Fucose is a deoxyhexose that is present in a wide variety of organisms. In mammals, fucose-containing glycans have important roles in blood transfusion reactions, selectin-mediated leukocyte-endothelial adhesion, host-microbe interactions, and numerous ontogenic events, including signaling events by the Notch receptor family. Alterations in the expression of fucosylated oligosaccharides have also been observed in several pathological processes, including cancer and atherosclerosis. Fucose deficiency is accompanied by a complex set of phenotypes both in humans with leukocyte adhesion deficiency type II (LAD II; also known as congenital disorder of glycosylation type IIc) and in a recently generated strain of mice with a conditional defect in fucosylated glycan expression. Fucosylated glycans are constructed by fucosyltransferases, which require the substrate GDP-fucose. Two pathways for the synthesis of GDP-fucose operate in mammalian cells, the GDP-mannose-dependent de novo pathway and the free fucose-dependent salvage pathway. In this review, we focus on the biological functions of mammalian fucosylated glycans and the biosynthetic processes leading to formation of the fucosylated glycan precursor GDP-fucose.

Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is so routine, and adverse effects are so infrequent, that providers may understandably overlook many of their pharmacotherapeutic principles. The purpose of this continuing education article is to provide a review and update of essential pharmacology for the various local anesthetic formulations in current use. Technical considerations will be addressed in a subsequent article.

New antibiotics are urgently needed to control infectious diseases. Metabolic enzymes could represent attractive targets for such antibiotics, but in vivo target validation is largely lacking. Here we have obtained in vivo information about over 700 Salmonella enterica enzymes from network analysis of mutant phenotypes, genome comparisons and Salmonella proteomes from infected mice. Over 400 of these enzymes are non-essential for Salmonella virulence, reflecting extensive metabolic redundancies and access to surprisingly diverse host nutrients. The essential enzymes identified were almost exclusively associated with a small subgroup of pathways, enabling us to perform a nearly exhaustive screen. Sixty-four enzymes identified as essential in Salmonella are conserved in other important human pathogens, but almost all belong to metabolic pathways that are inhibited by current antibiotics or that have previously been considered for antimicrobial development. Our comprehensive in vivo analysis thus suggests a shortage of new metabolic targets for broad-spectrum antibiotics, and draws attention to some previously known but unexploited targets.

It is impossible to provide effective dental care without the use of local anesthetics. This drug class has an impressive history of safety and efficacy, but all local anesthetics have the potential to produce significant toxicity if used carelessly. The purpose of this review is to update the practitioner on issues regarding the basic pharmacology and clinical use of local anesthetic formulations. Key Words: Local anesthetic pharmacology GENERAL PROPERTIES OF LOCAL ANESTHETICSLocal anesthetics interrupt neural conduction by inhibiting the influx of sodium ions. In most cases, this follows their diffusion through the neural membrane into the axoplasm, where they enter sodium channels and pre- The aromatic ring improves the lipid solubility of the compound, which can be enhanced further by aliphatic substitutions at locations designated (R). Greater lipid solubility enhances diffusion through nerve sheaths, as well as the neural membranes of individual axons comprising a nerve trunk. This property correlates with potency because a greater portion of an administered dose can enter neurons. Because bupivacaine is more lipid soluble than lidocaine, it is more potent and is prepared as a 0.5% concentration (5 mg/mL) rather than a 2% concentration (20 mg/mL).The terminal amine may exist in a tertiary form (3 bonds) that is lipid soluble or as a quaternary form (4 bonds) that is positively charged and renders the molecule water soluble. As explained above, the aromatic ring determines the actual degree of lipid solubility, but the terminal amine acts as an ''on-off switch'' allowing the local anesthetic to exist in either lipid-soluble or water-soluble conformations. The tertiary and quaternary forms each play a pivotal role in the sequence of events leading to conduction block.For the local anesthetic base to be stable in solution, it is formulated as a hydrochloride salt. As such, the molecules exist in a quaternary, water-soluble state at the time of injection. However, this form will not penetrate the neuron. The time for onset of local anesthesia is therefore predicated on the proportion of molecules that convert to the tertiary, lipid-soluble structure when exposed to physiologic pH (7.4). The ionization constant (pKa) for the anesthetic predicts the proportion of molecules that exists in each of these states. By definition, the pKa of a molecule represents the pH at which 50% of the molecules exist in the lipid-soluble tertiary form and 50% in the quaternary, water-soluble form. The pKa of all local anesthetics is Ͼ7.4 (physiologic pH), and therefore a greater proportion the molecules exists in the quaternary, water-soluble form when injected into tissue having normal pH of 7.4. Furthermore, the acidic environment associated with inflamed tissues favors the quaternary, water-soluble configuration even further. Presumably, this accounts for difficulty when attempting to anesthetize inflamed or infected tissues; fewer molecules exist as tertiary lipid-soluble forms that can penetrate nerves. In these situations, b...