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An Enzyme-Linked Immunosorbent Assay (ELISA)-Based Activity Assay for Amp-Activated Protein Kinase (AMPK)
Get PDFAMP-activated protein kinase (AMPK) is the master regulator of cellular and organismal energy homeostasis, playing an essential role in modulating metabolism and other cellular processes. Substantial efforts have been made to develop pharmacological modulators of AMPK activity due to their therapeutic potential against various diseases. Measuring AMPK activity in vitro is a fundamental step for testing AMPK activators and inhibitors. Here, we report an enzyme-linked immunosorbent assay (ELISA)-based AMPK activity assay with simple steps and high sensitivity. This assay offers a robust, in-house alternative to the traditional radioactive methods and other approaches that rely on specialized reagents or commercial kits
Effects of Metformin Use on Aneurysmal Subarachnoid Hemorrhage Outcomes
No full textBackground: Metformin is widely prescribed and has neuroprotective effects in animals, but its impact on brain injury after aneurysmal subarachnoid hemorrhage (aSAH) in humans is unclear.
Methods: This single-center retrospective review assessed patients with aSAH from 2009 to 2023, categorizing them based on pre-admission metformin use. The primary outcome was delayed cerebral ischemia (DCI), while secondary outcomes included in-hospital mortality, rebleeding, angiographic cerebral vasospasm (CVS), and favorable modified Rankin Scale (mRS) scores at discharge and the 3-month follow-up. Outcomes were analyzed using logistic regression. Sensitivity analysis was performed after excluding patients receiving comfort care.
Results: A total of 900 patients were included (47 metformin and 853 non-metformin). DCI rates were similar between groups (38.3% vs. 29.3%, aOR = 1.06 [0.49-2.28]). Rebleeding rates were 4.3% for metformin users and 5.6% for non-users (aOR = 0.47 [0.09-2.51]). In-hospital mortality was 4.3% in metformin users vs. 9.7% in non-users (aOR = 0.47 [0.08-2.84]). Angiographic CVS was 38.3% in metformin users and 52.8% in non-users (aOR = 0.49 [0.23-1.05]), and at 7 days, CVS was 29.8% vs. 47.6% (aOR = 0.46 [0.21-1.01]). Sensitivity analysis showed similar DCI rates (39.1% vs. 30.9%, aOR = 0.98 [0.45-2.15]) but lower CVS at 7 days for metformin users (aOR = 0.44 [0.20-0.98]).
Conclusion: Metformin use before aSAH did not significantly affect the risk of DCI or CVS. However, after excluding comfort care patients, the findings are highly speculative of reduced CVS risk at 7 days post-aSAH. Rebleeding and mortality rates were similar across groups. Future research with larger, multi-institutional datasets is needed to better understand metformin\u27s impact, particularly during and after aSAH
Psychiatric Manifestations of Encephalitis
Get PDFObjective: Encephalitis is a serious and potentially life-threatening condition of infectious or autoimmune cause. We aim to characterize the frequency and clinical spectrum of presenting psychiatric symptoms in encephalitis in order to inform earlier recognition and initiation of treatment.
Methods: This was a retrospective study of adult patients who met the 2013 International Encephalitis Consortium (IEC) and/or 2016 Graus criteria between February 2005 and February 2023. The study included two hospital systems in Houston, Texas, and Baltimore, Maryland and included a total of 642 patients. Psychiatric manifestations were grouped into five high-level categories: behavior, psychosis, mood, sleep disturbances, and catatonia.
Results: In our cohort of 642 patients, 318 (49.6%) had psychiatric symptoms at the time of initial presentation, including 78.2% with autoimmune etiologies and 35.2% with viral etiologies (P \u3c 0.001). Those with psychiatric symptoms were younger (median age 47.5 vs. 51.5; P \u3c 0.001), and more likely to have a history of documented psychiatric disorders, as well as longer lengths of hospital stay, and poorer discharge outcomes. Of patients initially admitted to a psychiatric service (n = 28), most had autoimmune causes, although 3 out of 28 (10.7%) had herpes viral infections; admission to a psychiatric service was associated with substantially longer interval to initiation of antivirals and immunotherapy. Autoimmune and infectious etiologies differed in the spectrum and frequency of psychiatric manifestations.
