Accuracy of Early Neuroprognostication in Pediatric Severe Traumatic Brain Injury.

BACKGROUND: Children with severe traumatic brain injury (sTBI) are at risk for neurological sequelae impacting function. Clinicians are tasked with neuroprognostication to assist in decision-making. We describe a single-center study assessing clinicians' neuroprognostication accuracy. METHODS: Clinicians of various specialties caring for children with sTBI were asked to predict their patients' functioning three to six months postinjury. Clinicians were asked to participate in the study if their patient had survived but not returned to baseline between day 4 and 7 postinjury. The outcome tool utilized was the functional status scale (FSS), ranging from 6 to 30 (best-worst function). Predicted scores were compared with actual scores three to six months postinjury. Lin concordance correlation coefficients were used to estimate agreement between predicted and actual FSS. Outcome was dichotomized as good (FSS 6 to 8) or poor (FSS ≥9). Positive and negative predictive values for poor outcome were calculated. Pessimistic prognostic prediction was defined as predicted worse outcome by ≥3 FSS points. Demographic and clinical variables were collected. RESULTS: A total of 107 surveys were collected on 24 patients. Two children died. Fifteen children had complete (FSS = 6) or near-complete (FSS = 7) recovery. Mean predicted and actual FSS scores were 10.8 (S.D. 5.6) and 8.6 (S.D. 4.1), respectively. Predicted FSS scores were higher than actual scores (P < 0.001). Eight children had collective pessimistic prognostic prediction. CONCLUSIONS: Clinicians predicted worse functional outcomes, despite high percentage of patients with near-normal function at follow-up clinic. Certain patient and provider factors were noted to impact accuracy and need to be studied in larger cohorts.

Chronotropic Incompetence During Exercise Testing as a Marker of Autonomic Dysfunction in Individuals with Early Parkinson's Disease.

BACKGROUND: An attenuated heart rate response to exercise, termed chronotropic incompetence, has been reported in Parkinson's disease (PD). Chronotropic incompetence may be a marker of autonomic dysfunction and a cause of exercise intolerance in early stages of PD. OBJECTIVE: To investigate the relationship between chronotropic incompetence, orthostatic blood pressure change (supine - standing), and exercise performance (maximal oxygen consumption, VO2peak) in individuals with early PD within 5 years of diagnosis not on dopaminergic medications. METHODS: We performed secondary analyses of heart rate and blood pressure data from the Study in Parkinson's Disease of Exercise (SPARX). RESULTS: 128 individuals were enrolled into SPARX (63.7±9.3 years; 57.0% male, 0.4 years since diagnosis [median]). 103 individuals were not taking chronotropic medications, of which 90 had a normal maximal heart rate response to exercise testing (155.3±14.0 bpm; PDnon-chrono) and 13 showed evidence of chronotropic incompetence (121.3±11.3 bpm; PDchrono, p < 0.05). PDchrono had decreased VO2peak compared to PDnon-chrono (19.7±4.5 mL/kg/min and 24.3±5.8 mL/kg/min, respectively, p = 0.027). There was a positive correlation between peak heart rate during exercise and the change in systolic blood pressure from supine to standing (r = 0.365, p < 0.001). CONCLUSIONS: A subgroup of individuals with early PD not on dopaminergic medication had chronotropic incompetence and decreased VO2peak, which may be related to autonomic dysfunction. Evaluation of both heart rate responses to incremental exercise and orthostatic vital signs may serve as biomarkers of early autonomic impairment and guide treatment. Further studies should investigate whether cardiovascular autonomic dysfunction affects the ability to exercise and whether exercise training improves autonomic dysfunction.

C-reactive protein as the biomarker of choice to monitor the effects of exercise on inflammation in Parkinson's disease.

Parkinson's disease (PD), a heterogeneous disease with no disease-modifying treatments available, is the fastest growing neurological disease worldwide. Currently, physical exercise is the most promising treatment to slow disease progression, with evidence suggesting it is neuroprotective in animal models. The onset, progression, and symptom severity of PD are associated with low grade, chronic inflammation which can be quantified by measuring inflammatory biomarkers. In this perspective, we argue that C-reactive protein (CRP) should be used as the primary biomarker for monitoring inflammation and therefore disease progression and severity, particularly in studies examining the impact of an intervention on the signs and symptoms of PD. CRP is the most studied biomarker of inflammation, and it can be detected using relatively well-standardized assays with a wide range of detection, allowing for comparability across studies while generating robust data. An additional advantage of CRP is its ability to detect inflammation irrespective of its origin and specific pathways, an advantageous characteristic when the cause of inflammation remains unknown, such as PD and other chronic, heterogeneous diseases.

