Targeting Inflammation After Myocardial Infarction.

PURPOSE OF REVIEW: Inflammation plays a key role in clearing cellular debris and recovery after acute myocardial infarction (AMI). Dysregulation of or prolonged inflammation may result in adverse cardiac remodeling and major adverse clinical events (MACE). Several pre-clinical studies and moderate sized clinical trials have investigated the role of immunomodulation in improving clinical outcomes in patients with AMI. RECENT FINDINGS: Clinical data from the Canakinumab Atherothrombosis Outcome (CANTOS) and Colchicine Cardiovascular Outcomes Trial (COLCOT) have provided encouraging results among patients with AMI. Several other clinical and pre-clinical trials have brought about the prospect of modulating inflammation at various junctures of the inflammatory cascade including inhibition of complement cascade, interleukins, and matrix metalloproteinases. In patients with AMI, modulation of residual inflammation via various inflammatory pathways and mediators may hold promise for further reducing MACE. Learning from current data and understanding the nuances of immunomodulation in AMI are key for future trials and before widespread dissemination of such therapies.

Suspected coronary fat embolism after liposuction.

A 38-year-old female presented with chest pain and ST elevation on electrocardiogram after an outpatient liposuction procedure. Emergent coronary angiography revealed complete occlusion of multiple coronary arteries, with fat embolism as the suspected etiology. Attempts to restore distal coronary flow with balloon dilatation, aspiration with Pronto catheter, and distal adenosine administration resulted in minimal improvement in flow. The material aspirated was consistent with fat. With supportive therapy, including Impella CP support, the patient's clinical condition improved. To our knowledge, this is the first reported case of multiple coronary occlusion after liposuction.

Epithelial membrane protein 2 (EMP2) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency.

Epithelial membrane protein-2 (EMP2) is a tetraspan protein predicted to regulate placental development. Highly expressed in secretory endometrium and trophectoderm cells, previous studies suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins. In order to test the role of EMP2 in pregnancy, mice lacking EMP2 (Emp2-/- ) were generated. Emp2-/- females are fertile but have reduced litter sizes when carrying Emp2-/- but not Emp2+/- fetuses. Placentas of Emp2-/- fetuses exhibit dysregulation in pathways related to neoangiogenesis, coagulation, and oxidative stress, and have increased fibrin deposition and altered vasculature. Given that these findings often occur due to placental insufficiency resulting in an oxygen-poor environment, the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was examined. Placentas from Emp2-/- fetuses had increased total HIF-1α expression in large part through an increase in uterine NK (uNK) cells, demonstrating a unique interplay between uNK cells and trophoblasts modulated through EMP2. To determine if these results translated to human pregnancy, placentas from normal, term deliveries or those complicated by placental insufficiency resulting in intrauterine growth restriction (IUGR) were stained for EMP2. EMP2 was significantly reduced in both villous and extravillous trophoblast populations in IUGR placentas. Experiments in vitro using human trophoblast cells lines indicate that EMP2 modulates angiogenesis by altering HIF-1α expression. Our results reveal a novel role for EMP2 in regulating trophoblast function and vascular development in mice and humans, and suggest that it may be a new biomarker for placental insufficiency. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma.

Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvß3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment.

Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium.

BACKGROUND: PMP22, a member of the GAS3 family of tetraspan proteins, is associated with a variety of neurological diseases. Previous studies have shown that PMP22 is expressed in proliferative endometrium, but its function within this tissue is poorly understood. In this study, we first characterized the expression of PMP22 in the human menstrual cycle and began to characterize its function in the endometrium. METHODS: Using a combination of immunohistochemistry and quantitative PCR, we characterized the expression of PMP22 in both proliferative and secretory endometrium. Differences in PMP22 expression between proliferative and secretory endometrium were determined using a Mann-Whitney U test. In order to investigate the influence of PMP22 on α6 integrin expression, cells were created that ectopically overexpressed PMP22 or expressed a siRNA to inhibit its expression. These cells were analyzed for changes in integrins and binding to extracellular matrices. RESULTS: In this study, we show that PMP22 expression is higher in proliferative phase than secretory phase. Functionally, we have begun to characterize the functional significance of this expression. Previous studies have suggested a link between PMP22 and α6 integrin, and therefore we asked whether PMP22 could associate or potentially modulate the expression of α6 integrin. Expression of both PMP22 and α6 integrin were detectable in endometrial epithelial and stromal cells, and we show that both proteins can associate and colocalize with each other. To understand if PMP22 directly altered the expression of a6 integrin, we examined cell lines with modulated levels of the protein. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression. CONCLUSION: These findings suggest a physiologic role for PMP22 on the expression of α6 integrin. We predict that this may be important for the maintainence of endometrial integrity and to the disease biology associated with altered levels of α6 integrin expression in the endometrium.

Prosthetic Valve Endocarditis From Trichosporon asahii in an Immunocompetent Patient.

Fungal endocarditis is a rare clinical entity. This report describes an unusual case of fungal endocarditis caused by infection with Trichosporon asahii in a 20-year-old immunocompetent man who received the diagnosis 1 year following biological aortic valve replacement. (Level of Difficulty: Beginner.).

Guidelines vs Actual Management of Skin and Soft Tissue Infections in the Emergency Department.