Interpretation: Psychiatric symptoms are common across etiologies of encephalitis and are associated with longer lengths of hospital stay and worse clinical outcomes. Specific patterns and dimensionality of psychiatric symptoms distinguish autoimmune from infectious causes
Forward Genetic Screen in Zebrafish Identifies New Fungal Regulators That Limit Host-Protective Candida-Innate Immune Interaction
No full textCandida is one of the most frequent causes of bloodstream infections, and our first line of defense against these invasive infections is the innate immune system. The early immune response is critical in controlling Candida albicans infection, but C. albicans has several strategies to evade host immune attack. Phagocytosis of C. albicans blocks hyphal growth, limiting host damage and virulence, but how C. albicans limits early recruitment and phagocytosis in vertebrate infection is poorly understood. To study innate immune evasion by intravital imaging, we utilized the transparent larval zebrafish infection model to screen 131 C. albicans mutants for altered virulence and phagocyte response. Infections with each of the seven hypovirulent mutants led to altered phagocyte recruitment and/or phagocytosis, falling into four categories. Of particular interest among these is NMD5, a predicted β-importin and newly identified virulence factor. The nmd5∆/∆ mutant fails to limit phagocytosis, and its virulence defects are eliminated when phagocyte activity is compromised, suggesting that its role in virulence is limited to immune evasion. These quantitative intravital imaging experiments are the first to document altered Candida-phagocyte interactions for several additional mutants and clearly distinguish recruitment from phagocytic uptake, suggesting that Candida modulates both events. This initial large-scale screen of individual C. albicans mutants in a vertebrate, coupled with high-resolution imaging of Candida-phagocyte interactions, provides a more nuanced view of how diverse mutations can lead to more effective phagocytosis, a key immune process that blocks germination and drives anti-fungal immunity.
Importance: Candida albicans is part of the human microbial community and is a dangerous opportunistic pathogen, able to prevent its elimination by the host immune system. Although Candida avoids immune attack through several strategies, we still understand little about how it regulates when immune phagocytes get recruited to the infection site and when they engulf fungal cells. We tested over 130 selected Candida mutants for their ability to cause lethal infection and found several hypovirulent mutants, which provoked altered innate immune responses, resulting in lower overall inflammation and greater host survival. Of particular interest is NMD5, which acts to limit fungal phagocytosis and is predicted to regulate the activity of stress-associated transcription factors. Our high-content screening was enabled by modeling Candida infection in transparent vertebrate zebrafish larva. Our findings help us understand how Candida survives immune attack during commensal and pathogenic growth, and may eventually inform new strategies for controlling disease
Short- and Long-Term Effects of Early Versus Delayed Treatment With Ocrelizumab on Cerebellar Volume Loss in Patients With RMS and PPMS
No full textBackground: The cerebellum is a functionally and anatomically complex structure, which, in multiple sclerosis (MS), is affected by focal white/gray matter lesions and by secondary neurodegeneration of afferent/efferent connections to the supratentorial brain and the spinal cord.
Objectives: To assess the efficacy of ocrelizumab compared with interferon β-1a (IFN β-1a)/placebo on cerebellar volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II) and in primary progressive MS (PPMS, ORATORIO).
Methods: Cerebellar volume change was computed using paired Jacobian integration and analyzed using a mixed-effect repeated measurement model.
Results: In RMS, ocrelizumab reduced cerebellar volume loss in the double-blind period (DBP) and the difference (30% at DBP end) was maintained in the open-label extension (OLE) after control patients (IFN β-a) were switched to ocrelizumab. In PPMS, there was a small numerical difference in the DBP, but a larger (up to 22%) difference in favor of ocrelizumab in the OLE.
Conclusions: In both RMS and PPMS, early treatment with ocrelizumab helps to prevent additional cerebellar volume loss compared with delayed switching to ocrelizumab. Further analysis is needed to fully understand the clinical impact of cerebellar atrophy
Mitochondrial-Targeted Therapies in Traumatic Brain Injury: From Bench to Bedside
No full textTraumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role of mitochondrial dysfunction in the pathophysiology of TBI, making mitochondria an attractive target for therapeutic intervention. This review comprehensively examines advancements in mitochondrial-targeted therapies for TBI, bridging the gap from basic research to clinical applications. We discuss the underlying mechanisms of mitochondrial damage in TBI, including oxidative stress, impaired bioenergetics, mitochondrial dynamics, and apoptotic pathways. Furthermore, we highlight the complex interplay between mitochondrial dysfunction, inflammation, and blood-brain barrier (BBB) integrity, elucidating how these interactions exacerbate injury and impede recovery. We also evaluate various preclinical studies exploring pharmacological agents, gene therapy, and novel drug delivery systems designed to protect and restore mitochondrial function. Clinical trials and their outcomes are assessed to evaluate the translational potential of mitochondrial-targeted therapies in TBI. By integrating findings from bench to bedside, this review emphasizes promising therapeutic avenues and addresses remaining challenges. It also provides guidance for future research to pave the way for innovative treatments that improve patient outcomes in TBI
At-Home Stroke Neurorehabilitation: Early Findings with the NeuroExo BCI System
No full textBackground: Democratized access to safe and effective robotic neurorehabilitation for stroke survivors requires innovative, affordable solutions that can be used not only in clinics but also at home. This requires the high usability of the devices involved to minimize costs associated with support from physical therapists or technicians.
