Factor XIII cross-links fibrin(ogen) independent of fibrin polymerization in experimental acute liver injury.

Intravascular fibrin clot formation follows a well-ordered series of reactions catalyzed by thrombin cleavage of fibrinogen leading to fibrin polymerization and cross-linking by factor XIIIa (FXIIIa). Extravascular fibrin(ogen) deposits are observed in injured tissues; however, the mechanisms regulating fibrin(ogen) polymerization and cross-linking in this setting are unclear. The objective of this study was to determine the mechanisms of fibrin polymerization and cross-linking in acute liver injury induced by acetaminophen (APAP) overdose. Hepatic fibrin(ogen) deposition and cross-linking were measured following APAP overdose in wild-type mice, mice lacking the catalytic subunit of FXIII (FXIII-/-), and in FibAEK mice, which express mutant fibrinogen insensitive to thrombin-mediated fibrin polymer formation. Hepatic fibrin(ogen) deposition was similar in APAP-challenged wild-type and FXIII-/- mice, yet cross-linking of hepatic fibrin(ogen) was dramatically reduced (>90%) by FXIII deficiency. Surprisingly, hepatic fibrin(ogen) deposition and cross-linking were only modestly reduced in APAP-challenged FibAEK mice, suggesting that in the APAP-injured liver fibrin polymerization is not strictly required for the extravascular deposition of cross-linked fibrin(ogen). We hypothesized that the oxidative environment in the injured liver, containing high levels of reactive mediators (eg, peroxynitrite), modifies fibrin(ogen) such that fibrin polymerization is impaired without impacting FXIII-mediated cross-linking. Notably, fibrin(ogen) modified with 3-nitrotyrosine adducts was identified in the APAP-injured liver. In biochemical assays, peroxynitrite inhibited thrombin-mediated fibrin polymerization in a concentration-dependent manner without affecting fibrin(ogen) cross-linking over time. These studies depict a unique pathology wherein thrombin-catalyzed fibrin polymerization is circumvented to allow tissue deposition and FXIII-dependent fibrin(ogen) cross-linking.

Von Willebrand factor delays liver repair after acetaminophen-induced acute liver injury in mice.

BACKGROUND & AIM: Acetaminophen (APAP)-induced acute liver failure is associated with substantial alterations in the hemostatic system. In mice, platelets accumulate in the liver after APAP overdose and appear to promote liver injury. Interestingly, patients with acute liver injury have highly elevated levels of the platelet-adhesive protein von Willebrand factor (VWF), but a mechanistic connection between VWF and progression of liver injury has not been established. We tested the hypothesis that VWF contributes directly to experimental APAP-induced acute liver injury. METHODS: Wild-type mice and VWF-deficient (Vwf-/-) mice were given a hepatotoxic dose of APAP (300 mg/kg, i.p.) or vehicle (saline). VWF plasma levels were measured by ELISA, and liver necrosis or hepatocyte proliferation was measured by immunohistochemistry. Platelet and VWF deposition were measured by immunofluorescence. RESULTS: In wild-type mice, VWF plasma levels, high molecular weight (HMW) VWF multimers, and VWF activity decreased 24 h after APAP challenge. These changes coupled to robust hepatic VWF and platelet deposition, although VWF deficiency had minimal effect on peak hepatic platelet accumulation or liver injury. VWF plasma levels were elevated 48 h after APAP challenge, but with relative reductions in HMW multimers and VWF activity. Whereas hepatic platelet aggregates persisted in livers of APAP-challenged wild-type mice, platelets were nearly absent in Vwf-/- mice 48 h after APAP challenge. The absence of platelet aggregates was linked to dramatically accelerated repair of the injured liver. Complementing observations in Vwf-/- mice, blocking VWF or the platelet integrin αIIbß3 during development of injury significantly reduced hepatic platelet aggregation and accelerated liver repair in APAP-challenged wild-type mice. CONCLUSION: These studies are the first to suggest a mechanistic link between VWF, hepatic platelet accumulation, and liver repair. Targeting VWF might provide a novel therapeutic approach to improve repair of the APAP-injured liver. LAY SUMMARY: Patients with acute liver injury due to acetaminophen overdose have highly elevated levels of the platelet-adhesive protein von Willebrand factor. It is not known whether von Willebrand factor plays a direct role in the progression of acute liver injury. We discovered that von Willebrand factor delays repair of the acetaminophen-injured liver in mice and that targeting von Willebrand factor, even in mice with established liver injury, accelerates liver repair.

