Atraumatic splenic rupture secondary to granulocyte-colony stimulating factor medication exposure.

Hematopoietic hormones such as granulocyte-colony stimulating factors are commonly used prevent neutropenia in patients undergoing chemotherapy and to prepare patients for bone marrow donations. In rare cases, splenic injury can result from exposure to this medication. We present the case of a 30-year-old man who presented to the emergency department the day after a bone marrow donation procedure complaining of severe, acute onset left upper quadrant abdominal pain, radiating to the shoulder. Neither the patient nor his family reported any abdominal trauma prior to or following the marrow donation procedure. An initial bedside ultrasound examination was positive for peritoneal fluid and distortion of the normal splenic architecture, raising suspicion for possible intraabdominal or splenic injury. An emergent confirmatory CT with contrast of the abdomen confirmed the initial ultrasound examination suspicion of an atraumatic splenic rupture and with evidence of venous bleeding but without active arterial extravasation. An emergent trauma surgery consultation was placed, and he underwent embolization with an uneventful recovery. This case report highlights the need for a high index of suspicion for atraumatic splenic rupture in patients exposed to these types of granulocyte-colony stimulating factors.

Point-of-care ultrasound findings in the diagnosis and management of Superior Mesenteric Artery (SMA) syndrome.

Superior mesenteric artery (SMA) syndrome is a potentially fatal condition that can be difficult to diagnose for emergency medicine physicians due to its rarity and vague gastrointestinal symptom presentation. Patients arriving at the emergency department (ED) with this condition may encounter delays in proper supportive care and treatment. We present the case of a 21-year-old female who was seen in the ED for nausea, non-bloody vomiting, and rapid weight loss. Through point-of-care ultrasound (POCUS) findings, she was diagnosed with SMA syndrome and received appropriate, supportive care for her condition before catastrophic complications could occur. This case demonstrates the utility of POCUS in SMA syndrome and the importance of considering this diagnosis despite its rarity.

Point-of-care ultrasound utilized for foreign body in a toe: A case report of botfly larvae.

BACKGROUND: Myiasis, as defined by the Centers for Disease Control and Prevention, is infection with fly larvae commonly occurring in tropical and subtropical areas. Whereas the presentation of skin infection with organisms such as Dermatobia hominis (human botfly) is more easily recognized in these regions, identification of myiasis in the United States is difficult due to its rarity. Due to unspecific signs and symptoms, myiasis may initially be mistaken for other conditions, like cellulitis. CASE REPORT: This case details a patient with pain, swelling, drainage, and erythema of the right second toe. The patient recently returned from Belize and reported an insect bite to the area approximately 1 month prior. She had been seen by health care professionals twice prior to presenting to our Emergency Department (ED) due to increasing pain. At those visits, the patient was prescribed antibiotics, failing to improve her symptoms. In the ED, point-of-care ultrasound (POCUS) of the soft tissue was performed and showed evidence of a foreign body consistent with cutaneous myiasis. Given the patient's history of travel to Belize and known insect bite, it is prudent to have an increased suspicion for cutaneous myiasis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: To prevent a delay in diagnosis and unnecessary antibiotics, clinicians should have a high level of suspicion for botfly if a patient reports recent travel in an endemic region and pain disproportionate to an insect bite. POCUS contributes to a more efficient recognition of the disease.

Model of brain activation predicts the neural collective influence map of the brain.

Efficient complex systems have a modular structure, but modularity does not guarantee robustness, because efficiency also requires an ingenious interplay of the interacting modular components. The human brain is the elemental paradigm of an efficient robust modular system interconnected as a network of networks (NoN). Understanding the emergence of robustness in such modular architectures from the interconnections of its parts is a longstanding challenge that has concerned many scientists. Current models of dependencies in NoN inspired by the power grid express interactions among modules with fragile couplings that amplify even small shocks, thus preventing functionality. Therefore, we introduce a model of NoN to shape the pattern of brain activations to form a modular environment that is robust. The model predicts the map of neural collective influencers (NCIs) in the brain, through the optimization of the influence of the minimal set of essential nodes responsible for broadcasting information to the whole-brain NoN. Our results suggest intervention protocols to control brain activity by targeting influential neural nodes predicted by network theory.

