Efficient Iterative Synthesis of O-Acetylated Tri- to Pentadecasaccharides Related to the Lipopolysaccharide of Shigella flexneri Type 3 a through Di- and Trisaccharide Glycosyl Donors.

Protection against bacterial infections, including shigellosis, can be achieved by antibodies against the bacterial surface polysaccharide. In line with our efforts to develop vaccine candidates for shigellosis, we report herein the synthesis of penta-, deca-, and pentadecasaccharides as well as tri-, octa-, and tridecasaccharides as the endchain and intrachain fragments, respectively, of the surface polysaccharide of Shigella flexneri 3 a, a prevalent serotype. The syntheses relied on the efficiency of the trichloroacetimidate glycosylation chemistry, whereby iteration with di- and trisaccharide building blocks provided fragments made of up to three mono-O-acetylated polysaccharide repeating units. Pd(OH)2 -mediated hydrogenation/hydrogenolysis enabled the concomitant removal or conversion of up to 31 protecting groups of 4 different origins to provide the targets as propyl glycosides. Oligosaccharides comprising the octasaccharide segment were shown to display high conformational similarities in solution.

Examination of mercaptobenzyl sulfonates as catalysts for native chemical ligation: application to the assembly of a glycosylated Glucagon-Like Peptide 1 (GLP-1) analogue.

3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). Whilst catalysing NCL processes at a similar rate to 4-mercaptophenyl acetic acid (MPAA), the increased polarity and solubility of 3-mercaptobenzyl sulfonate in particular may favour its selection as NCL catalyst in many instances.

Modulating LPS signal transduction at the LPS receptor complex with synthetic Lipid A analogues.

Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization.

A decade of laryngeal dysplasia in Paisley, Scotland.

Laryngeal dysplasia is a known premalignant condition. A recent consensus statement by otorhinolaryngologists and pathologists on the diagnosis and management of laryngeal dysplasia Mehanna et al. (Clin Otol 35:170-176, 2010) identified a need for retrospective data on epidemiological aspects of laryngeal dysplasia as well as responses to treatment. A retrospective search was made on the hospital pathology database for cases of laryngeal dysplasia. Searches were made under "Larynx", "Dysplasia", "Carcinoma in situ" and "Vocal Cord". The search dates were between 1998 to the present day. The returned records were checked with the pathology reports and the case notes of these patients requested for analysis. A proforma was completed for each patient with laryngeal dysplasia. These patients were then anonymised, entered into a spreadsheet and analysed. The initial search returned 937 patients. Of these patients, 505 (54%) had benign laryngeal pathology, 131 (14%) had laryngeal dysplasia and 301 (32%) had invasive cancer on biopsy. Patients who developed malignancy within 3 months of being diagnosed with laryngeal dysplasia were excluded. This left 110 patients for analysis. Of the dysplastic patients, 40 (36%) had mild dysplasia, 31 (28%) had moderate dysplasia and 39 (35%) had severe dysplasia/carcinoma in situ; 70% were male. The median age was 63 (min 21, max 90, ave 62.5); 74 (67%) were smokers or ex-smokers. Progression of dysplasia was seen in 7 (6%) patients. Malignant transformation was seen in 18 (16%) patients. The average time for malignant change was 43 months (min 4 months, max 192 months and median 15.5 months; 73 (66%) patients were treated by microlaryngeal resection, 2 (2%) were treated by vocal cord stripping, 28 (25%) were treated by endolaser therapy, and 1 (1%) patient was treated by using the microdebrider skimming blade and 6 (5%) were treated by radiotherapy. Cure of dysplasia or downgrading of severity in these treatment subgroups was 62 (85%), 2 (100%), 24 (86%), 1 (100%) and 4 (66%), respectively. Our study reiterates that laryngeal dysplasia carries a significant risk of developing malignancy. Management of this condition varies widely. Endolaser resection is becoming more frequently employed in the UK. Our study is biased heavily towards cold steel dissection. Although there is increasing practice in the UK to promote early discharge, we feel it may be safer to keep patients under surveillance for longer periods. Despite this, all patients who returned after discharge or failing to attend with invasive cancer did so with new symptoms.