Direct Amplification of Tissue Factor:Factor VIIa Procoagulant Activity by Bile Acids Drives Intrahepatic Coagulation.

OBJECTIVE: Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestatic patients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acid glycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone. CONCLUSIONS: The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.

Plasminogen Activator Inhibitor-1 Reduces Tissue-Type Plasminogen Activator-Dependent Fibrinolysis and Intrahepatic Hemorrhage in Experimental Acetaminophen Overdose.

Acetaminophen (APAP)-induced liver injury in mice is associated with activation of the coagulation cascade and deposition of fibrin in liver. Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. PAI-1 expression is increased in both experimental APAP-induced liver injury and patients with acute liver failure. Prior studies have shown that PAI-1 prevents intrahepatic hemorrhage and mortality after APAP challenge, but the downstream mechanisms are not clear. We tested the hypothesis that PAI-1 limits liver-related morbidity after APAP challenge by reducing tPA-dependent fibrinolysis. Compared with APAP-challenged (300 mg/kg) wild-type mice, hepatic deposition of cross-linked fibrin was reduced, with intrahepatic congestion and hemorrhage increased in PAI-1-deficient mice 24 hours after APAP overdose. Administration of recombinant wild-type human PAI-1 reduced intrahepatic hemorrhage 24 hours after APAP challenge in PAI-1-/- mice, whereas a mutant PAI-1 lacking antiprotease function had no effect. Of interest, tPA deficiency alone did not affect APAP-induced liver damage. In contrast, fibrinolysis, intrahepatic congestion and hemorrhage, and mortality driven by PAI-1 deficiency were reduced in APAP-treated tPA-/-/PAI-1-/- double-knockout mice. The results identify PAI-1 as a critical regulator of intrahepatic fibrinolysis in experimental liver injury. Moreover, the results suggest that the balance between PAI-1 and tPA activity is an important determinant of liver pathology after APAP overdose.

Necrotizing fasciitis and its mimics: what radiologists need to know.

OBJECTIVE: The purpose of this article is to review the imaging features of necrotizing fasciitis and its potential mimics. Key imaging features are emphasized to enable accurate and efficient interpretation of variables that are essential in appropriate management. CONCLUSION: Necrotizing fasciitis is a medical emergency with potential lethal outcome. Dissecting gas along fascial planes in the absence of penetrating trauma (including iatrogenic) is essentially pathognomonic. However, the lack of soft-tissue emphysema does not exclude the diagnosis. Mimics of necrotizing fasciitis include nonnecrotizing fasciitis (eosinophilic, paraneoplastic, inflammatory (lupus myofasciitis, Churg-Strauss, nodular, or proliferative), myositis, neoplasm, myonecrosis, inflammatory myopathy, and compartment syndrome. Necrotizing fasciitis is a clinical diagnosis, and imaging can reveal nonspecific or negative findings (particularly during the early course of disease). One should be familiar with salient clinical and imaging findings of necrotizing fasciitis to facilitate a more rapid and accurate diagnosis and be aware that its diagnosis necessitates immediate discussion with the referring physician.

Osteochondroma of the hip with adjacent bursal chondromatosis.

It is well established that irregular bursae can form adjacent to an osteochondroma (bursa exostotica) as a result of mechanical irritation and that these bursae can be complicated by inflammation, hemorrhage, or infection. Bursal chondromatosis is a rare complication, with only seven published cases in the literature according to our searches. We present the case of a 53-year-old female who presented with slowly progressive left hip/thigh pain and was found to have an osteochondroma arising from the lesser trochanter with numerous ossified bodies in the adjacent soft tissues. MRI demonstrated osteochondral bodies in a fluid-filled bursa adjacent to the osteochondroma, with several of the bodies noted to be fairly displaced from the osteochondroma cartilaginous cap. At surgery, the osteochondroma was removed and numerous bodies of varying sizes were excised, some of which were noted to be adherent to the bursal lining and others that were separated/distant from the cartilage cap. The question arises as to whether this process represents bursal chondromatosis resulting from benign neoplasia of cells lining the abnormal bursa, "cartilage shedding" from the osteochondromatous cap, or both. The purpose in presenting this case is to introduce a rare complication of an osteochondroma, demonstrate that soft tissue calcification and osteochondral densities displaced from an underlying osteochondroma are not always the result of sarcomatous degeneration, and provide support for the theory that cells lining a bursa in a nonphysiologic location can undergo benign neoplasia with subsequent formation of osteochondral bodies.