ErbB4 promotes malignant peripheral nerve sheath tumor pathogenesis via Ras-independent mechanisms.

BACKGROUND: We have found that erbB receptor tyrosine kinases drive Ras hyperactivation and growth in NF1-null malignant peripheral nerve sheath tumors (MPNSTs). However, MPNSTs variably express multiple erbB receptors with distinct functional characteristics and it is not clear which of these receptors drive MPNST pathogenesis. Here, we test the hypothesis that altered erbB4 expression promotes MPNST pathogenesis by uniquely activating key cytoplasmic signaling cascades. METHODS: ErbB4 expression was assessed using immunohistochemistry, immunocytochemistry, immunoblotting and real-time PCR. To define erbB4 functions, we generated mice that develop MPNSTs with floxed Erbb4 alleles (P0-GGFß3;Trp53+/-;Erbb4flox/flox mice) and ablated Erbb4 in these tumors. MPNST cell proliferation and survival was assessed using 3H-thymidine incorporation, MTT assays, Real-Time Glo and cell count assays. Control and Erbb4-null MPNST cells were orthotopically xenografted in immunodeficient mice and the growth, proliferation (Ki67 labeling), apoptosis (TUNEL labeling) and angiogenesis of these grafts was analyzed. Antibody arrays querying cytoplasmic kinases were used to identify erbB4-responsive kinases. Pharmacologic or genetic inhibition was used to identify erbB4-responsive kinases that drive proliferation. RESULTS: Aberrant erbB4 expression was evident in 25/30 surgically resected human MPNSTs and in MPNSTs from genetically engineered mouse models (P0-GGFß3 and P0-GGFß3;Trp53+/- mice); multiple erbB4 splice variants that differ in their ability to activate PI3 kinase and nuclear signaling were present in MPNST-derived cell lines. Erbb4-null MPNST cells demonstrated decreased proliferation and survival and altered morphology relative to non-ablated controls. Orthotopic allografts of Erbb4-null cells were significantly smaller than controls, with reduced proliferation, survival and vascularization. ERBB4 knockdown in human MPNST cells similarly inhibited DNA synthesis and viability. Although we have previously shown that broad-spectrum erbB inhibitors inhibit Ras activation, Erbb4 ablation did not affect Ras activation, suggesting that erbB4 drives neoplasia via non-Ras dependent pathways. An analysis of 43 candidate kinases identified multiple NRG1ß-responsive and erbB4-dependent signaling cascades including the PI3K, WNK1, STAT3, STAT5 and phospholipase-Cγ pathways. Although WNK1 inhibition did not alter proliferation, inhibition of STAT3, STAT5 and phospholipase-Cγ markedly reduced proliferation. CONCLUSIONS: ErbB4 promotes MPNST growth by activating key non-Ras dependent signaling cascades including the STAT3, STAT5 and phospholipase-Cγ pathways. ErbB4 and its effector pathways are thus potentially useful therapeutic targets in MPNSTs.

The American Journal of Pathology, Value Beyond Simple Metrics.

This Editorial highlights the value of The American Journal of Pathology beyond normal metrics.

Advances in Experimental Neuropathology: New Methods and Insights.

This Editorial introduces this month's special Neuropathology Theme Issue, a series of Reviews on advances in our understanding of rare human hereditary neuropathies, peripheral nervous system tumors, and common degenerative diseases.

Understanding Lung Development, Injury, and Repair.

This Editorial introduces the Lung Ontogeny and Injury Theme Issue, which provides critical insights into lung development, injury, and repair as well as key pulmonary diseases.

Coming into focus: computational pathology as the new big data microscope.

