Discovery of a Novel Pseudo-Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling.

The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.

Diagnostic Approach for Stroke Etiology in Takayasu Arteritis.

Takayasu arteritis (TA) is a rare inflammatory arteritis that is usually affecting young women and causes ischemic changes in the vessel wall. In this report of TA leading to an acute ischemic stroke, we describe a treatment-resistant case, with short interval flares and the challenge of defining the stroke etiology as a large vessel occlusive disease vs. an arteritis flare. We have used CT and MRI modalities to show the active disease and got diagnostic answers from this tool.

Anti-glutamate Dehydrogenase Antibody Positive Cerebellar Ataxia and Stiff Person Syndrome Responding to Dual Treatment with Steroids and Intravenous Immunoglobulin: A Case Presentation and Literature Review.

Anti-glutamic acid decarboxylase (anti-GAD) antibody syndrome (aGAS) has various presentations including cerebellar ataxia (CA) and stiff person syndrome (SPS). This is a treatable cause of CA and SPS. We present a case of a 49-year-old man who developed blurred vision, slurred speech, difficulty walking, unsteady gait, and clumsiness which had progressed over four months. The patient was found to have anti-GAD ab (+) CA and SPS and experienced significant symptomatic improvements after treatment with intravenous (IV) steroids followed by intravenous immunoglobulin (IVIG). The patient's improvement persisted when he was reevaluated at follow up one month later. Since anti-GAD ab related diseases, including anti-GAD CA and SPS, are rarely diagnosed, there is limited data regarding the treatment of this condition. As there are only a few cases in the literature similar to this one, highlighting the successful treatment of anti-GAD ab cerebellar ataxia and SPS with dual therapy (steroids followed by IVIG) is important.

Inter-predictability of Neuroprognostic Modalities After Cardiac Arrest.

Introduction At present, there is an emphasis on a multi-modal approach to neuro-prognostication after cardiac arrest using clinical examination, neurophysiologic testing, laboratory biomarkers, and radiological studies. However, this necessitates significant resource utilization and can be challenging in under-resourced clinical settings. Hence, we sought to determine the inter-predictability and correlation of prognostic tests performed in patients after cardiac arrest. Methods Fifty patients were included through neurophysiology laboratory data for this retrospective study. Clinical, radiological and neurophysiological data were collected. Neurophysiological data were re-evaluated by a board-certified neurophysiologist for the purpose of the study. Chi-square testing was used to evaluate the correlation between different diagnostic modalities. Results We found that a non-reactive electroencephalogram (EEG) had a predictive value of 79% for absent bilateral cortical responses (N20) with somatosensory evoked potentials (SSEP). On the other hand, absent bilateral cortical responses N20 had 87% predictive value for a non-reactive EEG. Also, absent cortical responses and non-reactive EEG had predictive values of 78% and 72% for anoxic injury on magnetic resonance imaging (MRI) brain respectively with a non-significant difference on chi-square testing. Individually, absent bilateral N20 SSEP, a non-reactive EEG and anoxic brain injury on MRI studies were highly predictive of poor outcome [modified Rankin scale (mRS) > 4] at hospital discharge. Conclusion Neuroprognostication in a post-cardiac arrest setting is often limited by self-fulfilling prophecy. Given the lack of absolute correlation between different modalities used in post-cardiac arrest patients, the value of the multi-modal approach to neuro-prognostication is highlighted by this study.

Diurnal pattern of seizures outside the hospital: is there a time of circadian vulnerability?

OBJECTIVE: To evaluate whether the distribution of seizures throughout the day is the same in ambulatory outpatient conditions as observed in inpatient conditions. METHODS: We analyzed records from consecutive patients who had ambulatory EEG monitoring for 24 to 72 hours using Digitrace™ EEG recording system. The participants maintained a log of symptoms and signaled the time when symptoms occurred by pushing an event button. Additionally, automatic seizure and spike detection was performed on each record using Persyst detection software. RESULTS: Of 831 reports analyzed, 44 unique patients had definite ictal events. There were a total of 129 electrographic seizures (34 subclinical) with timing as follows: frontal (31), temporal (71), and generalized, posterior, or central (27). Frontal lobe seizures occurred more frequently between 12 am and 12 pm as compared to temporal lobe seizures, which occurred more frequently between 12 pm and 12 am (p = 0.017). Analysis of frontal lobe seizures revealed a cluster of 10 seizures centered at 6:33 am (range 5:15-7:30 am) with p = 0.0064. Temporal lobe seizures had a cluster of 24 seizures centered at 8:49 pm (range 6:45-11:56 pm) with p = 0.0437. CONCLUSION: In ambulatory outpatient conditions, electrographic seizures follow day/night patterns similar to those observed in hospital conditions. Frontal seizures occur preferentially in the early morning hours and temporal lobe seizures occur in the early evening hours.