Cardiac Arrest Following Drug Abuse with Intravenous Tapentadol: Case Report and Literature Review.

BACKGROUND Tapentadol is a centrally acting opioid analgesic, with a dual mode of action, as a norepinephrine reuptake inhibitor and an agonist of the µ-opioid receptor (MOR). Tapentadol is used for the management of musculoskeletal pain, and neuropathic pain associated with diabetic peripheral neuropathy. CASE REPORT A 32-year-old woman attended hospital for evaluation of an intractable headache. Computed tomography and magnetic resonance imaging of the brain were negative. She was found unresponsive in the bathroom on the day following hospital admission, and despite resuscitative measures, the patient died following cardiac arrest. Autopsy toxicology revealed significantly elevated levels of tapentadol, and bedside evidence suggested that the patient had self-administered this medication intravenously before her death. CONCLUSIONS We report a rare adverse effect of tapentadol causing respiratory depression leading to cardiac arrest. Medical examiners and forensic toxicologists should be aware of the toxicity of this novel opiate drug.

Expressive aphasia caused by Streptococcus intermedius brain abscess in an immunocompetent patient.

BACKGROUND: Brain abscess is an uncommon but life-threatening infection. It involves a focal, intracerebral infection that begins in a localized area of cerebritis and develops into a collection of pus, surrounded by a well-vascularized capsule. Brain abscess still poses a significant problem in developing countries but rarely in developed countries. Predisposing factors vary in different parts of the world. With the introduction of antibiotics and imaging studies, the mortality rate has decreased between 5% and 15%. If left untreated it may lead to serious neurologic sequelae. The temporal lobe abscess can be caused by conditions like sinusitis, otitis media, dental infections, and mastoiditis if left untreated or partially treated. Additionally, in neurosurgical procedures like craniotomy, the external ventricular drain can get infected, leading to abscess formation. CASE PRESENTATION: We present the case study of an elderly female patient who presented with expressive aphasia caused by brain abscess, secondary to Streptococcus intermedius infection. The 72-year-old female with a medical history of hypertension came to hospital for evaluation with word-finding difficulty, an expressive aphasia that began a few days prior to presentation. Computed tomography of the head showed a left temporal lobe mass-like lesion, with surrounding vasogenic edema. The patient was empirically started on courses of antibiotics. The next day, she was subjected to magnetic resonance imaging of the brain, which showed a left temporal lobe septated rim-enhancing mass lesion, with bright restricted diffusion and diffuse surrounding vasogenic edema consistent with abscess. The patient was also seen by the neurosurgery department and underwent stereotactic, left temporal craniotomy, with drainage, and resection of abscess. Tissue culture grew S. intermedius sensitive to ampicillin sulbactam. Subsequently her expressive aphasia improved. CONCLUSION: Brain abscess has a high mortality, however a significant proportion of patients with appropriately treated abscess recover completely and can survive without significant neurologic damage. Advanced imaging modalities may yield more accurate methods of differentiation of mass lesions in the brain. Biopsy of brain lesion with early initiation of appropriate antibiotics will change the outcome.

Early Warning/Track-and-Trigger Systems to Detect Deterioration and Improve Outcomes in Hospitalized Patients.

As a global effort toward improving patient safety, a specific area of focus has been the early recognition and rapid intervention in deteriorating ward patients. This focus on "failure to rescue" has led to the construction of early warning/track-and-trigger systems. In this review article, we present a description of the data behind the creation and implementation of such systems, including multiple algorithms and strategies for deployment. Additionally, the strengths and weaknesses of the various systems and their evaluation in the literature are emphasized. Despite the limitations of the current literature, the potential benefit of these early warning/track-and-trigger systems to improve patient outcomes remains significant.