This editorial discusses the rise of computational pathology as a major driver of experimental pathology research.

Science isn't science if it isn't reproducible.

This Editorial introduces readers to the US National Institutes of Health's Proposed Principles and Guidelines for Reporting Preclinical Research.

High-throughput linear optical stretcher for mechanical characterization of blood cells.

This study describes a linear optical stretcher as a high-throughput mechanical property cytometer. Custom, inexpensive, and scalable optics image a linear diode bar source into a microfluidic channel, where cells are hydrodynamically focused into the optical stretcher. Upon entering the stretching region, antipodal optical forces generated by the refraction of tightly focused laser light at the cell membrane deform each cell in flow. Each cell relaxes as it flows out of the trap and is compared to the stretched state to determine deformation. The deformation response of untreated red blood cells and neutrophils were compared to chemically treated cells. Statistically significant differences were observed between normal, diamide-treated, and glutaraldehyde-treated red blood cells, as well as between normal and cytochalasin D-treated neutrophils. Based on the behavior of the pure, untreated populations of red cells and neutrophils, a mixed population of these cells was tested and the discrete populations were identified by deformability. © 2015 International Society for Advancement of Cytometry.

Carlina acaulis Exhibits Antioxidant Activity and Counteracts Aß Toxicity in Caenorhabditis elegans.

Carlina acaulis is a medicinal plant that has shown antioxidant activity in in vitro studies, but to date no corresponding in vivo data is available. Therefore, in the present study the antioxidant activity and its impact in counteracting Aß toxicity were studied in the Caenorhabditis elegans model. A dichloromethane extract of the roots of C. acaulis was prepared and characterised via gas-liquid-chromatography/mass-spectrometry (GLC-MS). The in vitro antioxidant activity was confirmed via 2,2-diphenyl-1-picrylhydracyl assay. The extract was further separated by thin layer chromatography into two fractions, one of which was a fraction of the dichloromethane extract of C. acaulis containing mostly Carlina oxide (CarOx). Different strains of C. elegans were employed to study the expression of hsp-16.2p::GFP as a marker for oxidative stress, delocalisation of the transcription factor DAF-16 as a possible mechanism of antioxidant activity, the effect of the drug under lethal oxidative stress, and the effect against beta-amyloid (Aß) toxicity in a paralysis assay. The C. acaulis extract and CarOx showed high antioxidant activity (stress reduction by 47% and 64%, respectively) in C. elegans and could activate the transcription factor DAF-16 which directs the expression of anti-stress genes. In paralysis assay, only the total extract was significantly active, delaying paralysis by 1.6 h. In conclusion, in vivo antioxidant activity was shown for C. acaulis for the first time in the C. elegans model. The active antioxidant compound is Carlina oxide. This activity, however, is not sufficient to counteract Aß toxicity. Other mechanisms and possibly other active compounds are involved in this effect.

Transgenic mice overexpressing neuregulin-1 model neurofibroma-malignant peripheral nerve sheath tumor progression and implicate specific chromosomal copy number variations in tumorigenesis.

Patients with neurofibromatosis type 1 (NF1) develop benign plexiform neurofibromas that frequently progress to become malignant peripheral nerve sheath tumors (MPNSTs). A genetically engineered mouse model that accurately models plexiform neurofibroma-MPNST progression in humans would facilitate identification of somatic mutations driving this process. We previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P(0)-GGFß3 mice) develop MPNSTs. To determine whether P(0)-GGFß3 mice accurately model human neurofibroma-MPNST progression, cohorts of these animals were monitored through death and were necropsied; 94% developed multiple neurofibromas, with 70% carrying smaller numbers of MPNSTs. Nascent MPNSTs were identified within neurofibromas, suggesting that these sarcomas arise from neurofibromas. Although neurofibromin expression was maintained, P(0)-GGFß3 MPNSTs exhibited Ras hyperactivation, as in human NF1-associated MPNSTs. P(0)-GGFß3 MPNSTs also exhibited abnormalities in the p16(INK4A)-cyclin D/CDK4-Rb and p19(ARF)-Mdm-p53 pathways, analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P(0)-GGFß3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 neoplasia-associated genes (including Pten, Tpd52, Myc, Gli1, Xiap, and Bbc3/PUMA). Array comparative genomic hybridization also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P(0)-GGFß3 mice represent a robust model of neurofibroma-MPNST progression useful for identifying novel genes driving neurofibroma and MPNST pathogenesis.