Intrathecal Dexamethasone in Febrile Infection-Related Epilepsy Syndrome: A Case Report.

Objectives: Febrile infection-related epilepsy syndrome (FIRES) is characterized by explosive onset refractory status epilepticus (RSE) in healthy individuals that is refractory to antiseizure medication (ASM), continuous anesthetic infusions (CIs), and immunomodulators. Recently, a case series of patients receiving intrathecal dexamethasone (IT-DEX) was reported with improved RSE control. Methods: We present a child with FIRES with favorable outcome after receiving concomitant anakinra and IT-DaEX. A 9-year-old male patient presented with encephalopathy following a febrile illness. He developed seizures evolving to RSE refractory to multiple ASM, 3 CIs, steroids, IVIG, plasmapheresis, ketogenic diet (KD), and anakinra. After continued seizures and inability to wean off CI, IT-DEX was initiated. Results: He received 6 doses of IT-DEX with resolution of RSE, rapid wean off CI, and improved inflammatory markers. At discharge, he was ambulating with assistance, speaking 2 languages, and ingesting food orally. Discussion: FIRES is a neurologically devastating syndrome with high mortality and morbidity. Proposed guidelines and various treatment strategies are becoming available in the literature. Although treatment with KD, anakinra, and tocilizumab has been successful in previous FIRES cases, our results suggest that the addition of IT-DEX may allow for faster weaning off CI and better cognitive outcomes when initiated early in the course.

Drug-resistant seizures associated with hyperinflammatory monocytes in FIRES.

OBJECTIVE: Therapeutic strategies for patients with febrile infection-related epilepsy syndrome (FIRES) are limited, ad hoc, and frequently ineffective. Based on evidence that inflammation drives pathogenesis in FIRES, we used ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) to characterize the monocytic response profile before and after therapy in a child successfully treated with dexamethasone delivered intrathecally six times between hospital Day 23 and 40 at 0.25 mg/kg/dose. METHODS: PBMCs were isolated from serial blood draws acquired during refractory status epilepticus (RSE) and following resolution associated with intrathecal dexamethasone therapy in a previously healthy 9-year-old male that presented with seizures following Streptococcal pharyngitis. Cells were stimulated with bacterial or viral ligands and cytokine release was measured and compared to responses in age-matched healthy control PBMCs. Levels of inflammatory factors in the blood and CSF were also measured and compared to pediatric healthy control ranges. RESULTS: During RSE, serum levels of IL6, CXCL8, HMGB1, S100A8/A9, and CRP were significantly elevated. IL6 was elevated in CSF. Ex vivo stimulation of PBMCs collected during RSE revealed hyperinflammatory release of IL6 and CXCL8 in response to bacterial stimulation. Following intrathecal dexamethasone, RSE resolved, inflammatory levels normalized in serum and CSF, and the PBMC hyperinflammatory response renormalized. SIGNIFICANCE: FIRES may be associated with a hyperinflammatory monocytic response to normally banal bacterial pathogens. This hyperinflammatory response may induce a profound neutrophil burden and the consequent release of factors that further exacerbate inflammation and drive neuroinflammation. Intrathecal dexamethasone may resolve RSE by resetting this inflammatory feedback loop.

Altered sleep during spontaneous cannabinoid withdrawal in male mice.

