The History of Academic Leadership Education in Orthopaedic Surgery.

Background: The growth of the American academic orthopaedic community over the last 53 years has been accompanied by an expanding need for academic leadership education. Methods: The transition of the Association of Orthopaedic Chairmen, to the Academic Orthopaedic Society, to the American Orthopaedic Association through its Academic Leadership Committee and American Orthopaedic Association Council of Residency Directors is reviewed. Results: Academic orthopaedic community members recognized that the evolving leadership needs of the academic community could be better addressed by transitioning to a new organization, the Academic Orthopaedic Society and eventually by creating a new structure within a well aligned and well-resourced existing organization, the American Orthopaedic Association. Conclusion: Organizational and leadership flexibility has been vital to serving the evolving need of the American academic orthopaedic community for leadership education.

A rare case of cavitary lung lesions in an adolescent: Granulomatosis with polyangiitis.

Granulomatosis with Polyangiitis (GPA) is a life threatening disease if left untreated which predominantly affects the adult population. As clinical presentation is often non-specific there is a heavy reliance on radiologic, laboratory and biopsy findings in diagnosis. We present a case of a 17-year-old male who presented with a history of tea colored urine and recurrent epistaxis who now complained of cough and congestion. The patient failed multiple courses of outpatient antibiotics and a CT of the chest while in the ED demonstrated multiple cavitary lesions. Subsequent workup and biopsy confirmed the diagnosis of GPA. It is important for the Radiologist and other clinicians to keep GPA in their differential when presented with a cavitary lung lesion as prompt treatment is required for good outcomes.

Effectiveness of Clinical Decision Tools in Predicting Pulmonary Embolism.

OBJECTIVE: The Wells criteria and revised Geneva score are two commonly used clinical decision tools (CDTs) developed to assist physicians in determining when computed tomographic angiograms (CTAs) should be performed to evaluate the high index of suspicion for pulmonary embolism (PE). Studies have shown varied accuracy in these CDTs in identifying PE, and we sought to determine their accuracy within our patient population. METHODS: Patients admitted to the Emergency Department (ED) who received a CTA for suspected PE from 2019 Jun 1 to 2019 Aug 31 were identified. Two CDTSs, the Wells criteria and revised Geneva score, were calculated based on data available prior to CTA and using the common D-Dimer cutoff of >500 µg/L. We determined the association between confirmed PE and CDT values and determined the association between the D-Dimer result and PE. RESULTS: 392 CTAs were identified with 48 (12.1%) positive PE cases. The Wells criteria and revised Geneva score were significantly associated with PE but failed to identify 12.5% and 70.4% of positive PE cases, respectively. Within our cohort, a D-Dimer cutoff of >300 µg/L was significantly associated with PE and captured 95.2% of PE cases. CONCLUSIONS: Both CDTs were significantly associated with PE but failed to identify PE in a significant number of cases, particularly the revised Geneva score. Alternative D-Dimer cutoffs may provide better accuracy in identifying PE cases.

Kikuchi Disease with enlargement of intramammary lymph node.

We describe a rare case of intramammary lymphadenopathy due to Kikuchi-Fujimoto disease. A 15-year old female presented to the Breast Clinic with complaints of a tender, palpable right breast lump. An ultrasound of the area of concern demonstrated an enlarged 2.9 cm intramammary lymph node with preservation of the fatty hilum. An ultrasound guided core biopsy of the lymph node confirmed the diagnosis of Kikuchi-Fujimoto disease.

Incidental vesicourachal diverticulum in a young female.

A vesicourachal remnant is the rarest presentation of the congenital urachal remnant anomalies, occurring approximately in 3% of those who have them. We discuss a case where a vesicourachal anomaly is discovered incidentally in a pediatric patient by ultrasound and subsequently confirmed by MRI. The urachus connects the dome of the bladder to the umbilical cord in fetal life. After birth, this structure is obliterated and becomes the median umbilical ligament. When complete obliteration does not occur, a urachal remnant is created.

Rare Presentation of Burned-Out Testicular Seminoma.

A 28 year old male who complained of abdominal pain over the past several months was found on CT to have lymphadenopathy along the right aspect of the inferior vena cava. The patient was subsequently seen by an oncologist where further work up of the lymphadenopathy was performed. A MR of the abdomen demonstrated right aortocaval and para-caval lymph nodes measuring to 3.7cm. A testicular ultrasound was then performed, which demonstrated an apparent peripheral focal hypoechoic region with no associated internal vascularity within the right testes. Biopsy of the retroperitoneal lymph nodes pathologically confirmed the diagnosis of seminoma. Keywords: Seminoma, Testicular Cancer, Retroperitoneal Adenopathy, Oncology, Burned-Out Tumor.