Neuregulin-1 overexpression and Trp53 haploinsufficiency cooperatively promote de novo malignant peripheral nerve sheath tumor pathogenesis.

Malignant peripheral nerve sheath tumors (MPNSTs) are Schwann cell-derived malignancies that arise from plexiform neurofibromas in patients with mutation of the neurofibromin 1 (NF1) gene. We have shown that the growth factor neuregulin-1 (NRG1) also contributes to human neurofibroma and MPNST pathogenesis and that outbred C57BL/6J × SJL/J transgenic mice overexpressing NRG1 in Schwann cells (P0-GGFß3 mice) recapitulate the process of neurofibroma-MPNST progression. However, it is unclear whether NRG1 acts predominantly within NF1-regulated signaling cascades or instead activates other essential cascades that cooperate with NF1 loss to promote tumorigenesis. We now report that tumorigenesis is suppressed in inbred P0-GGFß3 mice on a C57BL/6J background. To determine whether NRG1 overexpression interacts with reduced Nf1 or Trp53 gene dosage to "unmask" tumorigenesis in these animals, we followed cohorts of inbred P0-GGFß3;Nf1+/−, P0-GGFß3;Trp53+/− and control (P0-GGFß3, Nf1+/− and Trp53+/−) mice for 1 year. We found no reduction in survival or tumors in control and P0-GGFß3;Nf1+/− mice. In contrast, P0-GGFß3;Trp53+/− mice died on average at 226 days, with MPNSTs present in 95 % of these mice. MPNSTs in inbred P0-GGFß3;Trp53+/− mice arose de novo from micro-MPNSTs that uniformly develop intraganglionically. These micro-MPNSTs are of lower grade (WHO grade II-III) than the major MPNSTs (WHO grade III-IV); array comparative genomic hybridization showed that lower grade MPNSTs also had fewer genomic abnormalities. Thus, P0-GGFß3;Trp53+/− mice represent a novel model of low- to high-grade MPNST progression. We further conclude that NRG1 promotes peripheral nervous system neoplasia predominantly via its effects on the signaling cascades affected by Nf1 loss.

Commentary on a Classic JHC Article on the Development of Highly Sensitive Fluorochrome-labeled Tyramides for Immunocytochemistry.

This commentary reflects on the significance and impact of the highly cited companion article that was published in the Journal of Histochemistry and Cytochemistry in 1997 (Gijlswijk RPM et al. Fluorochrome-labeled Tyramides: Use in Immunocytochemistry and Fluorescence In Situ Hybridization. Journal of Histochemistry & Cytochemistry. 1997;45(3):375-382).

Diagnosing Emergent Heterotopic Pregnancy via Point-of-Care Ultrasound: A Case Report.

Patients undergoing assisted reproductive treatments are at a much higher risk for developing heterotopic pregnancy, a rare complication marked by concurrent intrauterine and ectopic pregnancies. Ruptured ectopic pregnancies are one of the leading causes of pregnancy-related mortality. We report the case of a 31-year-old woman undergoing ovulation induction that presented to the emergency department (ED) with worsening abdominal pain. Point-of-care ultrasound (POCUS) performed in the ED identified a heterotopic pregnancy in which the ectopic gestational sac had ruptured. The patient was immediately taken to the operating room for surgical management without obtaining a formal radiology-performed ultrasound. Nonspecific abdominal pain is one of the most common complaints for patients presenting to the ED. The usage of POCUS allows for rapid visualization of the abdominal cavity to diagnose the underlying cause of a patient's abdominal pain. This case demonstrates that complex etiologies can be reliably visualized and diagnosed without needing to wait for a formal radiology study.

