demonstrating that the application of fluid shear stress led to prolonged cell damage. The acute response in NT2-N cells subjected to an insult with the CSID is dependent on the loading rate, and these results suggest that initial membrane deformation may trigger subsequent events.