Ilya Berim

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia A NOVEL EFFECT OF CELECOXIB AND THE MECHANISM UNDERLYING IT

Selective inhibitors of cyclooxygenase-2 (COX-2), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have been developed for treating arthritis and other musculoskeletal complaints. Selective inhibition of COX-2 over COX-1 results in preferential decrease in prostacyclin production over thromboxane A2 production, thus leading to less gastric effects than those seen with nonselective COX inhibitors such as acetylsalicylic acid (aspirin). Here we show a novel effect of celecoxib via a mechanism that is independent of COX-2 inhibition. The drug inhibited the delayed rectifier (Kv2) potassium channels from Drosophila, rats, and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture. These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid, a potent inhibitor of both COX-1 and COX-2, to inhibit rat Kv2.1 channels. A genetically null mutant of Drosophila Shab (Kv2) channels reproduced the cardiac effect of celecoxib, and the drug was unable to further enhance the effect of the mutation. These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats, implicating the inhibition of Kv2 channels as the mechanism underlying this effect.

Diagnostic value of tumor antigens in malignant pleural effusion: A meta-analysis

The diagnostic value of tumor markers, carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, CA 19-9, CA 125, cytokeratin fragment (CYFRA), and neuron-specific enolase (NSE) in pleural fluid to differentiate between benign and malignant pleural effusion (MPE) has not yet been clearly established. A review of English language studies using human subjects was performed. Sensitivity and specificity values of the chosen tumor markers were pooled using a random effects model to generate hierarchical summary receiver operator curves to determine the diagnostic performance of each tumor marker. A total of 49 studies were included in the final analysis. Pooled sensitivity and specificity values for chosen tumor markers for diagnosing MPE are as follows: CEA, 0.549 and 0.962; CA 15-3, 0.507 and 0.983; CA 19-9, 0.376 and 0.980; CA 125, 0.575 and 0.928; CYFRA, 0.625 and 0.932; NSE, 0.613 and 0.884. The use of individual tumor markers in diagnosing MPE has many benefits (cost, invasiveness, and so forth). Although these tumor markers exhibit high specificity, the low sensitivity of each marker limits the diagnostic value. We conclude that tumor markers used individually are of insufficient diagnostic accuracy for clinical use. Tumor markers used in various combinations or from serum may have some potential worth further investigation.

Chronic inflammation and cancer: Emerging roles of triggering receptors expressed on myeloid cells

Inflammation is tightly regulated by a vast system that is intricately interconnected with innate immunity. Aberrations in expression or signaling, such as in innate immune receptors, can create excessive inflammation and, when chronic, often promote oncogenesis. The triggering receptor expressed on myeloid cells receptor family has been characterized as a major player in the amplification and signaling of the inflammatory response. In a number of chronic inflammatory conditions and malignancies, the triggering receptor expressed on myeloid cells has been implicated in disease severity and progression. In this article, the current understanding of triggering receptor expressed on myeloid cells function in pre-malignant, malignant and chronic inflammatory conditions is critically reviewed. The potential for therapeutic application is also discussed.

The benefits of long-term systemic antimicrobial therapy in chronic obstructive pulmonary disease.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are major contributors to the morbidity and mortality associated with this disease. Current approaches that likely reduce chronic obstructive pulmonary disease (COPD) exacerbations include smoking cessation, influenza and pneumococcal vaccinations, long-acting bronchodilator and inhaled corticosteroid therapy, pulmonary rehabilitation, and mucolytic drugs. However, with optimal treatment using all of these modalities, we are only able to reduce exacerbations by about 40%. A significant proportion of COPD exacerbations are bacterial, therefore long-term antimicrobial therapy could have a role in preventing exacerbations. Long-term antibiotic treatment in COPD regimens that are being evaluated include low-dose macrolide therapy, pulsed fluoroquinolone administration and the use of inhaled antibiotics. Although initial results have been promising with significant reductions in exacerbations with these regimens, additional studies are required to identify the appropriate patient and regimen and elucidate the risk–benefit as well as cost effectiveness of long-term antibiotics in COPD.

Management of oral antiplatelet agents and anticoagulation therapy before bronchoscopy

Although, bronchoscopy is a relatively safe procedure, small amount of bleeding in the airway can have serious consequences. Careful consideration of the risks of diagnostic and therapeutic bronchoscopic intervention can help minimize potential complications. With increasing number of patients using antiplatelet and anticoagulation therapies, strategies for minimizing thromboembolic and operative bleeding events need to be included in the risk and benefit analyses. Growing evidence suggests that aspirin is safe and does not increase bleeding during bronchoscopy. In addition, despite small studies reporting that it may be safe to perform bronchoscopic procedures that have low risk for bleeding such as endobronchial ultrasound with transbronchial needle aspiration on clopidogrel, it is still recommended to hold it for 7 days prior to performing elective bronchoscopy. It is recommended to hold vitamin K antagonist, as well as new oral anticoagulation agents prior to bronchoscopy. The timing for pre-procedural discontinuation of anticoagulation therapy and the decision to bridge depend on the agent used, the renal function and the thromboembolic risk. In this review article, we will discuss available data regarding management of anticoagulation and antiplatelet therapy as it applies to bronchoscopic procedures.