Rapid Education Event: A Streamlined Approach to Ultrasound Guided Nerve Block Procedural Training.

In the Emergency Medicine Residency setting, procedural ultrasound education often takes place at the bedside when the procedure becomes clinically necessary. As ultrasound technology and its applications continue to gain more importance, there is a greater need for effective and standardized educational models for teaching ultrasound-guided procedures. This pilot program aimed to demonstrate that residents and attending physicians can achieve procedural competence in fascia iliaca nerve block following a rapid and compact procedural education event. Our curriculum covered anatomy identification, procedural knowledge, and technical skills of probe manipulation. After completing our new curriculum, more than 90% of participants demonstrated adequate learning through the pre- and post-assessments and direct observation of procedural performance on a gel phantom model.

Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy.

We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8-FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.

Incidence of extensor pollicis longus tendon rupture after nondisplaced distal radius fractures.

PURPOSE: The incidence of extensor pollicis longus (EPL) tendon rupture in the setting of nondisplaced distal radius fractures is unknown. Extensor pollicis longus rupture is a known complication after distal radius fractures and is believed to occur more frequently after minimally displaced and nondisplaced distal radius fractures. Our study sought to define the incidence of EPL tendon rupture after nondisplaced distal radius fractures presenting to a level 1 trauma center. METHODS: Using our billing database, we identified distal radius fractures presenting to our institution between 2006 and 2009. We reviewed injury radiographs to identify fractures in which radiographic measurements were within predefined radiographic norms. Two fellowship-trained orthopedic hand surgeons, 1 fellowship-trained musculoskeletal radiologist, and 1 senior orthopedic surgery resident then reviewed these fractures. Only those fractures thought by all 4 reviewers to be nondisplaced were classified as nondisplaced for the purposes of this study. We then reviewed charts of these nondisplaced fractures to identify patients who subsequently sustained an EPL tendon rupture. RESULTS: We identified 3 EPL ruptures out of 61 nondisplaced fractures (5%). These occurred at an average of 6.6 weeks after distal radius fractures. CONCLUSIONS: The incidence of EPL rupture is higher than previously reported in the literature. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

BEE FIRST: A standardized point-of-care ultrasound approach to a patient with dyspnea.

Dyspnea is a common complaint in patients who present to the emergency department and can be due to numerous etiologies. This case report details a 90-year-old female with a history significant for hypertension, hyperlipidemia, and new diagnosis of ovarian malignancy whose symptoms increased over the past three days. Point-of-care Ultrasonography showed multiple B-lines, a plethoric IVC without respiratory variation, a markedly low EF and a lack of RV dilation. There was also no evidence of effusion which led the emergency medicine team to the diagnosis of acute decompensated heart failure. This quick diagnosis was possible due to using the standardized POCUS approach guided by the BEE FIRST algorithm. BEE FIRST can help physicians remember: B-lines are indicative of interstitial thickening, Effusion such as pericardial or pleural should be checked for, Ejection Fraction is useful in assessing for heart failure, IVC/Infection/Infarct correlates with central venous pressure, and can be used to assess volume status, check for enlargement, evidence of pneumonia, subpleural consolidation "shred sign", hepatization of lung, and/or pulmonary infarction related to pulmonary embolism, Right Heart Strain can indicate pulmonary embolism or pulmonary hypertension, Sliding Lung can assess for pneumothorax and pleural characteristics, and lastly, Thrombosis/Tumor can assess for myxoma and interrogation of lower extremities for deep vein thrombosis can aid in dyspnea differentiation. In this report, we demonstrate how the framework BEE FIRST offers a standardized stepwise approach to the utilization of POCUS in a patient with acute dyspnea in the ED setting.