Anti-seizure medication treatment trials prior to pre-surgical evaluation.

Purpose: Our study evaluates patterns of anti-seizure medication (ASM) usage prior to pre-surgical evaluation in drug resistant epilepsy (DRE). Methods: We conducted a retrospective study of patients with DRE presenting for pre-surgical evaluation from 1/1/2017 to 12/31/2018. We abstracted demographic data, ASM usage, MRI and EEG findings, and distance from home to our center. Results: In total, 54 patients (23 female) were included. The mean number of ASM trials at the time of pre-surgical evaluation was 5.62 (±3.3; range 1-15). A mean of 0.4 ASMs (±1.1; range 0-6) were initiated at our center prior to pre-surgical evaluation. MRI localization to regions other than the hippocampal or temporal region (p = 0.002) was associated with higher numbers of ASM trials. A trend for a larger number of ASM trials was seen for increased distance of patient primary residence from our center, right-sided ictal EEG laterality, and posterior quadrant or non-localized ictal EEG patterns. Conclusions: Only 17% of patients were referred for pre-surgical evaluation after a trial of 1-2 ASMs. On average, patients tried 5.6 different ASMs with most of those trials predating referral to our center. Temporal lobe lesions were associated with fewer ASM trials prior to referral. Female sex was associated with an average of two more ASM trials than males. Our data do not allow us to determine how access to care, patient choice, and physician opinions impact the variability of ASM trials prior to referral for surgical evaluation. Our data indicate that delays to pre-surgical evaluation continue to occur.

Systolic blood pressure measurements are unreliable for the management of acute spontaneous intracerebral hemorrhage.

PURPOSE: Whether systolic blood pressure (SBP) is reliable in acute spontaneous intracerebral (sICH) by assessing agreement between simultaneous BP measurements obtained from cuff non-invasive blood pressure (NIBP) and radial arterial invasive blood pressure (AIBP) devices. MATERIAL AND METHODS: Among 766 prospectively screened sICH subjects, 303 (39.5%) had NIBP and AIBP measurements. During the first 24 h, 2157 simultaneous paired measurement readings were abstracted. Paired NIBP/AIBP measurements were included in a Bland-Altman technique with 95% agreement limits and coefficients from regression analysis derived from a bootstrap procedure. RESULTS: Variance for SBP was 66.1 mmHg, which was larger than the 44.3 mg Hg for diastolic blood pressure (DBP) or the 46.1 mmHg for mean arterial pressure (MAP). Pairwise comparison of mean biases showed a significant difference between SBP when compared to DBP (p < 0.0001) or MAP (p < 0.0001). The mean bias between DBP and MAP was not different (p = 0.68). Regression-based Bland Altman analysis found significant bias (slope -0.16, 95% CI -0.23, -0.09, p < 0.05) over the range of mean SBP. Bias over the range of mean DBP or MAP was not significant. CONCLUSIONS: We concluded that SBP is an unreliable blood pressure measurement in patients with sICH.

Phosphonate and Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthases: A Structure-Guided Perspective.

Phosphonates and bisphosphonates have proven their pharmacological utility as inhibitors of enzymes that metabolize phosphate and pyrophosphate substrates. The blockbuster class of drugs nitrogen-containing bisphosphonates represent one of the best-known examples. Widely used to treat bone-resorption disorders, these drugs work by inhibiting the enzyme farnesyl pyrophosphate synthase. Playing a key role in the isoprenoid biosynthetic pathway, this enzyme is also a potential anticancer target. Here, we provide a comprehensive overview of the research efforts to identify new inhibitors of farnesyl pyrophosphate synthase for various therapeutic applications. While the majority of these efforts have been directed against the human enzyme, some have been targeted on its homologs from other organisms, such as protozoan parasites and insects. Our particular focus is on the structures of the target enzymes and how the structural information has guided the drug discovery efforts.

Neurosarcoidosis in a public safety net hospital: a study of 82 cases.

