Ulnar Nerve Translocation Following a Routine Distal Radius Fracture.

A 35-year-old right hand dominant male sustained a high energy closed right distal radius fracture with associated generalized paresthesias. Following closed reduction, the patient was found to have an atypical low ulnar nerve palsy upon outpatient follow-up. After continued symptoms and an equivocal wrist MRI the patient underwent surgical exploration. Intraoperatively, the ulnar nerve as well as the ring and small finger flexor digitorum superficialis tendons were found to be translocated around the ulnar head. The nerve and tendons were reduced, the median nerve was decompressed, and the fracture was addressed with volar plating. Post-operatively, the patient continued to have sensory deficits and stiffness of the ring and small fingers. After one year, he reported substantial improvements as demonstrated by full sensation (4.0 mm two-point discrimination) and fixed flexion contractures at the proximal and distal interphalangeal joints of the small finger. The patient returned to work without functional limitations. This case highlights a unique case of ulnar nerve and flexor tendon entrapment following a distal radius fracture. History, physical examination, and a high index of clinical suspicion is essential for proper management of this rare injury. Level of Evidence: V.

Role of Dynamic Stabilizers of the Elbow in Radiocapitellar Joint Alignment: A Prospective In Vivo Study.

PURPOSE: To investigate the effect of dynamic stabilizers of the elbow on radiocapitellar joint alignment, before and after the administration of regional anesthesia. METHODS: At a single institution, 14 patients were prospectively enrolled in a study using a within-subjects control design. Before performing a supraclavicular regional block, 10 fluoroscopic images (1 anteroposterior and 9 lateral views) of the elbow were obtained for each patient. The lateral images were obtained with the forearm in maximal supination, neutral rotation, and maximal pronation, and these forearm positions were repeated for 3 elbow positions: (1) full extension; (2) flexion to 90°, with 0° of shoulder internal rotation; and (3) flexion to 90°, with 90° of shoulder internal rotation. After obtaining the 10 initial images, a block was performed to achieve less than 3/5 motor strength of the imaged extremity, followed by obtaining the same 10 images in each patient. Radiocapitellar ratio, defined as the minimal distance between the right bisector of the radial head and the center of the capitellum divided by the diameter of the capitellum, was measured in each image. RESULTS: The 14 patients had a mean age of 47.8 ± 15.7 years, and 10 (71.4%) patients were women. A difference between radiocapitellar ratios measured before and after the regional block administration was observed for all lateral images (-1.0% ± 7.2% to -2.2% ± 8.0%), although this difference was less than the minimum clinically important difference. CONCLUSIONS: Paralysis of the dynamic stabilizers of the elbow produces a difference in the radiocapitellar joint alignment, but this did not reach the minimum clinically important difference. CLINICAL RELEVANCE: Paralysis of the dynamic stabilizers of the elbow via a supraclavicular nerve block produces no clinically relevant effect on the radiocapitellar alignment of uninjured elbows.

Zone 2 Flexor Tendon Repair Location and Risk of Catching on the A2 Pulley.

PURPOSE: To determine the region of the flexor digitorum profundus (FDP) and flexor digitorum superficialis (FDS) tendons in zone 2 that, when involved by a laceration repair, will reliably catch on the A2 pulley after surgery. METHODS: Using fresh-frozen cadavers (5 hands, 20 digits), excursions of the FDP and FDS tendons were measured in relation to the A2 pulley. The C1, A3, and C2 pulleys were resected. The digit was maximally flexed by applying traction to the flexor tendon in the forearm. An 8-0 suture tag was placed in the flexor tendons immediately distal to the A2 pulley. The digit was then passively fully extended to measure tendon excursion. Measurements were repeated with 50% venting and 100% release of the A4 pulley. Reference points such as tendon insertions and flexion creases were obtained. This protocol was repeated sequentially for the index, middle, ring, and little fingers. RESULTS: For all 20 fingers, the suture placed into the FDP just distal to the A2 pulley with the finger fully flexed traveled 1.6 ± 1.9 mm distal to the proximal edge of the A4 pulley with passive extension of the finger. The mean excursion for the FDP was 24.6 ± 3.2 mm, and 16.9 ± 3.1 mm for the FDS. The mean A2 pulley length was 16.2 ± 3.5 mm, and the mean distance between the distal edge of the A2 pulley and the proximal edge of the A4 pulley was 23.0 ± 3.3 mm. Venting the A4 pulley 50% and 100% increased FDP excursion a maximum of 0.9 and 1.9 mm, respectively. CONCLUSIONS: An FDP repair proximal to the A4 pulley will slide under the A2 pulley with full active digital flexion after surgery. If the distal FDP stump lies underneath the A4 pulley with the digit fully extended, the FDP repair will not likely engage the A2 pulley with full flexion after surgery. The FDP excursion can be reliably predicted as a percentage of the A2 (distal) to the A4 (distal) pulley distance. Most importantly, the distance between the repair site and the A4 pulley approximately equals the length of the A2 pulley that requires release to avoid postoperative triggering. CLINICAL RELEVANCE: Knowledge of this high-risk region of flexor tendon repair will guide surgeons regarding the potential need for partial release of the A2 pulley.

CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy.

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates ß-adrenergic receptor (ß-AR) signaling and ultimately limits ß-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to ß-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates ß-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.

A mouse model for fetal maternal stem cell transfer during ischemic cardiac injury.

Fetal cells enter the maternal circulation during pregnancies and can persist in blood and tissues for decades, creating a state of physiologic microchimerism. Microchimerism refers to acquisition of cells from another individual and can be due to bidirectional cell traffic between mother and fetus during pregnancy. Peripartum cardiomyopathy, a rare cardiac disorder associated with high mortality rates has the highest recovery rate amongst all etiologies of heart failure although the reason is unknown. Collectively, these observations led us to hypothesize that fetal cells enter the maternal circulation and may be recruited to the sites of myocardial disease or injury. The ability to genetically modify mice makes them an ideal system for studying the phenomenon of microchimerism in cardiac disease. Described here is a mouse model for ischemic cardiac injury during pregnancy designed to study microchimerism. Wild-type virgin female mice mated with eGFP male mice underwent ligation of the left anterior descending artery to induce a myocardial infarction at gestation day 12. We demonstrate the selective homing of eGFP cells to the site of cardiac injury without such homing to noninjured tissues suggesting the presence of precise signals sensed by fetal cells enabling them to target diseased myocardium specifically.

Fetal cells traffic to injured maternal myocardium and undergo cardiac differentiation.

RATIONALE: Fetal cells enter the maternal circulation during pregnancy and may persist in maternal tissue for decades as microchimeras. OBJECTIVE: Based on clinical observations of peripartum cardiomyopathy patients and the high rate of recovery they experience from heart failure, our objective was to determine whether fetal cells can migrate to the maternal heart and differentiate to cardiac cells. METHODS AND RESULTS: We report that fetal cells selectively home to injured maternal hearts and undergo differentiation into diverse cardiac lineages. Using enhanced green fluorescent protein (eGFP)-tagged fetuses, we demonstrate engraftment of multipotent fetal cells in injury zones of maternal hearts. In vivo, eGFP+ fetal cells form endothelial cells, smooth muscle cells, and cardiomyocytes. In vitro, fetal cells isolated from maternal hearts recapitulate these differentiation pathways, additionally forming vascular tubes and beating cardiomyocytes in a fusion-independent manner; ≈40% of fetal cells in the maternal heart express Caudal-related homeobox2 (Cdx2), previously associated with trophoblast stem cells, thought to solely form placenta. CONCLUSIONS: Fetal maternal stem cell transfer appears to be a critical mechanism in the maternal response to cardiac injury. Furthermore, we have identified Cdx2 cells as a novel cell type for potential use in cardiovascular regenerative therapy.

ß2-Adrenergic receptor signaling in the cardiac myocyte is modulated by interactions with CXCR4.

Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation, metastasis, and embryonic development. We previously demonstrated a nonchemotactic role for one such chemokine pair, stromal cell-derived factor-1α and its G-protein coupled receptor, CXCR4. Stromal cell-derived factor-1/CXCR4 are expressed on cardiac myocytes and have direct consequences on cardiac myocyte physiology by inhibiting contractility in response to the nonselective ß-adrenergic receptor (ßAR) agonist, isoproterenol. As a result of the importance of ß-adrenergic signaling in heart failure pathophysiology, we investigated the underlying mechanism involved in CXCR4 modulation of ßAR signaling. Our studies demonstrate activation of CXCR4 by stromal cell-derived factor-1 leads to a decrease in ßAR-induced PKA activity as assessed by cAMP accumulation and PKA-dependent phosphorylation of phospholamban, an inhibitor of SERCA2a. We determined CXCR4 regulation of ßAR downstream targets is ß2AR-dependent. We demonstrated a physical interaction between CXCR4 and ß2AR as determined by coimmunoprecipitation, confocal microscopy, and BRET techniques. The CXCR4-ß2AR interaction leads to G-protein signal modulation and suggests the interaction is a novel mechanism for regulating cardiac myocyte contractility. Chemokines are physiologically and developmentally relevant to myocardial biology and represent a novel receptor class of cardiac modulators. The CXCR4-ß2AR complex could represent a hitherto unknown target for therapeutic intervention.

Effects of CXCR4 gene transfer on cardiac function after ischemia-reperfusion injury.

Acute coronary occlusion is the leading cause of death in the Western world. There is an unmet need for the development of treatments to limit the extent of myocardial infarction (MI) during the acute phase of occlusion. Recently, investigators have focused on the use of a chemokine, CXCL12, the only identified ligand for CXCR4, as a new therapeutic modality to recruit stem cells to individuals suffering from MI. Here, we examined the effects of overexpression of CXCR4 by gene transfer on MI. Adenoviruses carrying the CXCR4 gene were injected into the rat heart one week before ligation of the left anterior descending coronary artery followed by 24 hours reperfusion. Cardiac function was assessed by echocardiography couple with 2,3,5-Triphenyltetrazolium chloride staining to measure MI size. In comparison with control groups, rats receiving Ad-CXCR4 displayed an increase in infarct area (13.5% +/- 4.1%) and decreased fractional shortening (38% +/- 5%). Histological analysis revealed a significant increase in CXCL12 and tumor necrosis factor-alpha expression in ischemic area of CXCR4 overexpressed hearts. CXCR4 overexpression was associated with increased influx of inflammatory cells and enhanced cardiomyocyte apoptosis in the infarcted heart. These data suggest that in our model overexpressing CXCR4 appears to enhance ischemia/reperfusion injury possibly due to enhanced recruitment of inflammatory cells, increased tumor necrosis factor-alpha production, and activation of cell death/apoptotic pathways.

In vivo detection of embryonic stem cell-derived cardiovascular progenitor cells using Cy3-labeled Gadofluorine M in murine myocardium.

OBJECTIVES: The aim of the current study is to test the ability to label and detect murine embryonic stem cell-derived cardiovascular progenitor cells (ES-CPC) with cardiac magnetic resonance (CMR) using the novel contrast agent Gadofluorine M-Cy3 (GdFM-Cy3). BACKGROUND: Cell therapy shows great promise for the treatment of cardiovascular disease. An important limitation to previous clinical studies is the inability to accurately identify transplanted cells. GdFM-Cy3 is a lipophilic paramagnetic contrast agent that contains a perfluorinated side chain and an amphiphilic character that allows for micelle formation in an aqueous solution. Previous studies reported that it is easily taken up and stored within the cytosol of mesenchymal stem cells, thereby allowing for paramagnetic cell labeling. Investigators in our laboratory have recently developed techniques for the robust generation of ES-CPC. We reasoned that GdFM-Cy3 would be a promising agent for the in vivo detection of these cells after cardiac cell transplantation. METHODS: ES-CPC were labeled with GdFM-Cy3 by incubation. In vitro studies were performed to assess the impact of GdFM-Cy3 on cell function and survival. A total of 500,000 GdFM-Cy3-labeled ES-CPC or control ES-CPC were injected into the myocardium of mice with and without myocardial infarction. Mice were imaged (9.4-T) before and over a 2-week time interval after stem cell transplantation. Mice were then euthanized, and their hearts were sectioned for fluorescence microscopy. RESULTS: In vitro studies demonstrated that GdFM-Cy3 was easily transfectable, nontoxic, stayed within cells after labeling, and could be visualized using CMR and fluorescence microscopy. In vivo studies confirmed the efficacy of the agent for the detection of cells transplanted into the hearts of mice after myocardial infarction. A correspondence between CMR and histology was observed. CONCLUSIONS: The results of the current study suggest that it is possible to identify and potentially track GdFM-Cy3-labeled ES-CPC in murine infarct models via CMR.