Cessation of cannabinoid use in humans often leads to a withdrawal state that includes sleep disruption. Despite important health implications, little is known about how cannabinoid abstention affects sleep architecture, in part because spontaneous cannabinoid withdrawal is difficult to model in animals. In concurrent work we report that repeated administration of the high-efficacy cannabinoid 1 (CB1) receptor agonist AM2389 to mice for 5 days led to heightened locomotor activity and paw tremor following treatment discontinuation, potentially indicative of spontaneous cannabinoid withdrawal. Here, we performed parallel studies to examine effects on sleep. Using implantable electroencephalography (EEG) and electromyography (EMG) telemetry we examined sleep and neurophysiological measures before, during, and after 5 days of twice-daily AM2389 injections. We report that AM2389 produces decreases in locomotor activity that wane with repeated treatment, whereas discontinuation produces rebound increases in activity that persist for several days. Likewise, AM2389 initially produces profound increases in slow-wave sleep (SWS) and decreases in rapid eye movement (REM) sleep, as well as consolidation of sleep. By the third AM2389 treatment, this pattern transitions to decreases in SWS and total time sleeping. This pattern persists following AM2389 discontinuation and is accompanied by emergence of sleep fragmentation. Double-labeling immunohistochemistry for hypocretin/orexin (a sleep-regulating peptide) and c-Fos (a neuronal activity marker) in lateral hypothalamus revealed decreases in c-Fos/orexin+ cells following acute AM2389 and increases following discontinuation, aligning with the sleep changes. These findings indicate that AM2389 profoundly alters sleep in mice and suggest that sleep disruption following treatment cessation reflects spontaneous cannabinoid withdrawal.

Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses.

Brain kappa-opioid receptors (KORs) are implicated in the pathophysiology of depressive and anxiety disorders, stimulating interest in the therapeutic potential of KOR antagonists. Research on KOR function has tended to focus on KOR-expressing neurons and pathways such as the mesocorticolimbic dopamine system. However, KORs are also expressed on non-neuronal cells including microglia, the resident immune cells in the brain. The effects of KOR antagonists on microglia are not understood despite the potential contributions of these cells to overall responsiveness to this class of drugs. Previous work in vitro suggests that KOR activation suppresses proinflammatory signaling mediated by immune cells including microglia. Here, we examined how KOR antagonism affects microglia function in vivo, together with its effects on physiological and behavioral responses to an immune challenge. Pretreatment with the prototypical KOR antagonist JDTic potentiates levels of proinflammatory cytokines (IL-1ß, IL-6) in blood following administration of lipopolysaccharide (LPS), an immune-activating agent, without triggering effects on its own. Using magnetic-activated cell sorting (MACs), we found that KOR antagonism potentiates LPS-induced cytokine expression within microglia. This effect is accompanied by potentiation of LPS-induced hyperthermia, although reductions in body weight and locomotion were not affected. Histological analyses confirm that LPS produces visible changes in microglia morphology consistent with activation, but this effect is not altered by KOR antagonism. Considering that inflammation is increasingly implicated in depressive and anxiety disorders, these findings raise the possibility that KOR antagonist actions on microglia may detract from actions on neurons that contribute to their therapeutic potential.

Frequency of Positive Cuff Leak Test Before Extubation in Robotic Surgeries Done in Steep Trendelenburg Position.

Anaesthesia for robotic surgeries done in steep trendelenburg position are associated with risks such as facial oedema, conjunctival chemosis, raised intraocular pressure, laryngeal oedema, and delayed awakening. We proposed the use of the cuff leak test in them to record the frequency of laryngeal oedema at the end of surgery and attempted to find its correlation with probable risk factors. We conducted a prospective observational study of 100 patients aiming primarily to assess the frequency of positive cuff leak test in robotic abdominal surgeries performed in trendelenburg position. The secondary outcomes were to check its correlation with intravenous fluid administration, duration of pneumoperitoneum, and angle of trendelenburg position. We also recorded the frequency of chemosis, the frequency of post-extubation stridor in 24 h post-operatively, and the frequency of reintubation. Out of 100 participants undergoing elective abdominal robotic surgery in trendelenburg position, ninety were analysed. Total 31.6% (n = 30) participants showed positive cuff leak test. Chemosis was observed in 31 (32.6%) participants. No patient experienced post-extubation stridor or required reintubation during post-operative follow up. There was a no correlation between cuff leak test and intravenous fluid, duration of pneumo-peritoneum, or with angle of trendelenburg. The frequency of positive cuff leak test was high in patients at the end of robotic surgery but none of these patients had post-extubation stridor or required reintubations. There was no correlation with the fluid, angle, or duration of surgery. Clinical Trials Registry of India (CTRI/2017/04/008289), ctri.nic.in.

