Treatment with the 5-Lipoxygenase Antagonist Zileuton Protects Mice from Postoperative Ileus.

INTRODUCTION: Previous work of our group showed that lipoxygenase (LOX) pathways become activated upon surgical manipulation of the bowel wall and revealed a beneficial immune modulating role of the LOX-derived anti-inflammatory mediator protectin DX in postoperative ileus (POI). While we found a particular role of 12/15-LOX in the anti-inflammatory LOX action during POI, the role of 5-LOX, which produces the pro-inflammatory leukotriene B4 (LTB4), remained unknown. The purpose of this study was to investigate the role of 5-LOX within the pathogenesis of POI in a mouse model. METHODS: POI was induced by intestinal manipulation (IM) of the small bowel in C57BL/6, 5-LOX-/-, and CX3CR1GFP/+. Mice were either treated with a vehicle or with the synthetic 5-LOX antagonist zileuton or were left untreated. Cellular localization of 5-LOX and LTB4 release were visualized by immunofluorescence or ELISA, respectively. POI severity was quantified by gastrointestinal transit (GIT) and leukocyte extravasation into the muscularis externa (ME) by immunohistochemistry. RESULTS: 5-LOX expression was detected 24 h after IM within infiltrating leukocytes in the ME. LTB4 levels increased during POI in wild type but not in 5-LOX-/- after IM. POI was ameliorated in 5-LOX-/- as shown by decreased leukocyte numbers and normalized GIT. Zileuton normalized the postoperative GIT and reduced the numbers of infiltrating leukocytes into the ME. DISCUSSION/CONCLUSION: Our data demonstrate that 5-LOX and its metabolite LTB4 play a crucial role in POI. Genetic deficiency of 5-LOX and pharmacological antagonism by zileuton protected mice from POI. 5-LOX antagonism might be a promising target for prevention of POI in surgical patients.

Comparison of a Continuous Noninvasive Temperature to Monitor Core Temperature Measures During Targeted Temperature Management.

BACKGROUND: Temperature modulating devices (TMD) currently utilize core temperature measurements during targeted temperature management (TTM) that are currently limited to esophageal (Et), bladder (Bt), or rectal (Rt) temperatures. We assessed the ability of a continuous noninvasive temperature monitor to accurately approximate core temperature during TTM. METHODS: All patients undergoing TTM using a gel pad surface TMD and an existing core temperature monitoring device were eligible for this study. Core and continuous noninvasive temperature monitoring values were simultaneously recorded for up to 72 h of TTM. The two sets of temperature data were downloaded from a clinical data acquisition storage system at 1-min intervals. The Bland-Altman method assessed agreement between the core and continuous noninvasive temperature monitor values, by measuring the mean difference (± 2 SD) between these values. RESULTS: There were 20 subjects that underwent study between January 2018 and March 2018 (55% women, age: 57 ± 14 years old, BMI: 28.9 + 9.8 kg/m2, 100% mechanically ventilated). The comparison patient temperature source was predominantly esophageal (n = 10) followed by bladder (n = 5) or rectal (n = 5). There were a total of 999 h of paired patient temperature data from esophageal (50%), bladder (25%), and rectal (25%) temperatures. Bland-Altman analysis demonstrated good agreement with the superficial temperature monitor and core temperature measures in all patients overall, with a difference mean of 0.06 ± 0.39 C (P = 0.99) and no proportional bias noted (ß =0.002, P = 0.917). CONCLUSIONS: Continuous noninvasive temperature monitoring is a suitable alternative method for assessing core temperature during TTM. Future studies should focus on developing connectivity with a continuous noninvasive temperature monitor to approximate core temperature during TTM.

Validation of seasonal mean radiant temperature simulations in hot arid urban climates.

We validated seasonal RayMan and ENVI-met mean radiant temperature (TMRT) simulations to assess model performance in a sensitivity analysis from cold to extremely hot conditions. Human-biometeorological validation data were collected in Tempe, Arizona via transects during five field campaigns between 2014 and 2017. Transects were conducted across seven locations in two to three-hour intervals from 6:00 to 23:00 LST with a Kestrel meter and thermal camera (2014-2015) and the mobile instrument platform MaRTy (2017). Observations across diverse urban forms, sky view factors, and seasons covered a wide range of solar radiation regimes from a minimum TMRT of 8.7 °C to a maximum of 84.9 °C. Both models produced large simulation errors across regimes with RMSE ranging from 8 °C to 12 °C (RayMan) and 11.2 °C to 16.1 °C (ENVI-met), exceeding a suggested TMRT accuracy of ±5 °C for heat stress studies. RayMan model errors were largest for engineered enclosed spaces, complex urban forms, and extreme heat conditions. ENVI-met was unable to resolve intra-domain spatial variability of TMRT and exhibited large errors with RMSE up to 25.5 °C for engineered shade. Both models failed to accurately simulate TMRT for hot conditions. Errors varied seasonally with overestimated TMRT in the summer and underestimated TMRT in the winter and shoulder seasons. Results demonstrate that models should not be used under micrometeorological or morphological extremes without in-situ validation to quantify errors and assess directional bias due to model limitations.

