Faculty Bibliography

The alpha rhythm is the longest-studied brain oscillation and has been theorized to play a key role in cognition. Still, its physiology is poorly understood. In this study, we used microelectrodes and macroelectrodes in surgical epilepsy patients to measure the intracortical and thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in both visual and somatosensory cortex propagates from higher-order to lower-order areas. In posterior cortex, alpha propagates from higher-order anterosuperior areas toward the occipital pole, whereas alpha in somatosensory cortex propagates from associative regions toward primary cortex. Several analyses suggest that this cortical alpha leads pulvinar alpha, complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortical layers. Together, these results suggest that the alpha rhythm likely reflects short-range supragranular feedback, which propagates from higher- to lower-order cortex and cortex to thalamus. These physiological insights suggest how alpha could mediate feedback throughout the thalamocortical system.

PURPOSE/OBJECTIVE:Up to a third of patients with epilepsy suffer from recurrent seizures despite therapeutic advances. RESULTS:Current epilepsy treatments are limited by experiential data from treating different types of epilepsy. For example, we lack evidence-based approaches to efficacious multi-drug therapies or identifying potentially serious or disabling adverse events before medications are initiated. Despite advances in neuroscience and genetics, our understanding of epilepsy pathogenesis and mechanisms of treatment-resistance remains limited. For most patients with epilepsy, precision medicine for improved seizure control and reduced toxicity remains a future goal. CONCLUSION/CONCLUSIONS:A third of epilepsy patients suffer from ongoing seizures and even more suffer from adverse effects of treatment. There is a critical need for more effective and safer therapies for epilepsy patients with frequent comorbitidies, including depression, anxiety, migraine, and cognitive impairments, as well as special populations (e.g., women, elderly). Advances from genomic sequencing techniques may identify new genes and regulatory elements that influence both the depth of the epilepsies' roots within brain circuitry as well as ASD resistance. Improved understanding of epilepsy mechanisms, identification of potential new therapeutic targets, and their assessment in randomized controlled trials are needed to reduce the burden of refractory epilepsy.

The Global Navigation Satellite System (GNSS) is currently one of the important tools for landslide monitoring and early warning. However, the majority of GNSS devices are installed in mountainous areas and a variety of vegetation. These harsh environments lead to defective signals at high elevation angles, rendering real-time successive and reliable positioning results for monitoring difficult. In this study, an environmental model derived from signal-to-noise ratio (SNR) is proposed to enhance the precision and convergence time of positioning in harsh environments. A series of experiments are conducted on weighting and ambiguity-fixed models to evaluate performance. The results indicate that the proposed SNR-dependent environment model could lead to a significant improvement in precision and convergence time; with an obtained root mean squared result on the millimeter level, a convergence time of a few seconds, and utilization which could reach 100%, for continuous and reliable positioning results. These results indicate that the proposed SNR-dependent environment model enhances the performance of GNSS monitoring and early warning to provide continuous and reliable positioning results in real-time.

IDH1/2 mutations are early drivers present in diverse human cancer types arising in various tissue sites. IDH1/2 mutation is known to induce a global hypermethylator phenotype. However, the effects on DNA methylation across IDH mutant cancers and functionally different genome regions, remain unknown. We analyzed DNA methylation data from IDH1/2 mutant acute myeloid leukemia, oligodendroglioma, astrocytoma, solid papillary breast carcinoma with reverse polarity, sinonasal undifferentiated carcinoma and cholangiocarcinoma, which clustered by their embryonal origin. Hypermethylated common probes affect predominantly gene bodies while promoters in IDH1/2 mutant cancers remain unmethylated. Enhancers showed global hypermethylation, however commonly hypomethylated enhancers were associated with tissue differentiation and cell fate determination. We demonstrate that some chromosomes, chromosomal arms and chromosomal regions are more affected by IDH1/2 mutations while others remain resistant to IDH1/2 mutation induced methylation changes. Therefore IDH1/2 mutations have different methylation effect on different parts of the genome, which may be regulated by different mechanisms.

