Nonoperative Treatment of Posterior Wall Acetabular Fractures After Dynamic Stress Examination Under Anesthesia: Revisited.

OBJECTIVES: Performing an examination under general anesthesia (EUA) using dynamic stress fluoroscopy of patients with posterior wall acetabular fractures has been used as a tool to determine hip stability and the need for surgical intervention. The purpose of this study was to further evaluate the effectiveness of this technique, from a source other than its primary advocates, in patients with posterior wall acetabular fractures less than or equal to 50% who were stable on EUA and treated nonoperatively. DESIGN: Retrospective case series. SETTING: University Level 1 Trauma Center. PARTICIPANTS: Seventeen patients with a posterior wall acetabular fracture stable on EUA treated nonoperatively. INTERVENTION: The patients were treated nonoperatively as guided by an EUA negative for instability. Patient follow-up averaged 30 months (range, 6-64 months). MAIN OUTCOME MEASUREMENTS: Outcome evaluation included the modified Merle d'Aubigné clinical score and the Short Musculoskeletal Function Assessment Questionnaire. Radiographic evaluation for subluxation or arthritis consisted of the 3 standard pelvic radiographs. RESULTS: Radiographic evaluation showed all hips to be congruent with a normal joint space. Sixteen of the 17 patients had radiographic outcomes rated as "excellent"; 1 patient was rated "good." The modified Merle d'Aubigné score (obtained in 12 patients) averaged very good, with only 1 having less than a good (graded as fair) clinical outcome. The Short Musculoskeletal Function Assessment Questionnaire scores (from 11 patients) were not significantly different from normal and were within the normal reported values for all indices and categories. There was no correlation between fracture fragment size and outcome. CONCLUSIONS: This study further supports the contention that a stable hip joint, as determined by EUA, after posterior wall acetabular fracture treated nonoperatively is predictive of continued joint congruity, an excellent radiographic outcome, and good-to-excellent early clinical and functional outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Apoptosis is differentially regulated by burn severity and dermal location.

BACKGROUND: The cellular processes that contribute to cell death in burns are poorly understood. This study evaluated the distribution and extent of apoptosis in an established rat model of acute dermal burn injury. MATERIALS AND METHODS: A branding iron (100 degrees C) was applied to the depilated dorsum of seven rats, creating burn contact times of 1-8, 10, 12, and 14 s. Biopsies were collected and immunohistochemistry performed for apoptosis and cell injury/necrosis by detection of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and high-mobility group box 1 (HMGB1), respectively. The slides were scored by evaluating staining in superficial, middle, and deep dermal fields. Within these, basal keratinocytes of the epidermis, mesenchymal cells, adnexal epithelia, and vasculature wall cells were morphometrically analyzed for stain detection of selected markers. RESULTS: TUNEL staining had an inverse relationship with contact time in most fields except in deep dermal mesenchymal cells where it was increased. HMGB1 nuclear staining was significantly decreased with progressive contact time consistent with transition to cell injury/necrosis. CONCLUSIONS: This study is the first to demonstrate that apoptosis rate is dependent on dermal location, cell type, and severity of thermal injury. Furthermore, this work suggests that for most dermal locations increased thermal injury corresponds with decreased apoptosis and increased cell injury/necrosis. Together, these findings indicate that many parameters can regulate apoptosis in burn wounds, and these results will be critical to understanding burn pathogenesis and assessing future therapies.

Pharmacologic modification to resuscitation fluid after thermal injury--is drotrecogin alfa the answer to arrest burn depth progression?