A genome-wide screen identifies conserved protein hubs required for cadherin-mediated cell-cell adhesion.

Cadherins and associated catenins provide an important structural interface between neighboring cells, the actin cytoskeleton, and intracellular signaling pathways in a variety of cell types throughout the Metazoa. However, the full inventory of the proteins and pathways required for cadherin-mediated adhesion has not been established. To this end, we completed a genome-wide (~14,000 genes) ribonucleic acid interference (RNAi) screen that targeted Ca(2+)-dependent adhesion in DE-cadherin-expressing Drosophila melanogaster S2 cells in suspension culture. This novel screen eliminated Ca(2+)-independent cell-cell adhesion, integrin-based adhesion, cell spreading, and cell migration. We identified 17 interconnected regulatory hubs, based on protein functions and protein-protein interactions that regulate the levels of the core cadherin-catenin complex and coordinate cadherin-mediated cell-cell adhesion. Representative proteins from these hubs were analyzed further in Drosophila oogenesis, using targeted germline RNAi, and adhesion was analyzed in Madin-Darby canine kidney mammalian epithelial cell-cell adhesion. These experiments reveal roles for a diversity of cellular pathways that are required for cadherin function in Metazoa, including cytoskeleton organization, cell-substrate interactions, and nuclear and cytoplasmic signaling.

The Drosophila Cadherin Fat regulates tissue size and planar cell polarity through different domains.

The Drosophila Cadherin Fat (Ft) has been identified as a crucial regulator of tissue size and Planar Cell Polarity (PCP). However, the precise mechanism by which Ft regulates these processes remains unclear. In order to advance our understanding of the action of Ft, we have sought to identify the crucial Ft effector domains. Here we report that a small region of the Ft cytoplasmic domain (H2 region) is both necessary and sufficient, when membrane localized, to support viability and prevent tissue overgrowth. Interestingly, the H2 region is dispensable for regulating PCP signaling, whereas the mutant Ft lacking the H2 region is fully capable of directing PCP. This result suggests that Ft's roles in PCP signaling and tissue size control are separable, and each can be carried out independently. Surprisingly, the crucial regions of Ft identified in our structure-function study do not overlap with the previously reported interaction regions with Atrophin, Dco, or Lowfat.

Visceral-locomotory pistoning in crawling caterpillars.

Animals with an open coelom do not fully constrain internal tissues, and changes in tissue or organ position during body movements cannot be readily discerned from outside of the body. This complicates modeling of soft-bodied locomotion, because it obscures potentially important changes in the center of mass as a result of internal tissue movements. We used phase-contrast synchrotron X-ray imaging and transmission light microscopy to directly visualize internal soft-tissue movements in freely crawling caterpillars. Here we report a novel visceral-locomotory piston in crawling Manduca sexta larvae, in which the gut slides forward in advance of surrounding tissues. The initiation of gut sliding is synchronous with the start of the terminal prolegs' swing phase, suggesting that the animal's center of mass advances forward during the midabdominal prolegs' stance phase and is therefore decoupled from visible translations of the body. Based on synchrotron X-ray data and transmission light microscopy results, we present evidence for a two-body mechanical system with a nonlinear elastic gut that changes size and translates between the anterior and posterior of the animal. The proposed two-body system--the container and the contained--is unlike any form of legged locomotion previously reported and represents a new feature in our emerging understanding of crawling.

Motor patterns associated with crawling in a soft-bodied arthropod.

Soft-bodied animals lack distinct joints and levers, and so their locomotion is expected to be controlled differently from that of animals with stiff skeletons. Some invertebrates, such as the annelids, use functionally antagonistic muscles (circumferential and longitudinal) acting on constant-volume hydrostatics to produce extension and contraction. These processes form the basis for most theoretical considerations of hydrostatic locomotion in organisms including larval insects. However, caterpillars do not move in this way, and their powerful appendages provide grip independent of their dimensional changes. Here, we show that the anterograde wave of movement seen in the crawling tobacco hornworm, Manduca sexta, is mediated by co-activation of dorsal and ventral muscles within a body segment, rather than by antiphasic activation, as previously believed. Furthermore, two or three abdominal segments are in swing phase simultaneously, and the activities of motor neurons controlling major longitudinal muscles overlap in more than four segments. Recordings of muscle activity during natural crawling show that some are activated during both their shortening and elongation. These results do not support the typical peristaltic model of crawling, but they do support a tension-based model of crawling, in which the substrate is utilized as an anchor to generate propulsion.