Evaluation of mismatch negativity as a marker for language impairment in autism spectrum disorder.

BACKGROUND: The identification of an early and objective marker of language impairment in autism spectrum disorder (ASD) has the potential to lead to earlier language intervention for affected children. The mismatch negativity (MMN), a passive auditory evoked potential, offers insight into the brain's ability to direct attention to novel sounds. Since exposure to speech is necessary for learning to map meaning onto phonemes, we predicted slower MMN responses to speech sounds would indicate presence of language impairment in ASD. METHODS: We explored the relationship between MMN latency in children ages 5-10 with ASD plus language impairment (ASD + LI), ASD minus language impairment (ASD-LI), and typically developing children (TD) during an auditory oddball experiment presenting speech and pure tone sounds. RESULTS: Contrary to our prediction, children with ASD + LI demonstrated decreased MMN latency in the left hemisphere in response to novel vowel sounds compared to children with ASD-LI and TD controls. Parent responses to the Sensory Experiences Questionnaire revealed that all participating individuals with ASD were hypersensitive to sounds. CONCLUSIONS: Our results lend support to the theory that some children with ASD + LI have increased connectivity in primary sensory cortices at the expense of connectivity to association areas of the brain. This may account for faster speech sound processing despite low language scores in these children. Future studies should focus on individuals with language impairment and hyper-or hyposensitivity to sounds.

Weighing the Cost and Benefit of Transcranial Direct Current Stimulation on Different Reading Subskills.

Adults struggling with low reading skills are underserved by limited available treatments. While brain stimulation techniques such as transcranial direct current stimulation (tDCS) has the potential to improve a variety of cognitive functions, little work has been done examining its potential to treat reading disabilities. Research on the effects of tDCS on reading abilities has been somewhat inconsistent perhaps in part due to discrepancies between studies in the nature of the tasks. In the current study, we examined the effect of tDCS to the left inferior parietal lobe (L IPL) on two reading tasks in low-to-average readers. We compared performance on a sight word efficiency (SWE) task and a rhyme judgment task before and after either stimulation to the L IPL, right superior parietal lobe (R SPL), or sham stimulation. Readers who received stimulation to the L IPL showed greater improvements on the SWE task, but less improvement on the rhyme judgment task compared to the R SPL and sham groups. This study demonstrates for the first time both a positive and negative effect of stimulation under the same stimulation parameters within the same participants. The results highlight the need to consider multiple tasks when assessing the potential of using tDCS as a treatment.

Cross-modal integration in the brain is related to phonological awareness only in typical readers, not in those with reading difficulty.

Fluent reading requires successfully mapping between visual orthographic and auditory phonological representations and is thus an intrinsically cross-modal process, though reading difficulty has often been characterized as a phonological deficit. However, recent evidence suggests that orthographic information influences phonological processing in typical developing (TD) readers, but that this effect may be blunted in those with reading difficulty (RD), suggesting that the core deficit underlying reading difficulties may be a failure to integrate orthographic and phonological information. Twenty-six (13 TD and 13 RD) children between 8 and 13 years of age participated in a functional magnetic resonance imaging (fMRI) experiment designed to assess the role of phonemic awareness in cross-modal processing. Participants completed a rhyme judgment task for word pairs presented unimodally (auditory only) and cross-modally (auditory followed by visual). For typically developing children, correlations between elision and neural activation were found for the cross-modal but not unimodal task, whereas in children with RD, no correlation was found. The results suggest that elision taps both phonemic awareness and cross-modal integration in typically developing readers, and that these processes are decoupled in children with reading difficulty.

Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.

PURPOSE: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. PATIENTS AND METHODS: This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. RESULTS: The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). CONCLUSION: Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma.

PURPOSE: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma. EXPERIMENTAL DESIGN: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m(2), whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m(2). Toxicity and response were assessed. RESULTS: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke. CONCLUSIONS: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.