HYPOTHESIS: The addition of drotrecogin alfa (DA), an anti-inflammatory useful in septic shock, to standard burn shock resuscitation fluids will protect burned, injured skin from further injury. METHODS: Anesthetized animals were subjected to a standardized burn pattern by applying a branding iron to 10 different locations on the back of the rat for 1 seconds to 14 seconds, creating a range of burn depths and severities. DESIGN: Animal burn shock and resuscitation model. PARTICIPANTS: Thirty-one male adult Sprague-Dawley rats. INTERVENTIONS: Control animals were resuscitated with lactated Ringer's solution (LRS) at 2 mL/kg/percent total body surface area/24 h; experimental animals received LRS plus DA 24 microg/kg/h (LRS + DA). OUTCOME MEASURES: Perfusion to each burned area was assessed using a laser Doppler imaging technology. Punch biopsies at each burned area were stained with hematoxylin and eosin and assessed for burn depth and for inflammation using previously reported measures. Samples from 14 animals were stained for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and caspase-3 (apoptosis markers). RESULTS: Increasing branding iron contact times worsened perfusion, burn depth, and apoptotic ratios. There was no correlation between inflammatory markers and burn contact time. The addition of DA leads to worse perfusion, deeper burns, worse inflammation, and decreased apoptotic ratios. CONCLUSIONS: Laser Doppler imaging is a useful technology to assess burn depth. The addition of DA to traditional resuscitation fluids for burn shock is deleterious to the injured, burned skin. Modifying the traditional burn shock resuscitation fluids, although intellectually attractive, needs to be rigorously studied.

Characterisation of site-biased DNA methyltransferases: specificity, affinity and subsite relationships.

DNA methylation is now seen as a primary signal in the cell for mediating transcriptional repression through chromatin formation. The construction and evaluation of enzymes capable of influencing this process in vivo is therefore of significant interest. We have fused the C5-cytosine DNA methyltransferases, M.HhaI and M.HpaII, which both methylate 4 bp sequences containing a CpG dinucleotide, to a three zinc finger protein recognising a 9 bp DNA sequence. DNA methylation analyses demonstrate specific DNA methylation by both enzymes at target sites comprising adjacent methyltransferase and zinc finger subsites, targeted M.HpaII being the most specific. Binding analysis of the targeted M.HpaII enzyme reveals an 8-fold preference for binding to its target site, compared to binding to a zinc finger site alone, and an 18-fold preference over binding to a methyltransferase site alone, thereby demonstrating enhanced binding by the fusion protein, compared to its component proteins. Both DNA binding and methylation are specific for the target site up to separations of approximately 40 bp between the zinc finger and methyltransferase subsites. Ex vivo plasmid methylation experiments are also described that demonstrate targeted methylation. These targeted enzymes, however, are shown to be not fully mono-functional, retaining a significant non-targeted activity most evident at elevated protein concentrations.

Hand Blisters in Major League Baseball Pitchers: Current Concepts and Management.

Friction blisters are a common sequela of many athletic activities. Their significance can range from minor annoyance to major performance disruptions. The latter is particularly true in baseball pitchers, who sustain repeated trauma between the baseball seams and the fingers of the pitching hand, predominately at the tips of the index and long fingers. Since 2010, 6 Major League Baseball (MLB) players accounted for 7 stints on the disabled list (DL) due to blisters. These injuries resulted in a total of 151 days spent on the DL. Since 2012, 8 minor league players spent time on the DL due to blisters. Moreover, there have been several documented and publicized instances of professional baseball pitchers suffering blisters that did not require placement on the DL but did result in injury time and missed starts. The purpose of this article is to review the etiology and pathophysiology of friction blisters with particular reference to baseball pitchers; provide an overview of past and current prevention methods; and discuss our experience in treating friction blisters in MLB pitchers.

2013 Winning Essay: The Accountable Care Paradigm Shift: New Ethical Considerations.

The current state of our health care system is analogous to the status of science that Kuhn describes as "a proliferation of compelling articulations, the willingness to try anything, the expression of explicit discontent, the recourse to philosophy and to debate over fundamentals" [27]. ACOs represent a paradigm shift in the way health care is delivered. As with any dramatic public policy change, ethical issues will arise. These are surmountable challenges, and with open communication, physicians such as the Midstate group can partner effectively with hospital systems to ensure the delivery of quality, evidence-based care while at the same reorienting the culture to be attentive to its fiduciary responsibilities.

Nonoperative Treatment of Posterior Wall Acetabular Fractures After Dynamic Stress Examination Under Anesthesia: Revisited.