Modulation of fat:dachsous binding by the cadherin domain kinase four-jointed.

In addition to quantitative differences in morphogen signaling specifying cell fates, the vector and slope of morphogen gradients influence planar cell polarity (PCP) and growth. The cadherin Fat plays a central role in this process. Fat regulates PCP and growth through distinct downstream pathways, each involving the establishment of molecular polarity within cells. Fat is regulated by the cadherin Dachsous (Ds) and the protein kinase Four-jointed (Fj), which are expressed in gradients in many tissues. Previous studies have implied that Fat is regulated by the vector and slope of these expression gradients. Here, we characterize how cells interpret the Fj gradient. We demonstrate that Fj both promotes the ability of Fat to bind to its ligand Ds and inhibits the ability of Ds to bind Fat. Consequently, the juxtaposition of cells with differing Fj expression results in asymmetric Fat:Ds binding. We also show that the influence of Fj on Fat is a direct consequence of Fat phosphorylation and identify a phosphorylation site important for the stimulation of Fat:Ds binding by Fj. Our results define a molecular mechanism by which a morphogen gradient can drive the polarization of Fat activity to influence PCP and growth.

Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy.

PURPOSE: Various neoadjuvant approaches have been evaluated for the treatment of locally advanced soft-tissue sarcomas. This retrospective study describes a uniquely modified version of the Eilber regimen developed at the University of Chicago. METHODS AND MATERIALS: We treated 34 patients (28 Stage III and 6 Stage IV) with locally advanced soft-tissue sarcomas of an extremity between 1995 and 2008. All patients received preoperative therapy including ifosfamide (2.5 g/m2 per day for 5 days) with concurrent radiation (28 Gy in 3.5-Gy daily fractions), sandwiched between various chemotherapy regimens. Postoperatively, 47% received further adjuvant chemotherapy. RESULTS: Most tumors (94%) were Grade 3, and all were T2b, with a median size of 10.3 cm. Wide excision was performed in 29 patients (85%), and 5 required amputation. Of the resected tumor specimens, 50% exhibited high (> or =90%) treatment-induced necrosis and 11.8% had a complete pathologic response. Surgical margins were negative in all patients. The 5-year survival rate was 42.3% for all patients and 45.2% for Stage III patients. For limb-preservation patients, the 5-year local control rate was 89.0% and reoperation was required for wound complications in 17.2%. The 5-year freedom-from-distant metastasis rate was 53.4% (Stage IV patients excluded), and freedom from distant metastasis was superior if treatment-induced tumor necrosis was 90% or greater (84.6% vs. 19.9%, p = 0.02). CONCLUSIONS: This well-tolerated concurrent chemoradiotherapy approach yields excellent rates of limb preservation and local control. The resulting treatment-induced necrosis rates are predictive of subsequent metastatic risk, and this information may provide an opportunity to guide postoperative systemic therapies.

Wing defects in Drosophila xenicid mutant clones are caused by C-terminal deletion of additional sex combs (Asx).

BACKGROUND: The coordinated action of genes that control patterning, cell fate determination, cell size, and cell adhesion is required for proper wing formation in Drosophila. Defects in any of these basic processes can lead to wing aberrations, including blisters. The xenicid mutation was originally identified in a screen designed to uncover regulators of adhesion between wing surfaces [1]. PRINCIPAL FINDINGS: Here, we demonstrate that expression of the betaPS integrin or the patterning protein Engrailed are not affected in developing wing imaginal discs in xenicid mutants. Instead, expression of the homeotic protein Ultrabithorax (Ubx) is strongly increased in xenicid mutant cells. CONCLUSION: Our results suggest that upregulation of Ubx transforms cells from a wing blade fate to a haltere fate, and that the presence of haltere cells within the wing blade is the primary defect leading to the adult wing phenotypes observed.

Movement encoding by a stretch receptor in the soft-bodied caterpillar, Manduca sexta.