Evaluation of radiation dose among patients admitted through a university hospital emergency department.

This study was conducted to evaluate the impact of different patient presentations/characteristics on medical imaging and radiation exposure. We collected data on the estimated effective radiation dose (EED) of patients admitted through our University Hospital ER, and analyzed the relationships of patient gender, age, admitting diagnosis, and admission duration on EED. All (592) patients admitted through our ER (with imaging) during 1-week periods in May/November 2009 were included. To compare EEDs according to admission diagnosis, seven categories were created: Cardiopulmonary, Gastrointestinal, Genitourinary, Neurologic, Trauma, Infectious, and Other. EEDs of patients with various admission durations were also evaluated. Units for all EEDs are mSv. Median EED (MEED) for all patients was 4.5. Males (7.8, females = 2.5) and adults (6.1, pediatrics = 1.8) experienced higher MEEDs, but significance was lost after controlling for other variables. MEED increased with admission duration (0.1 for <24 h, 1.8 for 1-3 days and 92.0 for >2 months). Trauma patients experienced the highest MEED (18.3), while patients with gastrointestinal/genitourinary diagnoses experienced the second highest MEED (13.0 mSv for both). Pediatric/male patients experienced heightened radiation exposure, but these relationships were largely due to other variables (higher male frequency/severity of trauma, pediatric patients had shorter admissions and diagnoses requiring less radiologic workup). Patients admitted following trauma and for prolonged durations showed elevated radiation exposure even after adjustment for all other variables. The identification of these relationships may aid in the development and focusing of future radiation awareness/reduction efforts to persons involved in the evaluation and care of patients with these presentations and characteristics.

Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity.

Drug-induced neurotoxicity is a leading cause of safety-related attrition for therapeutics in clinical trials, often driven by poor predictivity of preclinical in vitro and in vivo models of neurotoxicity. Over a dozen different iPSC-derived 3D spheroids have been described in recent years, but their ability to predict neurotoxicity in patients has not been evaluated nor compared with the predictive power of nonclinical species. To assess the predictive capabilities of human iPSC-derived neural spheroids (microBrains), we used 84 structurally diverse pharmaceuticals with robust clinical and pre-clinical datasets with varying degrees of seizurogenic and neurodegenerative liability. Drug-induced changes in neural viability and phenotypic calcium bursts were assessed using 7 endpoints based on calcium oscillation profiles and cel-lular ATP levels. These endpoints, normalized by therapeutic exposure, were used to build logistic regression models to establish endpoint cutoffs and evaluate probability for clinical neurotoxicity. The neurotoxicity score calculated from the logistic regression model could distinguish neurotoxic from non-neurotoxic clinical molecules with a specificity as high as 93.33% and a sensitivity of 53.49%, demonstrating a very low false positive rate for the prediction of seizures, convulsions, and neurodegeneration. In contrast, nonclinical species showed a higher sensitivity (75%) but much lower specificity (30.4%). The neural spheroids demonstrated higher likelihood ratio positive and inverse likelihood ratio neg-ative values compared with nonclinical safety studies. This assay has the potential to be used as a predictive assay to detect neurotoxicity in early drug discovery, aiding in the early identification of compounds that eventually may fail due to neurotoxicity.

Soft tissue aneurysmal bone cyst: a rare case in a middle aged patient.

Soft tissue aneurysmal bone cyst is a rare entity, with about 20 cases reported in literature, only 3 of which are in patients over 40 years of age. We present a case of a 41 year old Latin American female who presented for evaluation of atraumatic chest pain with radiation to the left shoulder. Her initial workup was negative, including radiographic imaging of the chest and left shoulder. 4 months later, she presented to her orthopedic surgeon with a palpable mass and mild left shoulder pain. Radiographs acquired at that time demonstrated a 7.0 × 5.5 × 6.7 cm mass with rim calcification in the region of the upper triceps muscle. Subsequent CT imaging showed central areas of hypodensity and thin septations, a few of which were calcified. MR evaluation showed hemorrhagic cystic spaces with multiple fluid-fluid levels and enhancing septations. Surgical biopsy was performed and pathology was preliminarily interpreted as cystic myositis ossificans, however on final review the diagnosis of soft tissue aneurysmal bone cyst was made. The lesion was then surgically excised and no evidence of recurrence was seen on a 3 year post-op radiograph. Following description of our case, we conduct a literature review of the imaging characteristics, diagnosis, and treatment of soft tissue aneurysmal bone cyst.

