Faculty Bibliography

Modern advances in total hip arthroplasty have included improved biomaterials, alternative bearings, so-called fourth-generation cement techniques, and enhanced in-growth prostheses. Recently, much attention has been focused on improving the surgical technique for total hip arthroplasty. This endeavor has included the development of mini-incision arthroplasty and has now progressed to minimally invasive procedures. Minimally invasive techniques are modified versions of the classic approaches to the hip, with the goal of decreasing soft tissue dissection and trauma. While these new surgical exposures may result in improved short-term outcomes, their long-term results have yet to be proven. In addition, they are technically demanding, may require specialized training, and can be associated with a difficult learning curve. Only the future will determine if mini-incision and minimally invasive arthroplasty are as successful as the well-proven standard surgical approaches used for the last three to four decades.

The immunodominant epitope of bovine type II collagen (CII256-270) in Aq mice carries a hydroxylysine-264 linked galactose (Gal-Hyl264), the recognition of which is central to the development of collagen-induced arthritis. This study explores the molecular interactions involved in the engagement of T-cell receptors (TCRs) with such epitopes. Responses of three anti-CII T-cell hybridomas and clone A9.2 (all sharing close TCR sequences) to a panel of CII256-270 analogues incorporating Gal-Hyl264 with a modified side chain were determined. Recognition of naturally occurring CII256-270 peptides by either group of T cells depended strictly upon the presence of the carbohydrate and, more precisely, its intact HO-4 group. Modifications of primary amino group on the hydroxylysine side chain eliminated T-cell reactivity, notwithstanding the presence of the galactosyl moiety. Moderate stereochemical changes, such as altered sugar orientation and methylation at the galactose anchor position, were still permissive. Conversely, robust transformations affecting the relative positions of the key elements were detrimental to TCR recognition. To conclude, these data provide strong new experimental evidence that integrity of both galactose HO-4 and hydroxylysine side chain primary amino groups are mandatory for activation of anti-Gal-Hyl264 TCRs. They also indicate that there is a certain degree of TCR plasticity in peptide-TCR interactions.

INTRODUCTION: A gap exists between asthma guidelines and actual care delivered. We developed an educational intervention using simulated physician-patient encounters as part of a project to improve asthma management by community-based primary care providers. We hypothesized that this type of skills-based interactive training would improve learners' care choices for simulated patients after training compared with their choices before training. METHODS: After a pilot project was done on a small group of providers, a larger group of primary care providers (PCPs) was recruited to be trained with our interactive materials. The pilot session, with 39 providers, showed that the cases were felt to be appropriate, that the time allocated for discussion was adequate, that the models were useful, that the experience was educational, and that the experience captured their interest. Two subsequent training sessions were held with 240 PCPs. Participants completed a questionnaire to elicit perceived barriers and self-efficacy and then viewed a short simulated physician-patient dialogue. They then completed a set of scaled questions about treatment choices. This served as a pretest assessment. A similar simulation was then shown, and the group discussed their thoughts on diagnosis and treatment. Finally, they viewed another physician-patient interaction and responded to the same questions as posed for the pretest assessment; the responses before and after assessment were compared. RESULTS: Following completion of the intervention, providers were significantly (p < 0.05) more likely to make use of controller medications, asthma equipment, and patient training. Significant (p < 0.05) increases were also seen in action plan development and the availability of office visits. Providers were significantly (p < 0.05) less likely to refer asthma patients to an emergency department or for hospitalization. Significant (p < 0.05) improvements were also seen in perceptions of self-efficacy and barriers to treatment. There were significant (p < 0.05) increases in learners' confidence about their own and patients' abilities to improve asthma care, and fewer barriers to asthma management were reported after the training. DISCUSSION: This method of training resulted in learners showing a measurable improvement in their intent to follow guidelines as applied to simulated patients. An evaluation addressing actual patient outcomes will need to be done.

When an essential amino acid is limited, a signaling cascade is triggered that leads to increased translation of the 'master regulator', activating transcription factor 4 (ATF4), and resulting in the induction of specific target genes. Binding of ATF4 to the amino acid response element (AARE) is an essential step in the transcriptional activation of CHOP (a CCAAT/enhancer-binding protein-related gene) by amino acid deprivation. We set out to identify proteins that interact with ATF4 and that play a role in the transcriptional activation of CHOP. Using a tandem affinity purification (TAP) tag approach, we identified p300/CBP-associated factor (PCAF) as a novel interaction partner of ATF4 in leucine-starved cells. We show that the N-terminal region of ATF4 is required for a direct interaction with PCAF and demonstrate that PCAF is involved in the full transcriptional response of CHOP by amino acid starvation. Chromatin immunoprecipitation analysis revealed that PCAF is engaged on the CHOP AARE in response to amino acid starvation and that ATF4 is essential for its recruitment. We also show that PCAF stimulates ATF4-driven transcription via its histone acetyltransferase domain. Thus PCAF acts as a coactivator of ATF4 and is involved in the enhancement of CHOP transcription following amino acid starvation.

The most noticeable morphological feature of the cerebellum is its folded appearance, whereby fissures separate its anterior-posterior extent into lobules. Each lobule is molecularly coded along the medial-lateral axis by parasagittal stripes of gene expression in one cell type, the Purkinje cells (PCs). Additionally, within each lobule distinct combinations of afferents terminate and supply the cerebellum with synchronized sensory and motor information. Strikingly, afferent terminal fields are organized into parasagittal domains, and this pattern bears a close relationship to PC molecular coding. Thus, cerebellum three-dimensional complexity obeys a basic coordinate system that can be broken down into morphology and molecular coding. In this review, we summarize the sequential stages of cerebellum development that produce its laminar structure, foliation, and molecular organization. We also introduce genes that regulate morphology and molecular coding, and discuss the establishment of topographical circuits within the context of the two coordinate systems. Finally, we discuss how abnormal cerebellar organization may result in neurological disorders like autism