In a wide variety of animals, stretch receptors provide proprioceptive feedback for motion control. However, for animals that lack a stiff skeleton, it is unclear what information is being detected and how this is incorporated into behavior. Because such animals can change their body shape from moment-to-moment, information about body configuration could be particularly important for coordination. This study uses larval stage Lepidoptera (Manduca sexta) to examine how the longitudinal stretch receptor organ (SRO) responds to behaviorally appropriate movements. We characterized the responses of the SRO to changes in strain using magnitudes and velocities matching those seen physiologically. We found that the SRO response characteristics are compatible with the regulation of stance and with the defensive response to noxious stimuli. However, we also found that movements during crawling produce SRO responses that are dominated by the interdependence of phasic, tonic and slowly adaptive components. Ablation of stretch receptors in the proleg-bearing, fourth abdominal segment did not have any observable effect on behaviors, which suggests that the SROs are not essential for coordinating overt movements. We discuss the implications of these findings in the context of specific behaviors, and explore how the SRO response might be utilized during animal behavior.

Integrins control the positioning and proliferation of follicle stem cells in the Drosophila ovary.

Adult stem cells are maintained in specialized microenvironments called niches, which promote self-renewal and prevent differentiation. In this study, we show that follicle stem cells (FSCs) in the Drosophila melanogaster ovary rely on cues that are distinct from those of other ovarian stem cells to establish and maintain their unique niche. We demonstrate that integrins anchor FSCs to the basal lamina, enabling FSCs to maintain their characteristic morphology and position. Integrin-mediated FSC anchoring is also essential for proper development of differentiating prefollicle cells that arise from asymmetrical FSC divisions. Our results support a model in which FSCs contribute to the formation and maintenance of their own niche by producing the integrin ligand, laminin A (LanA). Together, LanA and integrins control FSC proliferation rates, a role that is separable from their function in FSC anchoring. Importantly, LanA-integrin function is not required to maintain other ovarian stem cell populations, demonstrating that distinct pathways regulate niche-stem cell communication within the same organ.

Argon beam coagulation as an adjuvant for local control of giant cell tumor.

The argon beam coagulator is gaining popularity as an adjuvant therapy for treatment of giant cell tumors of bone. However, the effectiveness and functional implications of this treatment have not been assessed. To determine whether the argon beam coagulator could be a viable adjuvant treatment option, we examined the recurrence rate and functional outcome of patients with giant cell tumors who were treated with the argon beam coagulator, as an adjuvant to curettage and cementation. Thirty-seven patients who received argon beam coagulation as an adjuvant treatment for giant cell tumors diagnosed between 1993 and 2000 were identified. The median age of the patients was 32 years (range, 16-64 years). The mean followup was 73.7 months (range, 0.5-108 months). Three patients had osseous recurrences (8.3%) and one had a soft tissue recurrence. The 5-year Kaplan-Meier disease-free survival estimate was 87.2% (95% confidence interval, range, 76.3-99.8). No patient had radiographic evidence of arthritis. The average Musculoskeletal Tumor Society score was 28. Short form-36 evaluation showed no change in functional or mental perception in these patients compared with US norms. These data suggest argon beam coagulation as an adjuvant therapy is associated with in a low rate of local recurrence and is a reasonable adjuvant treatment option.

Staging of primary malignancies of bone.

Staging of bone sarcomas is the process whereby patients are evaluated with regard to histology, as well as the local and distant extent, of disease. Bone sarcomas are staged based on grade, size, and the presence and location of metastases. The system is designed to help stratify patients according to known risk factors. Proper staging helps define the prognosis for patients and helps guide their treatment. Furthermore, staging allows meaningful comparisons to be done among groups of patients.

Csk differentially regulates Src64 during distinct morphological events in Drosophila germ cells.

The Src family protein tyrosine kinases (SFKs) are crucial regulators of cellular morphology. In Drosophila, Src64 controls complex morphological events that occur during oogenesis. Recent studies have identified key Src64-dependent mechanisms that regulate actin cytoskeletal dynamics during the growth of actin-rich ring canals, which act as intercellular bridges between germ cells. By contrast, the molecular mechanisms that regulate Src64 activity levels and potential roles for Src64 in additional morphological events in the ovary have not been defined. In this report, we demonstrate that regulation of Src64 by Drosophila C-terminal-Src Kinase (Csk) contributes to the packaging of germline cysts by overlying somatic follicle cells during egg chamber formation. These results uncover novel roles for both Csk and Src64 in a dynamic event that involves adhesion, communication between cell types and control of cell motility. Strikingly, Src64 and Csk function in the germline to control packaging, not in migrating follicle cells, suggesting novel functions for this signaling cassette in regulating dynamic adhesion. In contrast to the role played by Csk in the regulation of Src64 activity during packaging, Csk is dispensable for ring canal growth control, indicating that distinct mechanisms control Src64 activity during different morphological events.