Inadvertent intravesicular placement of a vaginal contraceptive ring: a case report and review of literature.

The NuvaRing® is a deformable, ring-shaped hormonal contraceptive device which is typically vaginally self-inserted by the patient. While there are several potential side effects of usage, essentially all of them result from hormone delivery. Complications from incorrect placement are rare. We present the case of a 31 year old female who presented to our emergency department after being unable to retrieve a NuvaRing® for its scheduled removal. CT scan showed a hypodense intravesicular NuvaRing® which the patient had inadvertently placed transurethrally 3 weeks prior. Cystoscopy was performed and retrieval using a 3-pronged grasper was eventually successful after several failed attempts with an alligator grasper. Our purpose in presenting this case is to introduce the reader to a rare complication of incorrect NuvaRing® placement, explain how this complication may occur as a result of NuvaRing® construction/functionality, describe how alternative cystoscopic instruments may aid in cystoscopic retrieval, and review the 3 other case reports of intravesicular NuvaRing® placement to discuss the utility of various imaging modalities when clinical suspicion of the complication is high.

Ureteral rupture from aberrant Foley catheter placement: a case report.

We present the case of a 59 year old female with history of severe neurologic dysfunction from advanced multiple sclerosis who presented with lethargy and oliguria several hours after urethral Foley catheterization. A contrast-enhanced CT scan of the abdomen/pelvis showed an aberrantly placed Foley catheter with its balloon inflated in the proximal left ureter, a rare complication of Foley catheterization with only 5 other cases reported. Incomplete ureteral rupture was demonstrated and confirmed by a followup CT scan in the urographic phase. One of our institution's Interventional Radiologists then placed a nephroureteral stent across the injured ureter to facilitate healing. The patient expired 9 days after the procedure from unrelated sepsis from a chronic stage IV decubitus ulcer, so long term monitoring could not be performed. Following description of our case, we conduct a literature review of presentations, imaging characteristics, and treatment of ureteral Foley catheter placement.

Presacral myelolipoma: a case report and review of imaging findings.

Extra-adrenal myelolipoma is a relatively rare entity, with fewer than 50 cases reported in literature. We present a case of a 79 year-old female who presented for evaluation of hip fracture following trauma, where a lobulated presacral mass with mixed fat/soft tissue attenuation was incidentally seen on initial bone algorithm pelvic CT. Subsequent MRI showed signal characteristics of a lesion with mixed fat and soft tissue composition. The lesion demonstrated stability on follow-up imaging. An elective surgical resection was performed which yielded a grossly fatty mass. The diagnosis of presacral myelolipoma was confirmed on microscopic examination. Following description of our case, we conduct a literature review of the imaging characteristics, diagnosis, and treatment of presacral myelolipoma.

Summer anesthesiology externship: Demonstrating the ability of early clinical involvement to educate and increase specialty interest.

BACKGROUND: We describe the influence of a 6-week "Summer Anesthesiology Externship" featuring didactic, procedure, and simulation education on formation of medical students' specialty choice. METHODS: Eighteen months after externship completion, externs were sent a questionnaire with Likert scale agreement ratings of subspecialties/simulations and yes/no questions about student career interests before/after the program, stipend importance, and procedural skill performance during/after the program. RESULTS: General anesthesiology had the highest subspecialty approval rating (9.0). Externs strongly agreed that simulations successfully progressed at first year student understanding levels (9.2 mean agreement rating), increased confidence in being part of a care team (9.4 mean agreement rating), and provided personal/interpersonal development. Externs unanimously agreed that the program introduced them to the breadth of anesthesiology, and that practicing clinical/procedural skills improved confidence when performing the procedures later in medical school. Four of 14 students applied for the externship with some focus on anesthesiology as a career choice. After the externship, a significantly higher number of students (12 of 14) were strongly considering applying to the field (p<0.0001). Eleven of 14 ultimately entered anesthesiology residencies, a significantly higher rate than our general medical student classes (p<0.0001). CONCLUSIONS: Both CA1 and CA3 resident post-test scores improved at the end of the ultrasound guided regional workshop. Our study showed a 68% improvement in test scores, which is larger than the 50% improvement previously reported. These results show that fast learning can occur in this type of setting. Furthermore, knowledge acquired during the workshop was retained when CA1 residents were re-tested one year after the workshop. The ultrasound-guided regional anesthesia workshop will become part of the didactic series for our CA1 residents and will be a required learning activity. Additional work still needs to be done to find out the best way to test knowledge and skill outcomes in residents learning new technology and techniques.