Unexpected TEE Findings During Rheumatic Triple-Valve Surgery: Incidental, Yet Impactful.

This E-Challenge highlights an incidental prebypass transesophageal echocardiographic (TEE) finding of a right atrial membrane that impacted cardiac surgical management during triple-valve surgery. Two-dimensional and advanced 3-dimensional (3D) TEE were used in real-time to assist intraoperative decision-making. The findings, clinical course, discussion of the differential diagnosis, final diagnosis, and patient management are detailed here.

The Laminin-α1 Chain-Derived Peptide, AG73, Binds to Syndecans on MDA-231 Breast Cancer Cells and Alters Filopodium Formation.

Breast cancer is one of the most common forms of cancer affecting women in the United States, second only to skin cancers. Although treatments have been developed to combat primary breast cancer, metastasis remains a leading cause of death. An early step of metastasis is cancer cell invasion through the basement membrane. However, this process is not yet well understood. AG73, a synthetic laminin-α1 chain peptide, plays an important role in cell adhesion and has previously been linked to migration, invasion, and metastasis. Thus, we aimed to identify the binding partner of AG73 on breast cancer cells that could mediate cancer progression. We performed adhesion assays using MCF10A, T47D, SUM1315, and MDA-231 breast cell lines and found that AG73 binds to syndecans (Sdcs) 1, 2, and 4. This interaction was inhibited when we silenced Sdcs 1 and/or 4 in MDA-231 cells, indicating the importance of these receptors in this relationship. Through actin staining, we found that silencing of Sdc 1, 2, and 4 expression in MDA-231 cells exhibits a decrease in the length and number of filopodia bound to AG73. Expression of mouse Sdcs 1, 2, and 4 in MDA-231 cells provides rescue in filopodia, and overexpression of Sdcs 1 and 2 leads to increased filopodium length and number. Our findings demonstrate an intrinsic interaction between AG73 in the tumor environment and the Sdcs on breast cancer cells in supporting tumor cell adhesion and invasion through filopodia, an important step in cancer metastasis.

Linezolid-Induced Lactic Acidosis Sets Stage for Surgery to Rule Out Mesenteric Ischemia: A Case Report.

An 81-year-old woman with extensive peripheral vascular and coronary artery disease was admitted to the intensive care unit with a deep heel abscess and urinary tract infection. When cultures from the heel ulcer yielded vancomycin-resistant enterococci, she was started on the antibiotic linezolid. After several days of intravenous linezolid therapy, she developed severe lactic acidosis (pH 6.89) and elevation of pancreatic enzymes. An emergent exploratory laparotomy was performed to rule out mesenteric ischemia. Findings from the laparotomy were negative, and after elimination of other differential diagnoses, the metabolic acidosis was ultimately attributed to linezolid. Acidosis resolved after discontinuation of linezolid.

Intrapleural placement of a thoracic epidural catheter in a patient with spinal stenosis.

Due to the close proximity of the thoracic epidural space and parietal pleura, pleural puncture with intrapleural catheter placement is a potential complication of thoracic epidural anesthesia. The authors present a case of an obese patient with a history of spinal stenosis that underwent thoracotomy. Repeated failed attempts at epidural anesthesia were complicated by intrapleural placement of the catheter. The patient subsequently developed clinical signs of pneumothorax and required urgent thoracostomy.

Surgery for pediatric invasive fungal sinonasal disease.

OBJECTIVES/HYPOTHESIS: To evaluate the management and outcomes of children with invasive fungal sinonasal disease treated with radical surgery. STUDY DESIGN: Retrospective case series. METHODS: From 1994 to 2007, 11 pediatric patients were identified with invasive fungal sinonasal disease treated surgically by the same pediatric otolaryngologist. Collected data included demographics, oncologic diagnoses, absolute neutrophil counts, symptoms, computed tomography scan findings, biopsy and culture results, surgical procedures, concurrent medical therapies, complications, and survival. RESULTS: The studied patient population consisted of four males and seven females with an average age of 10 years (range, 2-14 years). Six patients were diagnosed with acute lymphoblastic leukemia and five with acute myeloid leukemia, which included 10 cases of relapsed disease. The average number of severely neutropenic days prior to diagnosis of an invasive fungal infection was 18 (range, 8-41 days). Culture results demonstrated Alternaria in seven patients and Aspergillus in four. Nine patients underwent an external medial maxillectomy, five of which were bilateral, and six underwent septectomy. All 11 patients (100%) were cured of their invasive fungal sinonasal disease without relapse. Three patients eventually died from unrelated causes. CONCLUSIONS: Invasive fungal sinonasal disease is a life-threatening problem in immunocompromised children, especially with relapsed leukemia. Successful treatment depends on timely and aggressive surgical, antifungal, and supportive therapies. To our knowledge, this study represents the largest series of pediatric patients with invasive fungal sinonasal disease managed via an aggressive surgical approach with the best outcomes to date. LEVEL OF EVIDENCE: 4.