Methods: This paper describes the early findings of the NeuroExo brain-machine interface (BMI) with an upper-limb robotic exoskeleton for stroke neurorehabilitation. This early feasibility study consisted of a six-week protocol, with an initial training and BMI calibration phase at the clinic followed by 60 sessions of neuromotor therapy at the homes of the participants. Pre- and post-assessments were used to assess users\u27 compliance and system performance.
Results: Participants achieved a compliance rate between 21% and 100%, with an average of 69%, while maintaining adequate signal quality and a positive perceived BMI performance during home usage with an average Likert scale score of four out of five. Moreover, adequate signal quality was maintained for four out of five participants throughout the protocol. These findings provide valuable insights into essential components for comprehensive rehabilitation therapy for stroke survivors. Furthermore, linear mixed-effects statistical models showed a significant reduction in trial duration (p-value \u3c 0.02) and concomitant changes in brain patterns (p-value \u3c 0.02).
Conclusions: the analysis of these findings suggests that a low-cost, safe, simple-to-use BMI system for at-home stroke rehabilitation is feasible
Detection of Oncogenic Fusions in Colorectal Cancer Using a Partner-Agnostic Next-Generation Sequencing Approach
No full textBackground: Gene fusions exist with low prevalence in colorectal cancer (CRC), and the clinical utility of fusion testing in advanced CRC remains unclear. We sought to identify oncogenic fusions in patients with advanced CRC using a fusion partner-agnostic circulating tumor DNA (ctDNA) assay to better understand their clinical relevance.
Methods: We performed a retrospective analysis using de-identified data from 18,558 patients with advanced CRC who underwent ctDNA next-generation sequencing with Guardant360® from 2017 to 2022. These samples were subsequently reanalyzed with a partner-agnostic bioinformatics method to identify both clonal and non-clonal fusions. We analyzed for associations between fusions and MSI-H status, as well prior EGFR-directed therapy signature.
Results: Fusions were identified in 221 (1.3%) of CRC patients analyzed. 193 patients had 258 activating fusions, while 28 patients had fusions of uncertain significance. Among patients with activating fusions, there were 18 clonal fusions (7%) and 240 (93%) subclonal fusions. Clonal fusions were more common in patients with MSI-H status, and subclonal fusions were associated with prior EGFR exposure signature.
Conclusions: Among patients with advanced CRC, partner-agnostic ctDNA fusion detection is possible and improves identification as a blood-based approach by extension of fusion calling partners. Detection of fusions in the ctDNA may provide rationale for potential therapeutic strategies according to clonality as informed by the ctDNA, whereas subclonal fusions may play a role in acquired resistance to EGFR inhibitors in KRAS/NRAS/BRAFwild-type tumors
The Association of Adult Medicaid Beneficiaries’ Characteristics and Their Experience During the COVID-19 Pandemic
No full textBackground: The COVID-19 pandemic disrupted the United States’ safety net program, Medicaid, for low-income individuals affecting access to care, increasing enrollment, and requiring new approaches to care delivery. The literature shows that beneficiaries’ personal characteristics influence their healthcare experience. This study investigated the association between Medicaid beneficiary characteristics and experience with their Medicaid health plan, examined if COVID-19 negatively impacted experience, and tested if COVID-19 moderated the relationship between beneficiary characteristics and experience.
Methods: The research sample was 76,976 adult Medicaid beneficiaries who voluntarily completed the annual Consumer Assessment of Healthcare Providers and Systems (CAHPS) health plan surveys in 2018 through 2021. First, we used logistic regression to analyze if adult Medicaid beneficiary characteristics (sex, race, ethnicity, age, education, and health status) were associated with better experiences (rating of healthcare experience, rating of personal doctor, rating of health plan, doctor communication, and customer service). Then, we used logistic regression to determine whether adult Medicaid beneficiaries had less favorable experiences during COVID-19. Last, we tested if COVID-19 moderated the relationship between the characteristics and experience measures using the Likelihood-Ratio test.
Results: Our findings indicate that there are significant associations between beneficiary characteristics and experience measures. We found that all the characteristics, except ethnicity, impact beneficiary experiences. In addition, there were significant positive, as opposed to negative, associations between COVID-19 and the experience measures. Lastly, COVID-19 had no significant impact on the relationships between any of the adult Medicaid beneficiary characteristics and the ratings of the experience measures.
Conclusion: COVID-19 was a major disruption to healthcare delivery. Our study supported previous findings on the association between beneficiary characteristics, except ethnicity, and experience. Unexpectedly, COVID-19 was positively associated with most experience measures. Finally, COVID-19 did not moderate the relationships between beneficiaries’ characteristics and their experience with their Medicaid health plans. Additional studies are needed to understand the complex nature of COVID-19’s impact on beneficiary characteristics and their experience