Boerhaave Syndrome Presenting as Tension Pneumothorax First Reported North American Case

Tension pneumothorax is a rare and potentially life-threatening clinical complication. A 43-year-old Caucasian woman with type 1 diabetes mellitus presented with nausea and retching and examination revealed dehydration. Laboratory parameters were consistent with a diagnosis of diabetic ketoacidosis, which responded to therapy. Suddenly, 30 hours later, she developed cardiorespiratory compromise due to a tension pneumothorax. After emergent decompression and catheter placement, computerized tomographic scan of the chest demonstrated esophageal-pleural fistula confirming Boerhaave syndrome as the etiology for the pneumothorax. The patient underwent emergent esophagectomy with pleural washout with a subsequent gastric pull-up surgery. Boerhaave syndrome frequently presents atypically with chest pain, dyspnea, and nausea. It communicates with the left pleural space in 80% to 90% of cases, but <5% of cases involve the right pleural cavity. Unexplained and rapidly progressive pleural effusions have been associated with this entity. Only 4 cases of Boerhaave syndrome causing tension pneumothorax have been reported in the literature so far.

Radial Probe Ultrasound-Guided Cryobiopsy.

Fluoroscopy-guided transbronchial forceps biopsy has a low diagnostic yield in patients with radiographic suspicion of interstitial lung disease. Cryobiopsy has a higher diagnostic yield likely due to preserved lung architecture and larger biopsies; however, there is an increased risk of major airway bleeding and pneumothorax. Simultaneous use of endobronchial balloon blocker allows for containment of bleeding after cryobiopsy to the affected lobe. In the current article we describe use of radial ultrasound in identification of a target lung parenchyma without a major blood vessel adjacent to distal bronchi. After fluoroscopic marking of the selected airway a 3 second cryobiopsy was performed after localization of cryoprobe. Simultaneous use of radial ultrasound and fluoroscopy can possibly decrease bleeding complication associated with cryobiopsy in patients with suspected interstitial lung disease.Fluoroscopy-guided transbronchial forceps biopsy has a low diagnostic yield in patients with radiographic suspicion of interstitial lung disease. Cryobiopsy has a higher diagnostic yield likely due to preserved lung architecture and larger biopsies; however, there is an increased risk of major airway bleeding and pneumothorax. Simultaneous use of endobronchial balloon blocker allows for containment of bleeding after cryobiopsy to the affected lobe. In the current article we describe use of radial ultrasound in identification of a target lung parenchyma without a major blood vessel adjacent to distal bronchi. After fluoroscopic marking of the selected airway a 3 second cryobiopsy was performed after localization of cryoprobe. Simultaneous use of radial ultrasound and fluoroscopy can possibly decrease bleeding complication associated with cryobiopsy in patients with suspected interstitial lung disease.

Transbronchial Saline Injection to Allow Visualization and Biopsy of Peripheral Lung Nodule on Linear Endobronchial Ultrasound.

Two peripheral lung nodules suspicious for lung cancer were noted in a patient. Surgical and CT-guided transthoracic needle biopsies were deemed to be high risk given advanced emphysema. The patient received nondiagnostic electromagnetic navigation bronchoscopy and endobronchial ultrasound (EBUS)-guided mediastinal needle biopsies. Repeat bronchoscopy was then performed. The lung nodules were difficult to visualize with both convex probe EBUS and electromagnetic navigation bronchoscopy guidance. Normal saline injection into vicinity of the peripheral lung nodule was then used in hopes of filling airspace with fluid and improving visualization of the lung nodule. After saline injection the nodule was visualized on convex probe EBUS, allowing for diagnostic needle aspirations.

Bent Metal in a Bone: A Rare Complication of an Emergent Procedure or a Deficiency in Skill Set?

Intraosseous (IO) access is an important consideration in patients with difficult intravenous (IV) access in emergent situations. IO access in adults has become more popular due to the ease of placement and high success rates. The most common sites of access include the proximal tibia and the humeral head. The complications associated are rare but can be catastrophic: subsequent amputation of a limb has been described in the literature. We report a 25-year-old female presenting with diabetic ketoacidosis (DKA) in whom emergent IO access was complicated by needle bending inside the humerus. Conventional bedside removal was impossible and required surgical intervention in operating room.

Release of Metal Particles From Needles Used for Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration

Release of metal particles into endobronchial ultrasoundguided transbronchial needle aspiration specimens by proprietary Olympus ViziShot needles (Olympus Ltd) has been demonstrated recently by Gounant et al 1 in a recent issue of CHEST (January 2011). Introduction of the same into mediastinal lymph nodes being sampled also appears to be likely. However, the mechanism and clinical signifi cance of such a phenomenon remains unclear. 2 Friction between the stylet and needle has been proposed as a potential source of metallic particulate matter production. We appreciate the effort of the researchers to look into the cause of excess dark metallic material noted on specimens, and we would like to share our experience. Several months ago, we started cleaning the stylet of the Olympus ViziShot needles with wet gauze during our procedures. We believed that a small amount of clotted blood in the working channel of the needle assembly was responsible for the progressive increase in resistance encountered during the insertion and removal of the stylet during procedures. We were surprised to see dark particles on the wet gauze mixed with small amounts of blood during several of our cases. Even when we cleaned the stylet before the procedure, a signifi cant amount of dark material was seen on the gauze ( Fig 1 ). This suggests that such particulate matter was present even prior to procedure initiation and could be due to friction between the stylet and the channel in the needle assembly unless it is some coating or lubricant on the stylet itself. We have also notifi ed Olympus of these fi ndings. Although the exact signifi cance and clinical implications of these fi ndings is not yet clear, they are clearly abnormal and are usually not seen with surgical instruments during other procedures. We applaud the authors for carefully studying this and bringing it to attention and hope that some minor changes in design many result in remediation of this concern.