OBJECTIVES: Performing an examination under general anesthesia (EUA) using dynamic stress fluoroscopy of patients with posterior wall acetabular fractures has been used as a tool to determine hip stability and the need for surgical intervention. The purpose of this study was to further evaluate the effectiveness of this technique, from a source other than its primary advocates, in patients with posterior wall acetabular fractures less than or equal to 50% who were stable on EUA and treated nonoperatively. DESIGN: Retrospective case series. SETTING: University Level 1 Trauma Center. PARTICIPANTS: Seventeen patients with a posterior wall acetabular fracture stable on EUA treated nonoperatively. INTERVENTION: The patients were treated nonoperatively as guided by an EUA negative for instability. Patient follow-up averaged 30 months (range, 6-64 months). MAIN OUTCOME MEASUREMENTS: Outcome evaluation included the modified Merle d'Aubigné clinical score and the Short Musculoskeletal Function Assessment Questionnaire. Radiographic evaluation for subluxation or arthritis consisted of the 3 standard pelvic radiographs. RESULTS: Radiographic evaluation showed all hips to be congruent with a normal joint space. Sixteen of the 17 patients had radiographic outcomes rated as "excellent"; 1 patient was rated "good." The modified Merle d'Aubigné score (obtained in 12 patients) averaged very good, with only 1 having less than a good (graded as fair) clinical outcome. The Short Musculoskeletal Function Assessment Questionnaire scores (from 11 patients) were not significantly different from normal and were within the normal reported values for all indices and categories. There was no correlation between fracture fragment size and outcome. CONCLUSIONS: This study further supports the contention that a stable hip joint, as determined by EUA, after posterior wall acetabular fracture treated nonoperatively is predictive of continued joint congruity, an excellent radiographic outcome, and good-to-excellent early clinical and functional outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Analytical Validation of AmpliChip p53 Research Test for Archival Human Ovarian FFPE Sections.

The p53 tumor suppressor gene (TP53) is reported to be mutated in nearly half of all tumors and plays a central role in genome integrity. Detection of mutations in p53 can be accomplished by many assays, including the AmpliChip p53 Research Test. The AmpliChip p53 Research Test has been successfully used to determine p53 status in hematologic malignancies and fresh frozen solid tissues but there are few reports of using the assay with formalin fixed, paraffin-embedded (FFPE) tissue. The objective of this study was to describe analytical performance characterization of the AmpliChip p53 Research Test to detect p53 mutations in genomic DNA isolated from archival FFPE human ovarian tumor tissues. Method correlation with sequencing showed 96% mutation-wise agreement and 99% chip-wise agreement. We furthermore observed 100% agreement (113/113) of the most prevalent TP53 mutations. Workflow reproducibility was 96.8% across 8 samples, with 2 operators, 2 reagent lots and 2 instruments. Section-to-section reproducibility was 100% for each sample across a 60 µm region of the FFPE block from ovarian tumors. These data indicate that the AmpliChip p53 Research Test is an accurate and reproducible method for detecting mutations in TP53 from archival FFPE human ovarian specimens.

Zinc-finger protein-targeted gene regulation: genomewide single-gene specificity.

Zinc-finger protein transcription factors (ZFP TFs) can be designed to control the expression of any desired target gene, and thus provide potential therapeutic tools for the study and treatment of disease. Here we report that a ZFP TF can repress target gene expression with single-gene specificity within the human genome. A ZFP TF repressor that binds an 18-bp recognition sequence within the promoter of the endogenous CHK2 gene gives a >10-fold reduction in CHK2 mRNA and protein. This level of repression was sufficient to generate a functional phenotype, as demonstrated by the loss of DNA damage-induced CHK2-dependent p53 phosphorylation. We determined the specificity of repression by using DNA microarrays and found that the ZFP TF repressed a single gene (CHK2) within the monitored genome in two different cell types. These data demonstrate the utility of ZFP TFs as precise tools for target validation, and highlight their potential as clinical therapeutics.