OBJECTIVE: To characterize clinical presentation, laboratory and imaging data, and treatment outcomes for neurosarcoidosis in an urban safety net hospital. METHODS: The research database of Cook County Health and Hospitals system was queried for all cases of sarcoidosis from 2006 to 2013. These cases plus those identified through a survey of neurology faculty were reviewed and flagged if suspected to be neurosarcoidosis. Data were extracted in a standardized fashion, upon review by two experienced neurologists; patients were classified as definite, probable or possible neurosarcoidosis. Disagreements on classification were resolved by consensus conference. RESULTS: 1706 cases of sarcoidosis were identified, with 82 (4.8%) classified as neurosarcoidosis. The cohort was predominantly African American (89%). Six were classified as definite, 34 as probable, and 42 as possible neurosarcoidosis. Neurosarcoidosis was the presenting symptom of sarcoidosis in 74% of cases. The most common presenting phenotype was myelopathy (21.7%), followed by optic nerve/chiasm involvement (16.0%) and epilepsy (11.3%). The facial nerve was involved in only 2% of cases. Chest x-ray showed abnormalities of sarcoidosis in 43.3% of cases, while chest CT did so in 78.6%. Corticosteroids were the initial treatment in 91% of cases, and outcomes were good in 53% of cases. CONCLUSION: Neurosarcoidosis remains a challenging diagnosis with the majority of patients without a previous diagnosis of systemic sarcoidosis. Chest imaging was supportive of the diagnosis in a majority of patients. Our cohort differs from others in the literature due to a low prevalence of facial nerve involvement. Prospective registry studies are needed.

The Influence of Weather on the Incidence of Primary Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage has been associated with changes in various weather conditions. The primary aim of this study was to examine the collective influence of temperature, barometric pressure, and dew point temperature on the incidence of primary spontaneous intracerebral hemorrhage (sICH). METHODS: Between January 2013 and December 2016, patients with sICH due to hypertension or amyloid angiopathy with a known time of onset were identified prospectively. Meteorological variables 6 hours prior to time of onset were obtained from the National Oceanic Atmospheric Administration via two weather stations. Using a Monte-Carlo simulation, random populations of meteorological conditions in a 6-hour time window during the same years were generated. The actual meteorological conditions 6-hours prior to sICH were compared to those from the randomly generated populations. The false discovery rate method was used to identify significant meteorological variables. RESULTS: Time of onset was identified in 455 of 603 (75.5%) patients. Distribution curves for change in temperature, mean barometric pressure, and change in barometric pressure 6-hours prior to hemorrhage ictus were found to be significantly different from the random populations. (FDR approach P < .05). For a given change in temperature associated with intracerebral hemorrhage, mean barometric pressure was higher (1018 millibar (mb) versus 1016 mb, P = .03). Barometric pressure data was not influenced by variations in temperature. CONCLUSIONS: We concluded that barometric pressure primarily influences the incidence of intracerebral hemorrhage. The association described in the literature between temperature and intracerebral hemorrhage is likely confounded by variations in barometric pressure.

Escherichia coli AlkB and single-stranded DNA binding protein SSB interaction explored by Molecular Dynamics Simulation.

Repair of alkylation damage in DNA is essential for maintaining genome integrity. Escherichia Coli (E.coli) DNA repair enzyme AlkB removes methyl adducts including 1-methyladenine and 3-methylcytosine present in DNA by oxidative demethylation from single-stranded DNA (ssDNA). E. coli single-stranded DNA binding protein (SSB) selectively binds ssDNA in a sequence-independent manner. We have recently shown that AlkB can repair methyl adduct present in SSB-coated ssDNA. In this study, we aimed to elucidate details of AlkB-mediated DNA repair of SSB-bound DNA substrate. Therefore, we generated a structural model of AlkB-SSB-ssDNA and using Molecular Dynamics simulation analysis we show that flexibility of SSB-bound DNA allows AlkB to bind in multiple ways. Our docking analysis of AlkB-SSB-ssDNA structure revealed that the Cyt109 base is present in the hydrophobic cavity of AlkB active site pocket. The characterization of AlkB-SSB interaction pattern would likely to help in understanding the mode of alkylated DNA adduct recognition by AlkB.

Preferential binding of fullerene and fullerenol with the N-terminal and middle regions of amyloid beta peptide: an in silico investigation.

Amyloid beta (Aß) deposits are implicated in the pathogenesis of debilitating neurodegenerative disorders such as Alzheimer's disease. In the present study, the interactions of carbon-based nanoparticles (NPs) such as fullerene and fullerenol having different surface chemistry with Aß were investigated using molecular dynamics simulations and docking studies. A detailed analysis of docking results showed that in 68% of the Aß conformations, fullerene and fullerenol showed interactions with the N-terminal region of the peptide. However, the high-affinity binding site (E=-48.31 kJ/mol) of fullerene resides in the hydrophobic middle region of the peptide, whereas fullerenol interacts favorably with the charged N-terminal region with a binding energy of -50.42 kJ/mol. The above differences in binding could be attributed to the surface chemistry of fullerene and fullerenol. Moreover, the N-terminal and middle regions of Aß play an important role in Aß aggregation. Therefore, the binding of fullerene and fullerenol could inhibit amyloid aggregation. This information will be helpful in designing NPs for targeting amyloid-related disorders.