Classification and treatment of Class II subdivision malocclusions.

INTRODUCTION: Patients with Class II subdivision malocclusions are a challenge for clinicians because reestablishing symmetry in 1 arch or both arches is often a treatment goal. In patients with mandibular skeletal asymmetry, surgery is often a treatment option. However, patients may be unwilling to undergo surgery, and other options might have to be considered. The aim of this study was to evaluate the etiologies and outcomes of Class II subdivision patients treated at the University of Washington graduate orthodontic clinic in Seattle from 1995 through 2011. METHODS: A search of patients treated between 1995 and 2011 resulted in the identification of 110 consecutively treated Class II subdivision subjects with complete records. Ninety-eight subjects could be classified into 1 of 3 groups, based on midline position and dental or skeletal etiology. Initial and final models were used to measure the peer assessment rating scores, midlines, overjet, overbite, and molar positions. Initial and final cephalograms were traced and measured. Charts were reviewed for information regarding treatment. RESULTS: Twenty-five percent of the 98 subjects had their maxillary and mandibular midlines coincident with the facial midline; their asymmetries were due to a maxillary posterior dental asymmetry. Another 15% had maxillary midlines deviated from their facial midlines, caused by maxillary anterior and posterior dental asymmetry. About 50% of the subjects had mandibular midlines that were not coincident with their facial midlines, and most of them exhibited some degree of mandibular skeletal asymmetry. Over the past 15 years, treatment strategies used at the University of Washington indicated trends toward less surgery, fewer extractions, less use of headgear, and more reliance on fixed functional appliances. Ideal correction of midlines was not always achieved, especially in patients with mandibular skeletal asymmetry, with undercorrection occurring more commonly than overcorrection. Final peer assessment rating scores were comparable, regardless of the origin of the asymmetry or the extractions status. Mandibular incisor proclination was increased when fixed functional appliances were used, as well as when a Class I molar relationship was the target for the Class II side. CONCLUSIONS: Class II subdivision malocclusions were grouped into 3 main categories; the largest category was mandibular asymmetry. Interesting trends were noted with regard to treatment strategies, midline and molar corrections, and mandibular incisor proclination.

Tethered thiazolidinone dimers as inhibitors of the bacterial type III secretion system.

Disruption of protein-protein interactions by small molecules is achievable but presents significant hurdles for effective compound design. In earlier work we identified a series of thiazolidinone inhibitors of the bacterial type III secretion system (T3SS) and demonstrated that this scaffold had the potential to be expanded into molecules with broad-spectrum anti-Gram negative activity. We now report on one series of thiazolidinone analogs in which the heterocycle is presented as a dimer at the termini of a series of linkers. Many of these dimers inhibited the T3SS-dependent secretion of a virulence protein at concentrations lower than that of the original monomeric compound identified in our screen.

Design and synthesis of bis-carbamate analogs of cyclic bis-(3'-5')-diguanylic acid (c-di-GMP) and the acyclic dimer PGPG.

The bacterial second messenger cyclic bis-(3'-5')-diguanylic acid (c-di-GMP) regulates diverse Gram-negative bacterial virulence functions. The pathways that control, or are controlled by, c-di-GMP suggest that c-di-GMP signaling systems may encompass potential drug targets. It is presently undetermined, however, whether up- or down-modulation of c-di-GMP signaling would be the desired therapeutic state. We addressed potential drug target validation by synthesizing nonhydrolysable carbamate analogs of both the cyclic dinucleotide and the acyclic (seco) dinucleotide. A molecular docking simulation of the carbamate isostere suggests that this analog is capable of assuming the correct conformation and pose at a c-di-GMP binding site.

Substituted 2-imino-5-arylidenethiazolidin-4-one inhibitors of bacterial type III secretion.

Diverse species of pathogenic Gram-negative bacteria use secretion systems to export a variety of protein toxins and virulence factors that help establish and maintain infection. Disruption of such secretion systems is a potentially effective therapeutic strategy. We developed a high-throughput screen and identified a tris-aryl substituted 2-imino-5-arylidenethiazolidin-4-one, compound 1, as an inhibitor of the type III secretion system. Expansion of this chemotype enabled us to define the essential pharmacophore for type III secretion inhibition by this structural class. A synthetic diversity set helped us identify N-3 as the most permissive locus and led to the design of a panel of novel N-3-dipeptide-modified congeners with improved activity and physiochemical properties. We now report on the synthesis of these compounds, including a novel solid phase approach to the rapid generation of the dipeptide-thiazolidinone hybrids, and their in vitro characterization as inhibitors of type III secretion in Salmonella enterica serovar Typhimurium.

An inhibitor of gram-negative bacterial virulence protein secretion.

Bacterial virulence mechanisms are attractive targets for antibiotic development because they are required for the pathogenesis of numerous global infectious disease agents. The bacterial secretion systems used to assemble the surface structures that promote adherence and deliver protein virulence effectors to host cells could comprise one such therapeutic target. In this study, we developed and performed a high-throughput screen of small molecule libraries and identified one compound, a 2-imino-5-arylidene thiazolidinone that blocked secretion and virulence functions of a wide array of animal and plant Gram-negative bacterial pathogens. This compound inhibited type III secretion-dependent functions, with the exception of flagellar motility, and type II secretion-dependent functions, suggesting that its target could be an outer membrane component conserved between these two secretion systems. This work provides a proof of concept that compounds with a broad spectrum of activity against Gram-negative bacterial secretion systems could be developed to prevent and treat bacterial diseases.

Rearrangement of a Tricyclic 2,5-Cyclohexadienone: Towards a General Synthetic Route to the Daphnanes and (+)-Resiniferatoxin.

Light as a reagent: A highly functionalized structure that serves as a daphnane template can be formed by the photorearrangement of a 2,5-cyclohexadienone subunit within a complex tricyclic ring system. The chemistry we describe should not only find use in the total synthesis of resiniferatoxin and related daphnanes, but should also provide useful templates for access to complex analogues.