[Formula presented] BACKGROUND: We recently showed that patients with Sickle Cell Disease (SCD), a hereditary hemolytic disorder, have low incidence of HIV-1 infection [1] and reduced ex vivo HIV-1 infection [2]. PBMC from SCD patients exhibited increased expression of iron export protein, ferroportin and reduced cellular iron levels leading to CDK2 inhibition, reduced SAMHD1 phosphorylation and increased expression of IkBalpha. Ferroportin expression is regulated by liver-produced hepcidin that facilitates ferroportin internalization and degradation. Ferroportin Q248H mutation has an allele frequency of 2.2-13.4% in African populations. We previously reported reduced sensitivity of ferroportin Q248H mutant to physiologic hepcidin concentrations in patients with sickle cell disease [3]. XXOBJECTIVE(S): To analyze the effect of ferroportin Q248H mutation on HIV-1 infection in vitro and in disease progression among a cohort of HIV-1 infected African-American women. XXMETHOD(S): HEK293 cells were used to express ferroportin Q248H mutant and test cellular ferritin and intracellular labile iron using calcein-AM. Confocal microscopy was used to visualize ferroportin expression. HIV-1 transcription was measured in 293T cells transfected with HIV-1 LTR-Luciferase vector and Tat expressing vector. Ex vivo infection was analyzed in monocyte-derived macrophages infected with VSVg-pseudotyped HIV-1 virus. Ferroportin Q248H mutation was genotyped using Thermo Fisher probe (C_25753769_10) and genotyping services at University of Utah. XXRESULT(S): We observed reduced intracellular iron in ferroportin Q248H expressing cells compared to WT ferroportin even when the cells were treated with hepcidin. In the absence of hepcidin, both WT ferroportin and Q248H ferroportin efficiently inhibited HIV-1 transcription and replication. Hepcidin induced HIV-1 transcription and replication in the cells with WT ferroportin but not Q248H mutant ferroportin. HIV-1 replication was reduced in primary macrophages obtained from patients with ferroportin Q248H mutation. To test whether expression of ferroportin Q248H offered protection from HIV-1 infection, we analyzed a cohort of HIV-1 infected women (WIHS). We genotyped 970 African-American subjects of whom 628 were HIV-1 infected and 342 were non-infected. The prevalence of Q248H hetero or homozygote mutations was 7.0% in non-infected and 11.8% among HIV-1 infected individuals (Odds Ratio=1.77, p=0.02). Analysis of HIV viral load showed significant lower viral load in the subjects with ferroportin Q248H mutation compared to WT. XXCONCLUSION(S): Our findings point to the contribution of iron metabolism in HIV-1 restriction and the potential role of the ferroportin Q248H mutation in the regulation of HIV-1 infection in vivo. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, 5G12MD007597 and P30AI087714). We thank Women's Interagency HIV-1 study (WIHS) for sharing DNA samples and providing access to the clinical data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. REFERENCES: 1. Nouraie M, Nekhai S, Gordeuk VR. Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study. Sex Transm Infect. 2012;88(7):528-533. 2. Kumari N, Ammosova T, Diaz S, et al. Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease. Blood Adv. 2016;1(3):170-183. 3. Nekhai S, Xu M, Foster A, et al. Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin. Haematologica. 2013;98(3):455-463. Disclosures: Anastos: NINR: Research Funding; NHGRI: Research Funding; NICHD: Research Funding; NIMH: Research Funding; NHLBI: Research Funding; NCI: Research Funding; NIAID: Research Funding; NINDS: Research Funding; NIDCR: Research Funding; NIMHD: Research Funding; NLM: Research Funding; Fogarty: Research Funding; NIDDK: Research Funding; NIA: Research Funding; NIAAA: Research Funding; NIDA: Research Funding.XXCopyright

OBJECTIVE:There is a high risk of readmission within 30 days of index acute ischemic stroke (AIS), but effect of readmission to a different hospital is not known. We performed a retrospective cohort study to assess our hypothesis that 30-day readmission outcomes after AIS are worse for those readmitted to another hospital vs the discharging hospital. METHODS:We utilized the 2013 Nationwide Readmissions Database to identify patients with index stroke admissions with ICD-9-CM codes. We identified all-cause readmissions with Clinical Classification Software. Outcomes included length of stay (LOS), total charges of hospitalization, and in-hospital mortality during 30-day readmission. Using linear and logistic regression, outcomes were compared in those readmitted to another hospital vs the discharging hospital. RESULTS:= 0.0079). CONCLUSIONS:Readmission to another hospital within 30 days of AIS index admission was independently associated with longer LOS, increased total charges, and greater in-hospital mortality compared to readmission to the same hospital.

OBJECTIVE:Patients with medically refractory epilepsy often undergo intracranial electroencephalography (iEEG) monitoring to identify a seizure focus and determine their candidacy for surgical intervention. This clinically necessary monitoring period provides an increasingly utilized research opportunity to study human neurophysiology, however ethical concerns demand a thorough appreciation of the associated risks. We measured the incidence of research stimulation-associated seizures in a large multi-institutional dataset in order to determine whether brain stimulation was statistically associated with seizure incidence and identify potential risk factors for stimulation-associated seizures. APPROACH/METHODS:188 subjects undergoing iEEG monitoring across ten institutions participated in 770 research stimulation sessions over 3.5 yr. Seizures within 30 min of a stimulation session were included in our retrospective analysis. We analyzed stimulation parameters, seizure incidence, and typical seizure patterns, to assess the likelihood that recorded seizures were stimulation-induced, rather than events that occurred by chance in epilepsy patients prone to seizing. MAIN RESULTS/RESULTS:In total, 14 seizures were included in our analysis. All events were single seizures, and no adverse events occurred. The mean amplitude of seizure-associated stimulation did not differ significantly from the mean amplitude delivered in sessions without seizures. In order to determine the likelihood that seizures were stimulation induced, we used three sets of analyses: visual iEEG analysis, statistical frequency, and power analyses. We determined that three of the 14 seizures were likely stimulation-induced, five were possibly stimulation-induced, and six were unlikely stimulation-induced. Overall, we estimate a rate of stimulation-induced seizures between 0.39% and 1.82% of sessions. SIGNIFICANCE/CONCLUSIONS:The rarity of stimulation-associated seizures and the fact that none added morbidity or affected the clinical course of any patient are important findings for understanding the feasibility and safety of intracranial stimulation for research purposes.