Primary and acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: an update.

Epidermal growth factor receptor (EGFR) is a critical target in the treatment of nonsmall cell lung cancer (NSCLC). The mutations involving EGFR are more prevalent in patients of Asian ancestry, women, never smokers, and those with adenocarcinoma histology. Primary mechanism of resistance to EGFR-TKIs includes in frame insertion mutation in exon 20, de novo T790M mutation also on exon 20, activating mutations in KRAS, loss of PTEN, and amplification of c-MET whereas acquired resistance results from development of secondary alteration in ATP domain of T790M. There are many novel targeting agents in development to overcome resistance to EGFR TKIs.

New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein.

Nuclear factor-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase complex, is a critical component of the NF-κB pathway. Hypomorphic mutations in the X-linked human NEMO gene cause various forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). All known X-linked EDA-ID-causing mutations impair NEMO protein expression, folding, or both. We describe here 2 EDA-ID-causing missense mutations that affect the same residue in the CC2-LZ domain (D311N and D311G) that do not impair NEMO production or folding. Structural studies based on pull-down experiments showed a defect in noncovalent interaction with K63-linked and linear polyubiquitin chains for these mutant proteins. Functional studies on the patients' cells showed an impairment of the classic NF-κB signaling pathways after activation of 2 NEMO ubiquitin-binding-dependent receptors, the TNF and IL-1ß receptors, and in the CD40-dependent NF-κB pathway. We report the first human NEMO mutations responsible for X-linked EDA-ID found to affect the polyubiquitin binding of NEMO rather than its expression and folding. These experiments demonstrate that the binding of human NEMO to polyubiquitin is essential for NF-κB activation. They also demonstrate that the normal expression and folding of NEMO do not exclude a pathogenic role for NEMO mutations in patients with EDA-ID.

Regulation of mature ADAM17 by redox agents for L-selectin shedding.

L-selectin is constitutively expressed by neutrophils and plays a key role in directing these cells to sites of inflammation. Upon neutrophil activation, L-selectin is rapidly and efficiently down-regulated from the cell surface by ectodomain shedding. We have directly shown that A disintegrin and metalloprotease 17 (ADAM17) is a primary and nonredundant sheddase of L-selection by activated neutrophils in vivo. Following cell activation, intracellular signals lead to the induction of ADAM17's enzymatic activity; however, the target of this inducer mechanism remains unclear. Our study provides evidence of an activation mechanism that involves the extracellular region of the mature form of cell surface ADAM17 and not its intracellular region. We demonstrate that the catalytic activity of purified ADAM17 lacking a prodomain and its intracellular region is diminished under mild reducing conditions by DTT and enhanced by H(2)O(2) oxidation. Moreover, H(2)O(2) reversed ADAM17 inhibition by DTT. The treatment of neutrophils with H(2)O(2) also induced L-selectin shedding in an ADAM17-dependent manner. These findings suggest that thiol-disulfide conversion occurring in the extracellular region of ADAM17 may be involved in its activation. An analysis of ADAM17 revealed that within its disintegrin/cysteine-rich region are two highly conserved, vicinal cysteine sulfhydryl motifs (cysteine-X-X-cysteine), which are well-characterized targets for thiol-disulfide exchange in various other proteins. Using a cell-based ADAM17 reconstitution assay, we demonstrate that the cysteine-X-X-cysteine motifs are critical for L-selectin cleavage. Taken together, our findings suggest that reduction-oxidation modifications of cysteinyl sulfhydryl groups in mature ADAM17 may serve as a mechanism for regulating the shedding of L-selectin following neutrophil stimulation.

Successful plasmapheresis for extreme hyperbilirubinemia caused by acute Epstein-Barr virus.

Epstein-Barr virus (EBV) infection can be complicated by cholestatic jaundice and hemolytic anemia, although both complications rarely occur simultaneously. An 18-year-old female developed acute EBV infection complicated by cold agglutinin hemolysis and cholestasis. Corticosteroid and ursodeoxycholic acid were initiated but bilirubin peaked at 1297.47 micromol/L (75.7 mg/dL). Plasmapheresis was initiated and with the corticosteroids, resulted in resolution of extreme hyperbilirubinemia. The patient recovered rapidly, is healthy 2 years later and is neurologically intact. The early use of plasmapheresis with corticosteroids and ursodeoxycholic should be considered in EBV infections complicated by extreme hyperbilirubinemia to prevent the rare complication of adult-onset kernicterus.