Vasospasm Risk in Surgical ICU Patients With Grade I Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is associated with high mortality. The initial hemorrhage causes death in approximately 25% of patients, with most subsequent mortality being attributable to delayed cerebral ischemia (DCI). Delayed cerebral ischemia generally occurs on post-bleed days 4 through 20, with the incidence peaking at day 8. Because of the risks of DCI, patients with SAH are usually monitored in an intensive care unit (ICU) for 14 to 21 days. Unfortunately, prolonged ICU admissions are expensive and are associated with well-documented risks to patients. We hypothesized that a subset of patients who are at low risk of DCI should be safe to transfer out of the ICU early. All patients admitted to Montefiore Medical Center from 2008 to 2013 with grade I SAH who had their aneurysms successfully protected, had an uncomplicated postoperative course, and had no clinical or ultrasonographic evidence of DCI after day 8 were retrospectively studied. The primary outcome was clinical or ultrasonographic evidence of the development of DCI after day 8. Secondary outcomes included length of ICU and hospital stay and hospital mortality. Forty patients who met the above-mentioned criteria were identified. Of these, only 1 (2.5%) developed ultrasonographic evidence of DCI after day 8 but required no intervention. The mean length of stay in the ICU was until post-bleed day 13, and the mean hospital length of stay was until post-bleed day 14. The in-hospital mortality was 0 of 40. Thus, we identified a low-risk subset of patients with grade I SAH who may be candidates for early transfer out of the ICU.

Anti-ß2GPI antibodies stimulate endothelial cell microparticle release via a nonmuscle myosin II motor protein-dependent pathway.

The antiphospholipid syndrome is characterized by thrombosis and recurrent fetal loss in patients with antiphospholipid antibodies (APLAs). Most pathogenic APLAs are directed against ß2-glycoprotein I (ß2GPI), a plasma phospholipid binding protein. One mechanism by which circulating antiphospholipid/anti-ß2GPI antibodies may promote thrombosis is by inducing the release of procoagulant microparticles from endothelial cells. However, there is no information available concerning the mechanisms by which anti-ß2GPI antibodies induce microparticle release. In seeking to identify proteins phosphorylated during anti-ß2GPI antibody-induced endothelial activation, we observed phosphorylation of nonmuscle myosin II regulatory light chain (RLC), which regulates cytoskeletal assembly. In parallel, we observed a dramatic increase in the formation of filamentous actin, a two- to fivefold increase in the release of endothelial cell microparticles, and a 10- to 15-fold increase in the expression of E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and tissue factor messenger RNA. Microparticle release, but not endothelial cell surface E-selectin expression, was blocked by inhibiting RLC phosphorylation or nonmuscle myosin II motor activity. These results suggest that distinct pathways, some of which mediate cytoskeletal assembly, regulate the endothelial cell response to anti-ß2GPI antibodies. Inhibition of nonmuscle myosin II activation may provide a novel approach for inhibiting microparticle release by endothelial cells in response to anti-ß2GPI antibodies.

The actin cytoskeleton regulates exocytosis of all neutrophil granule subsets.

A comprehensive analysis of the role of the actin cytoskeleton in exocytosis of the four different neutrophil granule subsets had not been performed previously. Immunoblot analysis showed that, compared with plasma membrane, there was less actin associated with secretory vesicles (SV, 75%), gelatinase granules (GG, 40%), specific granules (SG, 10%), and azurophil granules (AG, 5%). Exocytosis of SV, SG, and AG was measured as increased plasma membrane expression of CD35, CD66b, and CD63, respectively, with flow cytometry, and GG exocytosis was measured as gelatinase release with an ELISA. N-formylmethionyl-leucyl-phenylalanine (FMLP) stimulated exocytosis of SV, GG, and SG with an ED(50) of 15, 31, and 28 nM, respectively, with maximal response at 10(-7) M FMLP by 5 min, while no exocytosis of AG was detected. Disruption of the actin cytoskeleton by latrunculin A and cytochalasin D induced a decrease in FMLP-stimulated CD35 expression after an initial increase. Both drugs enhanced the rate and extent of FMLP-stimulated GG, SG, and AG exocytosis, while the EC(50) for FMLP was not altered. We conclude that the actin cytoskeleton controls access of neutrophil granules to the plasma membrane, thereby limiting the rate and extent of exocytosis of all granule subsets. Differential association of actin with the four granule subsets was not associated with graded exocytosis.

Proteomic analysis of human neutrophils.