BACKGROUND: Infections of skin and soft tissue (SSTI) commonly cause visits to hospital emergency departments (EDs). The Infectious Diseases Society of America (IDSA) has published guidelines for the management of SSTI, but it is unclear how closely these guidelines are followed in practice. METHODS: We reviewed records of patients seen in the ED at a large tertiary care hospital to determine guidelines adherence in 4 important areas: the decision to hospitalize, choice of antibiotics, incision and drainage (I&D) of abscesses, and submission of specimens for culture. RESULTS: The decision to hospitalize did not comply with guidelines in 19.6% of cases. Nonrecommended antibiotics were begun in the ED in 71% of patients with nonpurulent infections and 68.4% of patients with purulent infections. Abscesses of mild severity were almost always treated with antibiotics, and I&D was often not done (both against recommendations). Blood cultures were done (against recommendations) in 29% of patients with mild-severity cellulitis. Abscess drainage was almost always sent for culture (recommendations neither favor nor oppose). Overall, treatment fully complied with guidelines in 20.1% of cases. CONCLUSIONS: Our results show a striking lack of concordance with IDSA guidelines in the ED management of SSTI. Social factors may account for discordant decisions regarding site of care. Use of trimethoprim/sulfamethoxazole (TMP/SMX) in cellulitis was the most common source of discordance; this practice is supported by some medical literature. Excess antibiotics were often used in cellulitis and after I&D of simple abscesses, opposing antibiotic stewardship. Ongoing education of ED doctors and continued review of published guidelines are needed.

Complex Left Atrial Appendage Morphology Is an Independent Risk Factor for Cryptogenic Ischemic Stroke.

Importance: Ischemic strokes pose a significant health burden. However, the etiology of between 20 and 40% of these events remains unknown. Left atrial appendage morphology may influence the occurrence of thromboembolic events. Design: A retrospective cross-sectional study was conducted to investigate the role of LAA morphology in patients with atrial fibrillation (AF) and cardioembolic-associated stroke and patients with cryptogenic stroke without atrial fibrillation. LAA morphology is classified into two groups: (1) simple (chicken-wing) vs. (2) complex (non-chicken wing) based on transesophageal echocardiography (TEE) findings. In addition to the LAA morphology, left atrial parameters, including orifice diameter, depth, emptying velocity, and filling velocity, were collected for both groups. Mathematical, computational models were constructed to investigate flow velocities in chicken-wing and non-chicken wing morphological patterns to assess LAA function further. Findings: TEE values for volume, size, emptying, and filling velocities were similar between simple and complex LAA morphology groups. Patients with cryptogenic stroke without coexisting AF were noted to have significantly higher rates of complex LAA morphology. Chicken-wing LAA morphology was associated with four-fold higher flow rate (kg/s) in computational simulations. Conclusions: Complex LAA morphology may be an independent contributing factor for cryptogenic strokes. Further studies are warranted to investigate the mechanism involved in LAA morphology and thromboembolic events.

Incidence, Predictors, and Significance of Ventricular Arrhythmias in Patients With Continuous-Flow Left Ventricular Assist Devices: A 15-Year Institutional Experience.

OBJECTIVES: The aim of this study was to evaluate the incidence, predictors, and associated mortality of pre-implantation, early, and late ventricular arrhythmias (VAs) in patients receiving continuous-flow left ventricular assist devices (CFLVADs). BACKGROUND: VAs are common both pre- and post-implantation of left ventricular assist devices. Limited data exist on their prognostic impact in contemporary CFLVADs. METHODS: A retrospective review was performed to identify patients who underwent CFLVAD implantation between 2000 and 2015 with 2 years of follow-up. All VAs, defined as ventricular fibrillation, ventricular tachycardia lasting >30 s, or a ventricular rhythm requiring defibrillation, were analyzed. VAs occurring within 30 days of implantation were defined as early. Recorded outcomes included death and receipt of cardiac transplant. RESULTS: A total of 517 patients were included for analysis. Early VAs were associated with a significant reduction in survival (hazard ratio: 1.83; 95% confidence interval: 1.28 to 2.61; p = 0.001) compared with patients with late or no VAs. Pre-implantation variables independently predictive of early VAs included prior cardiac surgery (odds ratio: 1.90; 95% confidence interval: 1.09 to 3.32; p = 0.023) and pre-CFLVAD ventricular tachycardia storm (odds ratio: 3.15; 95% confidence interval: 1.49 to 6.69; p = 0.003). The incidence of early VAs from 2000 to 2007 was as high as 47%, whereas the highest incidence from 2008 to 2015 was <22%. CONCLUSIONS: VAs within 30 days after CFLVAD implantation are associated with an increased risk for death. Predictors of early VAs include prior cardiac surgery and pre-CFLVAD ventricular tachycardia storm. Temporal trends have shown a decrease in VA from 2000 to 2015. Strategies to reduce arrhythmia burden shortly after CFLVAD implantation warrant further investigation.

Chest wall malignant peripheral nerve sheath tumor in a 21-year old female.

Malignant peripheral nerve sheath tumors are aggressive sarcomas that derive from peripheral nerve cells and are associated with a poor prognosis. We report a rare case of malignant peripheral nerve sheath tumor in the anterior chest wall of a 21-year-old female. The patient underwent induction chemotherapy, and resection of the mass with negative margins. She subsequently underwent radiation therapy.

Military service and lung disease.

OBJECTIVE: Lung diseases associated with military service are often a reflection of the conditions seen in the local civilian population, and with a few notable exceptions, are often related to unique environmental and occupational exposures. METHODS: This article reviews important pulmonary diseases that have been associated with military service in the past 100 years in a question-and-answer format. RESULTS: Traditionally, bacterial and viral pneumonias were the most common sources of military morbidity and mortality. With improved preventive medicine and antimicrobial therapy, other diseases related to battlefield injuries or inhalational exposures have assumed greater importance. CONCLUSIONS: The etiology of military morbidity and mortality has evolved over the past century. Many of the discoveries related to vaccine efficacy, trauma resuscitation, interstitial lung disease, and even carcinomas have a strong military association.

Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src.

Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2), a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK)/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling.