An Exploratory Report on Electrographic Changes in the Cerebral Cortex Following Mild Traumatic Brain Injury with Hyperthermia in the Rat.

Traumatic brain injury (TBI) has the potential to perturb perception by disrupting electrical propagation within and between the thalamus and cerebral cortex. Moderate and severe TBI may result in posttraumatic epilepsy, a condition characterized by convulsive tonic-clonic seizures. Spike/wave discharges (SWDs) of generalized nonconvulsive seizures, also called absence seizures, may also occur as a consequence of brain trauma. As mild hyperthermia has been reported to exacerbate histopathological and behavioral outcomes, we used an unbiased algorithm to detect periodic increases in power across different frequency bands following single or double closed head injury (CHI) under normothermia and hyperthermia conditions. We demonstrated that mild TBI did not significantly alter the occurrence of events containing increases in power between the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta1 (12-20 Hz) frequency bands in the Sprague Dawley rat 12 weeks after injury. However, when hyperthermia (39°C) was induced before and after CHI, electrographic events containing a similar waveform and harmonic frequency to SWDs were observed in a subset of animals. Further experiments utilizing chronic recordings will need to be performed to determine if these trends lead to absence seizures.

Neurotherapeutic capacity of P7C3 agents for the treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a significant public health problem around the world. A promising area of research is the characterization of small, drug-like molecules that have potent clinical properties. One pharmacotherapeutic agent in particular, an aminopropyl carbazole called P7C3, was discovered using an in vivo screen to identify new agents that augmented the net magnitude of adult hippocampal neurogenesis. P7C3 greatly enhanced neurogenesis by virtue of increasing survival rates of immature neurons. The potent neuroprotective efficacy of P7C3 is likely due to enhanced nicotinamide phosphoribosyltransferase (NAMPT) activity, which supports critical cellular processes. The scaffold of P7C3 was found to have favorable pharmacokinetic properties, good bioavailability, and was nontoxic. Preclinical studies have shown that administration of the P7C3-series of neuroprotective compounds after TBI can rescue and reverse detrimental cellular events leading to improved functional recovery. In several TBI models and across multiple species, P7C3 and its analogues have produced significant neuroprotection, axonal preservation, robust increases in the net magnitude of adult neurogenesis, protection from injury-induced LTP deficits, and improvement in neurological functioning. This review will elucidate the exciting and diverse therapeutic findings of P7C3 administration in the presence of a complex and multifactorial set of cellular and molecular challenges brought forth by experimental TBI. The clinical potential and broad therapeutic applicability of P7C3 warrants much needed investigation into whether these remedial effects can be replicated in the clinic. P7C3 may serve as an important step forward in the design, understanding, and implementation of pharmacotherapies for treating patients with TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI.

Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including "The Lancet Neurology Commission" and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

Increased Expression of Epileptiform Spike/Wave Discharges One Year after Mild, Moderate, or Severe Fluid Percussion Brain Injury in Rats.

In this study, we describe increased expression of cortical epileptiform spike/wave discharges (SWD) in rats one year after mild, moderate, or severe fluid percussion traumatic brain injury (fpTBI). Groups of rats consisted of animals that had received mild, moderate, or severe fpTBI, or sham operation one year earlier than electrocorticography (ECoG) recordings. In addition, we included a group of age-matched naïve animals. ECoG was recorded from awake animals using epidural electrodes implanted on the injured hemisphere (right), sham-operated hemisphere (right), or right hemisphere in naïve animals. The SWDs were detected automatically using Fast Fourier Transformation and a novel algorithm for comparing changes in spectral power to control (nonepileptical) ECoG. The fpTBI resulted in increased expression of SWDs one year after injury compared with sham-operated or naïve animals. The number of SWD-containing ECoG epochs recorded in a 1 h recording session were: naïve 12.9 ± 10.3, n = 8, sham 23.6 ± 8.2, n = 10, mild TBI 78.9 ± 23.9, n = 10, moderate TBI 61.3 ± 32.5, n = 12, severe TBI 72.5 ± 28.3, n = 11 (mean ± standard error of the mean). Increased expression of SWDs was not related to injury severity. SWDs were observed to a lesser extent even in sham-operated and naïve animals. The data indicate that fpTBI exacerbates expression of SWDs in the rat and that this increase may be observed at least one year after injury. As others have discussed, the spontaneous occurrence of these epileptiform events in rodents limits the use of this model for investigations of acquired epilepsy, at least of the nonconvulsive type, after TBI.