Apolipoprotein E-/- Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function.

OBJECTIVE: We previously reported that hemopexin (Hx), a heme scavenger, is significantly increased and associated with proinflammatory high-density lipoprotein under atherogenic conditions. Although it is established that Hx together with macrophages plays a role in mitigating oxidative damage, the role of Hx in the development of atherosclerosis is unknown. APPROACH AND RESULTS: We used Hx and apoE double-knockout mice (HxE(-/-)) to determine the role of Hx in the development of atherosclerosis. HxE(-/-) mice had significantly more free heme, reactive oxygen species, and proinflammatory high-density lipoprotein in their circulation, when compared with control apoE(-/-) mice. Atherosclerotic plaque area (apoE(-/-)=9.72±2.5×10(4) µm(2) and HxE(-/-)=27.23±3.6×10(4) µm(2)) and macrophage infiltration (apoE(-/-)=38.8±5.8×10(3) µm(2) and HxE(-/-)=103.4±17.8×10(3) µm(2)) in the aortic sinus were significantly higher in the HxE(-/-) mice. Atherosclerotic lesions in the aortas were significantly higher in the HxE(-/-) mice compared with apoE(-/-) mice. Analysis of polarization revealed that macrophages from HxE(-/-) mice were more M1-like. Ex vivo studies demonstrated that HxE(-/-) macrophage cholesterol efflux capacity was significantly reduced when compared with apoE(-/-) mice. Injection of human Hx into HxE(-/-) mice reduced circulating heme levels and human Hx pretreatment of naive bone marrow cells ex vivo resulted in a shift from M1- to M2-like macrophages. CONCLUSIONS: We conclude that Hx plays a novel protective role in alleviating heme-induced oxidative stress, improving inflammatory properties of high-density lipoprotein, macrophage phenotype and function, and inhibiting the development of atherosclerosis in apoE(-/-) mice.

Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases.

PURPOSE OF REVIEW: Hemoglobin and its scavenger proteins haptoglobin and hemopexin (Hx) associate with HDL and influence the inflammatory properties of HDL. Moreover, HDL from Hx-null mice is proinflammatory. In addition, Hx deficiency is implicated in a number of other inflammatory diseases such as septic shock and experimental autoimmune encephalomyelitis. This article highlights studies that demonstrate novel insights into the physiological protective role of Hx in inflammatory diseases. RECENT FINDINGS: Recent studies demonstrate that Hx-dependent uptake of extracellular heme leads to the deactivation of Bach1 repression leading to the transcriptional activation of antioxidant heme oxygenase-1 gene. Levels of circulating Hx have been implicated in the prognosis for patients with septic shock. In addition, Hx therapy has been shown to be beneficial in cardiovascular disease, cerebral ischemic injury, and experimental autoimmune encephalomyelitis. SUMMARY: These studies suggest that heme scavenging is a major mechanism by which Hx defends against oxidative stress and related inflammatory disorders. Hx therapy may provide a novel protective role against heme and oxidative stress-mediated inflammatory conditions including atherosclerosis.

Easy-to-implement oral cavity modification to expand simulation-based training in airway management.

INTRODUCTION: Injuries to the oral cavity and teeth can occur during routine intubation and general anesthesia but often occur in emergency situations when the priority of securing the airway supersedes preanesthetic evaluation. This study demonstrates the feasibility of modifying the oral cavity to increase the dental fidelity during emergency airway management. METHODS: A Laerdal Manikin was used to manipulate the preexisting Polyester (hard) and the Vinyl (flexible) dentition sets that are interchangeable among the Laerdal family of manikins. Items easily available in a dental laboratory such as dental acrylic and dental impression material were used to create modifications. RESULTS: Laerdal dentition sets were altered to simulate common dental (tooth-related) trauma encountered during intubation such as a fracture, luxation, or avulsion injuries. Anatomic variations such as carious (decayed) teeth, loose teeth, and class II malocclusion (overbite) were also fabricated. Tooth luxation was engineered to occur with pressure by a laryngoscope, and bleeding teeth were also created to demonstrate excessive pressure applied during direct laryngoscopy. It is feasible to improve the realism of the Laerdal family of manikins with simple modifications. CONCLUSIONS: This project proves the concept of feasibly fabricating anatomic variations to increase the fidelity of existing simulation manikins. Other anatomic variations present challenges to airway management, and future research will aim at creating additional modifications. In addition, future research will seek to quantify the improvement in airway management skills by anesthesia and emergency medicine providers by training on manikins with variable oral cavity anatomy.

