A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis.

Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.

Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability and increased thrombotic risk in critically ill patients. To our knowledge, no studies have evaluated whether aspirin use is associated with reduced risk of mechanical ventilation, intensive care unit (ICU) admission, and in-hospital mortality. METHODS: A retrospective, observational cohort study of adult patients admitted with COVID-19 to multiple hospitals in the United States between March 2020 and July 2020 was performed. The primary outcome was the need for mechanical ventilation. Secondary outcomes were ICU admission and in-hospital mortality. Adjusted hazard ratios (HRs) for study outcomes were calculated using Cox-proportional hazards models after adjustment for the effects of demographics and comorbid conditions. RESULTS: Four hundred twelve patients were included in the study. Three hundred fourteen patients (76.3%) did not receive aspirin, while 98 patients (23.7%) received aspirin within 24 hours of admission or 7 days before admission. Aspirin use had a crude association with less mechanical ventilation (35.7% aspirin versus 48.4% nonaspirin, P = .03) and ICU admission (38.8% aspirin versus 51.0% nonaspirin, P = .04), but no crude association with in-hospital mortality (26.5% aspirin versus 23.2% nonaspirin, P = .51). After adjusting for 8 confounding variables, aspirin use was independently associated with decreased risk of mechanical ventilation (adjusted HR, 0.56, 95% confidence interval [CI], 0.37-0.85, P = .007), ICU admission (adjusted HR, 0.57, 95% CI, 0.38-0.85, P = .005), and in-hospital mortality (adjusted HR, 0.53, 95% CI, 0.31-0.90, P = .02). There were no differences in major bleeding (P = .69) or overt thrombosis (P = .82) between aspirin users and nonaspirin users. CONCLUSIONS: Aspirin use may be associated with improved outcomes in hospitalized COVID-19 patients. However, a sufficiently powered randomized controlled trial is needed to assess whether a causal relationship exists between aspirin use and reduced lung injury and mortality in COVID-19 patients.

Quality of life assessment for patients undergoing irreversible electroporation (IRE) for treatment of locally advanced pancreatic cancer (LAPC).

BACKGROUND: IRE is a non-thermal ablative modality that has been shown to be safe and efficacious in LAPC and liver tumors, but few studies have shown its effects on patients' (QOL). The goal of this study is to evaluate quality-of-life (QOL) before and after irreversible electroporation (IRE) therapy for treatment of locally advanced pancreatic carcinoma (LAPC). METHODS: Between 11/2014 and 12/2016, patients scheduled for IRE therapy for LAPC were offered QOL questionnaires (EORTC QLQ-C30 V2.0) before surgery and 1,3 and 6-months after surgery. Descriptive statistics, one-way ANOVA and effect-size calculations were used in analysis of the 15 modules. RESULTS: Eight-four prospective patients were enrolled with a median age of 59.08 years (range 27.38-75.72) all who completed 6 months QOL surveys. Global health status scale showed lower average score at 3 and 6 months(p = 0.001). Symptoms scales constipation and insomnia showed higher averages at 3 months (p = 0.007 and p = 0.003 respectively), while dyspnea had higher average at 6 months (p < 0.001). Finally, changes were noted with worse diarrhea symptoms scale at 1 and 3 months (p < 0.001). Otherwise all QOL side effects were normalized at 3 months after IRE. CONCLUSIONS: The preponderance of symptoms at 3-6 months, symptom profile, and the use of additional therapy on majority of patients suggests other interrelated clinical factors influenced results (e.g. chemotherapy toxicity). This demonstrates that IRE therapy does not adversely affect QOL in the short term in patients with LAPC.

Wide versus narrow margins after partial hepatectomy for hepatocellular carcinoma: Balancing recurrence risk and liver function.

BACKGROUND: The goal of this study was to compare the outcome after partial hepatectomy for hepatocellular carcinoma (HCC) in which a margin less than or equal to 5 mm or greater than 5 mm was achieved. METHODS: A review of our 3300-patient prospective HPB database was performed from 12/2002 to 4/2015. Patients were stratified into two groups: resection margins ≤5 ("narrow") and >5 mm ("wide") as measured on final pathologic assessment. RESULTS: One-hundred thirty patients were included in the analysis (margin ≤5 mm, n = 41 and margin >5 mm, n = 89). At the time of analysis 54 patients had developed 56 recurrences, 15 (37%) in the narrow margin group and 41 (46%) in the wide margin group, p = 0.45. The pattern of recurrence was similar in the two groups: intrahepatic 11 (79%) versus 30 (75%), p = 1, and extra-hepatic 6 (43%) versus 17 (43%), p = 1. Median disease-free survival was similar in both groups, 18.1 versus 19.5 months (p = 0.85). CONCLUSIONS: A narrow resection margin (5 mm or less) does not detract from oncologic outcomes after partial hepatectomy for HCC. Tailoring resection margins may lead to greater preservation of hepatic parenchyma. Factors other than margin status represent the driving forces for local and systemic recurrence.

Evolution of Movement Disorders Surgery Leading to Contemporary Focused Ultrasound Therapy for Tremor.

Progressively less invasive neurosurgical approaches for the treatment of movement disorders have evolved, beginning with open craniotomy for placement of lesions within pyramidal structures followed by refined stereotactic ablation of extrapyramidal targets that encouraged nondestructive electrode stimulation of deep brain structures. A noninvasive approach using transcranial high-energy focused ultrasound has emerged for the treatment of intractable tremor. The ability to target discreet intracranial sites millimeters in size through the intact skull using focused acoustic energy marks an important milestone in movement disorders surgery. This article describes the evolution of magnetic resonance-guided focused ultrasound for ventrolateral thalamotomy for tremor.

Alarmingly High Segregation Frequencies of Quinolone Resistance Alleles within Human and Animal Microbiomes Are Not Explained by Direct Clinical Antibiotic Exposure.

Antibiotic resistance poses a major threat to human health. It is therefore important to characterize the frequency of resistance within natural bacterial environments. Many studies have focused on characterizing the frequencies with which horizontally acquired resistance genes segregate within natural bacterial populations. Yet, very little is currently understood regarding the frequency of segregation of resistance alleles occurring within the housekeeping targets of antibiotics. We surveyed a large number of metagenomic datasets extracted from a large variety of host-associated and non host-associated environments for such alleles conferring resistance to three groups of broad spectrum antibiotics: streptomycin, rifamycins, and quinolones. We find notable segregation frequencies of resistance alleles occurring within the target genes of each of the three antibiotics, with quinolone resistance alleles being the most frequent and rifamycin resistance alleles being the least frequent. Resistance allele frequencies varied greatly between different phyla and as a function of environment. The frequency of quinolone resistance alleles was especially high within host-associated environments, where it averaged an alarming ∼ 40%. Within host-associated environments, resistance to quinolones was most often conferred by a specific resistance allele. High frequencies of quinolone resistance alleles were also found within hosts that were not directly treated with antibiotics. Therefore, the high segregation frequency of quinolone resistance alleles occurring within the housekeeping targets of antibiotics in host-associated environments does not seem to be the sole result of clinical antibiotic usage.