Background Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics’ delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions. Methods Three groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5–8 × 10 7 MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed. Results In all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET. Conclusion Using [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials. Electronic supplementary material The online version of this article (10.1186/s12974-019-1543-z) contains supplementary material, which is available to authorized users. ...

The deadliest complication of Plasmodium falciparum infection is cerebral malaria (CM), with a case fatality rate of 15 to 25% in African children despite effective antimalarial chemotherapy. No adjunctive treatments are yet available for this devastating disease. We previously reported that the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) rescued mice from experimental CM (ECM) when administered late in the infection, a time by which mice had already suffered blood–brain barrier (BBB) dysfunction, brain swelling, and hemorrhaging. Herein, we used longitudinal MR imaging to visualize brain pathology in ECM and the impact of a new DON prodrug, JHU-083, on disease progression in mice. We demonstrate in vivo the reversal of disease markers in symptomatic, infected mice following treatment, including the resolution of edema and BBB disruption, findings usually associated with a fatal outcome in children and adults with CM. Our results support the premise that JHU-083 is a potential adjunctive treatment that could rescue children and adults from fatal CM.

SummaryPrecise methods for transgene regulation are important to study signaling pathways and cell lineages in biological systems where gene function is often recycled within and across lineages. We engineered a genetic toolset for flexible transgene regulation in these diverse cellular contexts. Specifically, we created an optimized piggyBac transposon-based system, allowing for the facile generation of stably transduced cell lineages in vivo and in vitro. The system, termed pB-Tet-GOI (piggyBac-transposable tetracycline transactivator-mediated flexible expression of a genetic element of interest), incorporates the latest generation of tetracycline (Tet) transactivator and reverse Tet transactivator variants—along with engineered mutants—in order to provide regulated transgene expression upon addition or removal of doxycycline (dox). Altogether, the flexibility of the system allows for dox-induced, dox-suppressed, dox-resistant (i.e., constitutive), and dox-induced/constitutive regulation of transgenes. This versatile strategy provides reversible temporal regulation of transgenes with robust inducibility and minimal leakiness.

BACKGROUND As the rate of elective cervical spine surgery increases, studies of complications may improve quality of care. Symptomatic postoperative cervical epidural hematomas (PCEH) are rare but result in significant morbidity. Because of their low incidence, the risk factors and complications associated with symptomatic PCEH remain unclear. OBJECTIVE To clarify the prevalence, timing, variables, and complications associated with PCEH following elective cervical spine surgery. METHODS Using the American College of Surgeons National Surgical Quality Improvement Program database, cervical spine surgeries performed between 2012 and 2016 were identified using Current Procedural Terminology codes. Symptomatic PCEH was defined as readmission or reoperation events specifically associated with International Classification of Diseases code diagnoses of postoperative hematoma within 30 d of index surgery. Multivariate models were created to assess the independent association of symptomatic PCEH with other postoperative complications. RESULTS There were 53233 patients included for analysis. The overall incidence of symptomatic PCEH was 0.4% (n = 198). Reoperation occurred in 158 cases (78.8%), of which 2 required a second reoperation (1.3%). The majority (91.8%) of hematomas occurred within 15 d of surgery. Multivariate analysis identified male gender, American Society of Anesthesiologists classes 3 to 5, bleeding disorder, increasing number of operative levels, revision surgery, dural repair, and perioperative transfusion as independent factors associated with PCEH. Upon controlling for those confounders, PCEH was independently associated with cardiac arrest, stroke, deep vein thrombosis, surgical site infection, and pneumonia. CONCLUSION Postoperative epidural hematomas requiring readmission or reoperation following elective cervical spine surgery occurred at an incidence of 0.4%. Symptomatic PCEHs are associated with increased rates of numerous major morbidities.

Background: Surgical site infections are common and costly complications after spine surgery. Prophylactic antibiotics are the standard of care; however, the appropriate duration of antibiotics has yet to be adequately addressed. We sought to determine whether the duration of antibiotic administration (preoperatively only versus preoperatively and for 24 hours postoperatively) impacts postoperative infection rates. Methods: All patients undergoing inpatient spinal procedures at a single institution from 2011 to 2018 were evaluated for inclusion. A minimum of 1 year of follow-up was used to adequately capture postoperative infections. The 1:1 nearest-neighbor propensity score matching technique was used between patients who did and did not receive postoperative antibiotics, and multivariable logistic regression analysis was conducted to control for confounding. Results: A total of 4,454 patients were evaluated and, of those, 2,672 (60%) received 24 hours of postoperative antibiotics and 1,782 (40%) received no postoperative antibiotics. After propensity-matched analysis, there was no difference between patients who received postoperative antibiotics and those who did not in terms of the infection rate (1.8% compared with 1.5%). No significant decrease in the odds of postoperative infection was noted in association with the use of postoperative antibiotics (odds ratio = 1.17; 95% confidence interval, 0.620 to 2.23; p = 0.628). Additionally, there was no observed increase in the risk of Clostridium difficile infection or in the short-term rate of infection with multidrug-resistant organisms. Conclusions: There was no difference in the rate of surgical site infections between patients who received 24 hours of postoperative antibiotics and those who did not. Additionally, we found no observable risks, such as more antibiotic-resistant infections and C. difficile infections, with prolonged antibiotic use. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.