Impact of restricted marital practices on genetic variation in an endogamous Gujarati group.

Recent studies have examined the influence on patterns of human genetic variation of a variety of cultural practices. In India, centuries-old marriage customs have introduced extensive social structuring into the contemporary population, potentially with significant consequences for genetic variation. Social stratification in India is evident as social classes that are defined by endogamous groups known as castes. Within a caste, there exist endogamous groups known as gols (marriage circles), each of which comprises a small number of exogamous gotra (lineages). Thus, while consanguinity is strictly avoided and some randomness in mate selection occurs within the gol, gene flow is limited with groups outside the gol. Gujarati Patels practice this form of "exogamic endogamy." We have analyzed genetic variation in one such group of Gujarati Patels, the Chha Gaam Patels (CGP), who comprise individuals from six villages. Population structure analysis of 1,200 autosomal loci offers support for the existence of distinctive multilocus genotypes in the CGP with respect to both non-Gujaratis and other Gujaratis, and indicates that CGP individuals are genetically very similar. Analysis of Y-chromosomal and mitochondrial haplotypes provides support for both patrilocal and patrilineal practices within the gol, and a low-level of female gene flow into the gol. Our study illustrates how the practice of gol endogamy has introduced fine-scale genetic structure into the population of India, and contributes more generally to an understanding of the way in which marriage practices affect patterns of genetic variation.

Prevalence of common disease-associated variants in Asian Indians.

BACKGROUND: Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity. RESULTS: We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (ALOX5), hypertension (CYP3A5, AGT, GNB3), diabetes (CAPN10, TCF7L2, PTPN22), prostate cancer (DG8S737, rs1447295), Hirschsprung disease (RET), and age-related macular degeneration (CFH, LOC387715). In addition, we examined polymorphisms associated with skin pigmentation (SLC24A5) and with the ability to taste phenylthiocarbamide (TAS2R38). All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of ALOX5 g.8322G>A and g.50778G>A, and PTPN22 g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (CYP3A5, AGT, GNB3), as well as for those associated with the ability to taste phenylthiocarbamide (TAS2R38). CONCLUSION: Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the design of future studies that investigate the genetic causes of these diseases in India. Our results also support the inclusion of the Indian population in disease-related genetic studies, as it exhibits unique genotype as well as phenotype characteristics that may yield new insights into the underlying causes of common diseases that are not available in other populations.

Acute plasmalemma permeability and protracted clearance of injured cells after controlled cortical impact in mice.

Cell death after traumatic brain injury (TBI) evolves over days to weeks. Despite advances in understanding biochemical mechanisms that contribute to posttraumatic brain cell death, the time course of cell injury, death, and removal remains incompletely characterized in experimental TBI models. In a mouse controlled cortical impact (CCI) model, plasmalemma permeability to propidium iodide (PI) was an early and persistent feature of posttraumatic cellular injury in cortex and hippocampus. In cortical and hippocampal brain regions known to be vulnerable to traumatic cell death, the number of PI+ cells peaked early after CCI, and increased with increasing injury severity in hippocampus but not cortex (P<0.05). Propidium iodide labeling correlated strongly with hematoxylin and eosin staining in injured cells (r=0.99, P<0.001), suggesting that plasmalemma damage portends fatal cellular injury. Using PI pulse labeling to identify and follow the fate of a cohort of injured cells, we found that many PI+ cells recovered plasmalemma integrity by 24 h and were terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling negative, but nonetheless disappeared from injured brain by 7 days. Propidium iodide-positive cells in dentate gyrus showed significant ultrastructural damage, including plasmalemma and nuclear membrane damage or overt membrane loss, in all cells when examined by laser capture microdissection and transmission electron microscopy 1 to 24 h after CCI. The data suggest that plasmalemma damage is a fundamental marker of cellular injury after CCI; some injured cells might have an extended window for potential rescue by neuroprotective strategies.