Are unexpected positive dipstick urine bilirubin results clinically significant? A retrospective review.

BACKGROUND: Urine-bilirubin measurement is common in urinalysis dipsticks, which are known to yield a high rate of false positive results. We evaluated the usefulness of this test after multiple physicians in our system reported that they do not act on positive dipstick urine bilirubin findings. METHODS: We queried past records to determine how many samples with positive urine bilirubin results had associated abnormal results for liver function tests (LFTs) within 2 weeks before the positive urine bilirubin result. (LFTs included aspartate aminotransferase [AST], alanine transaminase [ALT], gamma-glutamyl transpeptidase [GGT], and total bilirubin.) We labeled positive results on these test as expected positives. We labeled the positive test results for samples from patients who had not had abnormal LFT results within 2 weeks before the current testing as unexpected positives. RESULTS: During a 20-month period, we performed 241,929 urine-bilirubin tests. Of these, 831 (0.3%) yielded positive results. Of these positives, 60% were from patients who had abnormal LFT results in the previous 2 weeks. The remaining 40% of positive results were deemed to be unexpected positives. Of these, 80% had had LFTs ordered within 2 weeks after the positive urine bilirubin results. A total of 85% of those LFTs yielded an abnormal result. CONCLUSION: In patients with an unexpected positive urine bilirubin test result, 85% had abnormal LFT results after their positive urine bilirubin result. However, these unexpected positives amounted to only 0.13% of all test results. Urine bilirubin does not appear to add significant information toward the diagnosis of most patients.

Studying the vendor perspective on clinical decision support.

In prior work, using a Rapid Assessment Process (RAP), we have investigated clinical decision support (CDS) in ambulatory clinics and hospitals. We realized that individuals in these settings provide only one perspective related to the CDS landscape, which also includes content vendors and electronic health record (EHR) vendors. To discover content vendors' perspectives and their perceived challenges, we modified RAP for industrial settings. We describe how we employed RAP, and show its utility by describing two illustrative themes. We found that while the content vendors believe they provide unique much-needed services, the amount of labor involved in content development is underestimated by others. We also found that the content vendors believe their products are resources to be used by practitioners, so they are somewhat protected from liability issues. To promote adequate understanding about these issues, we recommend a "three way conversation" among content vendors, EHR vendors, and user organizations.

Untreated peristomal skin complications among long-term colorectal cancer survivors with ostomies.

This ethnography of family caregiving explored why peristomal skin complications are common and undertreated among colorectal cancer survivors with intestinal ostomies. Data were collected through in-depth interviews with 31 cancer survivors and their family caregivers, fieldwork, structured assessments, and medical records review, and analyzed with qualitative theme and matrix analyses. Survivors who received help changing the skin barrier around their stoma had fewer obstacles to detection and treatment of peristomal skin complications. Half of the survivors received unpaid help with ostomy care, and all such help came from spouses. Married couples who collaborated in ostomy care reported that having assistance in placing the ostomy appliance helped with preventing leaks, detecting skin changes, and modifying ostomy care routines. In addition, survivors who struggled to manage ostomy care independently reported more obstacles to alleviating and seeking treatment for skin problems. Oncology nurses can improve treatment of peristomal skin problems by asking patients and caregivers about ostomy care and skin problems, examining the peristomal area, and facilitating routine checkups with a wound, ostomy, and continence nurse.