NK cell expression of Tim-3: First impressions matter.

Given the heightened interest in manipulation of co-signaling cascades for cancer immunotherapy, we sought to determine how/whether tumors decorated with therapeutic monoclonal antibodies (mAbs) impact the expression of co-signaling molecules on human NK cells. Stimulation of NK cells with aggregated IgG1 resulted in the upregulation of HAVCR2 - the gene encoding T-cell immunoglobulin and mucin-containing domain (Tim)-3 - known to be involved in the induction of peripheral T cell tolerance. This upregulation of HAVCR2 was recapitulated at the protein level, following NK cell stimulation by either mAb opsonized tumors, recombinant human IgG1 Fc multimer, and/or non-Fc stimuli e.g. IL-12/IL-18. The patterns of Tim-3 expression were temporally distinct from the FcR mediated induction of the co-signaling molecule, 4-1BB (CD137), with Tim-3 increases observed twenty minutes following exposure to Fc multimers and remaining at high levels for at least six hours, while increases in CD137 expression were first observed at the four-hour time point. Importantly, these Tim-3+ NK cells were functionally diverse, as evidenced by the fact that their ability to produce IFN-γ in response to an NK cell responsive tumor was strictly dependent upon the stimuli employed for Tim-3 induction. These data suggest that Tim-3 upregulation is the common end-result of NK cell activation by a variety of unique and overlapping stimuli and is not an independent marker of NK cell exhaustion. Furthermore, our observations potentially explain the diverse functionality attributed to Tim-3+ NK cells and should be considered prior to use of anti-Tim-3 inhibitory mAbs for cancer immunotherapy.

Bradycardia Associated with Steroid Use for Laryngeal Edema in an Adult: A Case Report and Literature Review.

Steroids are used for specific indications in the perioperative period to reduce laryngeal or spinal cord edema, or for prophylaxis and treatment of postoperative nausea and vomiting. Given the other potential causes for hemodynamic alterations in the perioperative setting, it is important for physicians to be aware of cardiovascular side effects of short term steroids. Changes in blood pressure and heart rate, cardiac dysrhythmias, and even death have been described in patients receiving short term intravenous steroids. Bradycardia has been reported following short term methylprednisolone and dexamethasone therapy in both adult and pediatric patients. There are only two case reports in the literature of bradycardia following short term intravenous dexamethasone use in adult patients. This is the first case report that describes bradycardia following the use of dexamethasone in the postoperative setting for management of laryngeal edema in an adult. Telemetry and twelve lead electrocardiograms revealed sinus bradycardia and correlated directly with administration of dexamethasone in our patient. Bradycardia resolved following discontinuation of dexamethasone. We advocate for hemodynamic monitoring in patients receiving more than one dose of intravenous steroid therapy in the perioperative period, especially those with known cardiac and hepatic comorbidities and those taking medications with negative chronotropic effects.

Complications Associated with Decompressive Craniectomy: A Systematic Review.

Decompressive craniectomy (DC) has been used for many years in the management of patients with elevated intracranial pressure and cerebral edema. Ongoing clinical trials are investigating the clinical and cost effectiveness of DC in trauma and stroke. While DC has demonstrable efficacy in saving life, it is accompanied by a myriad of non-trivial complications that have been inadequately highlighted in prospective clinical trials. Missing from our current understanding is a comprehensive analysis of all potential complications associated with DC. Here, we review the available literature, we tabulate all reported complications, and we calculate their frequency for specific indications. Of over 1500 records initially identified, a final total of 142 eligible records were included in our comprehensive analysis. We identified numerous complications related to DC that have not been systematically reviewed. Complications were of three major types: (1) Hemorrhagic (2) Infectious/Inflammatory, and (3) Disturbances of the CSF compartment. Complications associated with cranioplasty fell under similar major types, with additional complications relating to the bone flap. Overall, one of every ten patients undergoing DC may suffer a complication necessitating additional medical and/or neurosurgical intervention. While DC has received increased attention as a potential therapeutic option in a variety of situations, like any surgical procedure, DC is not without risk. Neurologists and neurosurgeons must be aware of all the potential complications of DC in order to properly advise their patients.