Proteomics is the study of the set of proteins, or proteome, expressed by a cell under specific conditions. Proteomics methodology consists of protein extraction, protein separation, and protein identification. Currently, two-dimensional gel electrophoresis (2DE) and matrix-assisted laser-desorption ionization time of flight mass spectrometry are the most widespread methods for proteomic studies. The recent introduction of precast immobilized pH gradient gel strips, precast gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels, and well-designed electrophoresis equipment has made 2DE a highly reproducible and relatively simple method for protein separation. Inherent limitations of the procedure, however, require approaches in sample preparation that may be cell- or tissue-dependent. This chapter describes a methodology for proteomic analysis of human neutrophils and discusses its applications.

Proteomic analysis of human neutrophil granules.

Stimulated exocytosis of intracellular granules plays a critical role in conversion of inactive, circulating neutrophils to fully activated cells capable of chemotaxis, phagocytosis, and bacterial killing. The functional changes induced by exocytosis of each of the granule subsets, gelatinase (tertiary) granules, specific (secondary) granules, and azurophil (primary) granules, are poorly defined. To improve the understanding of the role of exocytosis of these granule subsets, a proteomic analysis of the azurophil, specific, and gelatinase granules from human neutrophils was performed. Two different methods for granule protein identification were applied. First, two-dimensional (2D) gel electrophoresis followed by MALDI-TOF MS analysis of peptides obtained by in-gel trypsin digestion of proteins was performed. Second, peptides from tryptic digests of granule membrane proteins were separated by two-dimensional microcapillary chromatography using strong cation exchange and reverse phase microcapillary high pressure liquid chromatography and analyzed with electrospray ionization tandem mass spectrometry (2D HLPC ESI-MS/MS). Our analysis identified 286 proteins on the three granule subsets, 87 of which were identified by MALDI MS and 247 were identified by 2D HPLC ESI-MS/MS. The increased sensitivity of 2D HPLC ESI-MS/MS, however, resulted in identification of over 500 proteins from subcellular organelles contaminating isolated granules. Defining the proteome of neutrophil granule subsets provides a basis for understanding the role of exocytosis in neutrophil biology. Additionally, the described methods may be applied to mobilizable compartments of other secretory cells.

Myeloid-related protein-14 is a p38 MAPK substrate in human neutrophils.

The targets of the p38 MAPK pathway that mediate neutrophil functional responses are largely unknown. To identify p38 MAPK targets, a proteomic approach was applied in which recombinant active p38 MAPK and [(32)P]ATP were added to lysates from unstimulated human neutrophils. Proteins were separated by two-dimensional gel electrophoresis, and phosphoproteins were visualized by autoradiography and identified by MALDI-TOF. Myeloid-related protein-14 (MRP-14) was identified as a candidate p38 MAPK substrate. MRP-14 phosphorylation by p38 MAPK was confirmed by an in vitro kinase reaction using purified MRP-14/MRP-8 complexes. The site of MRP-14 phosphorylation by p38 MAPK was identified by tandem mass spectrometry and site-directed mutagenesis to be Thr(113). MRP-14 phosphorylation by p38 MAPK in intact neutrophils was confirmed by [(32)P]orthophosphate loading, followed by fMLP stimulation in the presence and absence of a p38 MAPK inhibitor, SB203580. Confocal microscopy of Triton X-100 permeabilized neutrophils showed that a small amount of MRP-14 was associated with cortical F-actin in unstimulated cells. fMLP stimulation resulted in a p38 MAPK-dependent increase in MRP-14 staining at the base of lamellipodia. By immunoblot analysis, MRP-14 was present in plasma membrane/secretory vesicle fractions and gelatinase and specific granules, but not in azurophil granules. The amount of MRP-14 associated with plasma membrane/secretory vesicle and gelatinase granule fractions increased after fMLP stimulation in a p38 MAPK-dependent manner. Direct phosphorylation of the MRP-14/MRP-8 complex by p38 MAPK increased actin binding in vitro by 2-fold. These results indicate that MRP-14 is a potential mediator of p38 MAPK-dependent functional responses in human neutrophils.