Longitudinal Course of Traumatic Brain Injury Biomarkers for the Prediction of Clinical Outcomes: A Review.

Protein biomarkers are often measured at hospital presentation to diagnose traumatic brain injury (TBI) and predict patient outcomes. However, a biomarker measurement at this single time point is no more accurate at predicting patient outcomes than less invasive and more cost-effective methods. Here, we review evidence that TBI biomarkers provide greater prognostic value when measured repeatedly over time, such that a trajectory of biomarker concentrations can be evaluated. PubMed, Google Scholar, and Cochrane Central Register were searched to identify studies from the last decade in which established TBI biomarkers had been measured at more than one time point following acute TBI, and which related their findings to patient outcomes. Twenty-two studies were identified, 18 of which focused on adults and 4 of which focused on children. Three general biomarker trajectories were identified: persistently high, persistently low, and reversal of decreasing concentrations. Downtrend reversal was highly specific to predicting poor patient outcomes. Four studies demonstrated that biomarker trajectories can be affected by therapeutic interventions. Additional studies demonstrated that biomarkers measured at a later time point offered superior prognostic value than a single measurement obtained at initial hospital presentation. Among other details, longitudinal biomarker trajectory assessments may identify ongoing injury and predict patient deterioration before clinical symptoms develop and thus help guide therapeutic interventions.

Ketamine Alters Hippocampal Cell Proliferation and Improves Learning in Mice after Traumatic Brain Injury.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Traumatic brain injury induces cellular proliferation in the hippocampus, which generates new neurons and glial cells during recovery. This process is regulated by N-methyl-D-aspartate-type glutamate receptors, which are inhibited by ketamine. The authors hypothesized that ketamine treatment after traumatic brain injury would reduce hippocampal cell proliferation, leading to worse behavioral outcomes in mice. METHODS: Traumatic brain injury was induced in mice using a controlled cortical impact injury, after which mice (N = 118) received either ketamine or vehicle systemically for 1 week. The authors utilized immunohistochemical assays to evaluate neuronal, astroglial, and microglial cell proliferation and survival 3 days, 2 weeks, and 6 weeks postintervention. The Morris water maze reversal task was used to assess cognitive recovery. RESULTS: Ketamine dramatically increased microglial proliferation in the granule cell layer of the hippocampus 3 days after injury (injury + vehicle, 2,800 ± 2,700 cells/mm, n = 4; injury + ketamine, 11,200 ± 6,600 cells/mm, n = 6; P = 0.012). Ketamine treatment also prevented the production of astrocytes 2 weeks after injury (sham + vehicle, 2,400 ± 3,200 cells/mm, n = 13; injury + vehicle, 10,500 ± 11,300 cells/mm, n = 12; P = 0.013 vs. sham + vehicle; sham + ketamine, 3,500 ± 4,900 cells/mm, n = 14; injury + ketamine, 4,800 ± 3,000 cells/mm, n = 13; P = 0.955 vs. sham + ketamine). Independent of injury, ketamine temporarily reduced neurogenesis (vehicle-exposed, 105,100 ± 66,700, cells/mm, n = 25; ketamine-exposed, 74,300 ± 29,200 cells/mm, n = 27; P = 0.031). Ketamine administration improved performance in the Morris water maze reversal test after injury, but had no effect on performance in sham-treated mice. CONCLUSIONS: Ketamine alters hippocampal cell proliferation after traumatic brain injury. Surprisingly, these changes were associated with improvement in a neurogenesis-related behavioral recall task, suggesting a possible benefit from ketamine administration after traumatic brain injury in mice. Future studies are needed to determine generalizability and mechanism.

Disease severity and treatment in adolescent idiopathic scoliosis: the impact of race and economic status.

BACKGROUND CONTEXT: Ethnic disparities have been documented in the incidence and treatment of many diseases. Additionally, race and socioeconomic status (SES) have been shown to affect disease severity and access to care in the recent orthopedic literature. PURPOSE: To assess the role, if any, that race, SES, and health insurance type play in disease severity and treatment decisions in patients with adolescent idiopathic scoliosis. STUDY DESIGN: Retrospective chart review. PATIENT SAMPLE: Pediatric patients seen in a single surgeon's practice over 6 years (2004-2009). OUTCOME MEASURES: Treatment modality (observation, bracing, or surgery). METHODS: Data were obtained from 403 patients seen over 6 years (2004-2009). A patient-reported questionnaire was used to collect race, age, family income, and parent marital status data. Race was self-reported as "Asian," "black or African American," "Hispanic or Latino," "white or Caucasian," or "Other." Socioeconomic status was determined using family income and type of health insurance as indicators. Major curve magnitude and prescribed initial treatment (observation, brace, or surgery) were assessed from physician records. An independent sample t test was used to detect differences in curve magnitude of the different racial groups. A Pearson chi-square analysis was used to detect group differences for curves in surgical patients, defined as curves greater than 40°, and their initial treatment. RESULTS: Patients self-identified with one of the following racial groups: white (N=219), black (N=86), Hispanic (N=44), Asian (N=37), or Other (N=17). Mean curve magnitude was greater in black than in white patients (33° vs. 28°, p<.05). Black patients were more likely to present with curves in the surgical range (34% vs. 24%, p<.05) and were more likely to have surgery as their initial treatment than white patients (34% vs. 19%, p<.05). Black patients had more limited health care plans and lower incomes compared with whites (p<.001). Patients with higher access insurance plans presented at a younger age than patients with more limited access plans, irrespective of race (13.6 vs. 14.1, p<.05). There was no difference in Cobb angle at presentation by income or type of insurance. CONCLUSIONS: Curve magnitude and percentage of patients with curves in the surgical range were greater in black than in white patients. There was no difference in age on presentation or treatment offered across all racial groups. Black patients were more likely to have surgery as their initial treatment than white patients. While race did have an impact on disease severity in this single surgeon's practice, SES did not.

Nutraceutical-mediated restoration of wild-type levels of IKBKAP-encoded IKAP protein in familial dysautonomia-derived cells.

SCOPE: The reported ability to modulate the production of the wild-type transcript in cells bearing the splice-altering familial dysautonomia (FD)-causing mutation in the IKBKAP gene prompted an evaluation of the impact of commonly consumed nutraceuticals on the splicing of this transcript. METHODS AND RESULTS: Screening efforts revealed the ability of the isoflavones, genistein, and daidzein, to impact splicing and increase the production of the wild-type, exon-20-containing, transcript, and the full-length IKBKAP-encoded IΚB kinase complex associated protein(IKAP) in FD-derived cells. Genistein was also found to impact splicing in neuronal cells, a cell type profoundly impacted by FD. The simultaneous exposure of FD-derived cells to genistein and epigallocatechin gallate (EGCG) resulted in the almost exclusive production of the exon-20-containing transcript and the production of wild-type amounts of IKAP protein. CONCLUSION: This study represents the first demonstration that the isoflavones, genistein and daidzein, possess splice-altering capabilities and that simultaneous treatment with genistein and EGCG reverses the splice-altering impact of the FD-causing mutation. These findings support the clinical evaluation of the therapeutic impact of the combined administration of these two commonly consumed nutraceuticals on this patient population and suggest a broader evaluation of the impact of these nutraceuticals on the in vivo RNA splicing process.