Traumatic brain injury (TBI) remains a major cause of disability among young adults in both civilian and military settings contributing to a high burden on healthcare systems (Badhiwala et al., 2019). Sequel of TBI, even mild injuries, include motor and sensory dysfunction, neurocognitive decline, neuropsychiatric complications, as well as increased risk of neurodegenerative and neurovascular events such as Alzheimer’s disease and stroke (Breunig et al., 2013; Burke et al., 2013; Li et al., 2017). Despite the acute nature of the insult in TBI, pathological changes in the traumatized brain are better recognized as a chronic rather than an acute neurological disease, a phenomenon that remains under-investigated. Robust clinical data support the role of neuroinflammation in propagating neurodegenerative changes following TBI with a pivotal role of the complement system as an early trigger and chronic propagator of this response (Alawieh et al., 2018, 2021; Mallah et al., 2021). Hereby, we discuss how the role of complement pathways in different phases of injury after TBI was investigated using clinically relevant targeted complement inhibitors (Alawieh and Tomlinson, 2016; Alawieh et al., 2018, 2021; Mallah et al., 2021).
Pseudomonas aeruginosa is a prevalent pathogen in cystic fibrosis (CF) lungs which displays strong resistance to various antibiotic classes, contributing to antimicrobial resistance (AMR). P aeruginosa populations in CF lungs exhibit considerable genetic and phenotypic diversity, raising questions about their susceptibility to non-traditional antimicrobials, such as bacteriocins. R-pyocins, bacteriocins produced by P. aeruginosa, are highly potent, non-replicating phage tail-like protein complexes with a narrow killing spectrum. The diversity of P. aeruginosa variants within CF lung infections may lead to varying susceptibility to R-pyocins due to changes in the lipopolysaccharide (LPS) structure, which acts as the R-pyocin receptor. However, the extent of susceptibility to the five known R-pyocin subtypes (R1-R5) remains unknown, especially considering the diverse P. aeruginosa populations in CF lungs. Additionally, the connection between LPS phenotype and R-pyocin susceptibility is not well understood. We tested 139 P. aeruginosa variants from 17 sputum samples of seven CF patients for R2-pyocin susceptibility and analyzed their LPS phenotypes. Our findings revealed that approximately 83% of sputum samples contained diverse P. aeruginosa populations without R2-pyocin resistant variants, while all samples had some susceptible variants. Moreover, there was no clear correlation between LPS phenotypes and R-pyocin susceptibility. The absence of a clear correlation between LPS phenotypes and R-pyocin susceptibility suggests that LPS packing density may significantly influence R-pyocin susceptibility among CF variants. Our research supports the potential use of R-pyocins as therapeutic agents, as numerous infectious CF variants appear to be susceptible to R2-pyocins, even within diverse P. aeruginosa populations.
Background
Oxidative injury to retinal pigment epithelium (RPE) and retinal photoreceptors has been linked to a number of retinal diseases, including age-related macular degeneration (AMD). Reactive oxygen species (ROS)-mediated gene expression has been extensively studied at transcriptional levels. Also, the post-transcriptional control of gene expression at the level of translational regulation has been recently reported. However, the microRNA (miRNA/miR)-mediated post-transcriptional regulation in human RPE cells has not been thoroughly looked at. Increasing evidence points to a potential role of miRNAs in diverse physiological processes.
Methodology/Principal Findings
We demonstrated for the first time in a human retinal pigment epithelial cell line (ARPE-19) that the post-transcriptional control of gene expression via miRNA modulation regulates human catalase, an important and potent component of cell's antioxidant defensive network, which detoxifies hydrogen peroxide (H2O2) radicals. Exposure to several stress-inducing agents including H2O2 has been reported to alter miRNA expression profile. Here, we demonstrated that a sublethal dose of H2O2 (200 µM) up-regulated the expression of miR-30b, a member of the miR-30 family, which inhibited the expression of endogenous catalase both at the transcript and protein levels. However, antisense (antagomirs) of miR-30b was not only found to suppress the miR-30b mimics-mediated inhibitions, but also to dramatically increase the expression of catalase even under an oxidant environment.
Conclusions/Significance
We propose that a microRNA antisense approach could enhance cytoprotective mechanisms against oxidative stress by increasing the antioxidant defense system.
by
Matthew J. Singleton;
Muhammad Imtiaz-Ahmad;
Hooman Kamel;
Wesley O neal;
Suzanne E. Judd;
Virginia J. Howard;
George Howard;
Elsayed Z. Soliman;
Prashant D. Bhave
Background
Atrial fibrillation (AF) is associated with a 5‐fold increased stroke risk. While most patients with AF warrant anticoagulation, optimal treatment remains uncertain for patients with AF without cardiovascular comorbidities because the risk of stroke in this population has not been well‐characterized.
Methods and Results
Participants (N=28 253; 55% women, mean age 64.6±9.4 years), from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study (2003–present) were classified into 1 of 4 groups based on the presence or absence of AF and the presence or absence of cardiovascular comorbidities. Cox proportional hazards analysis was used to compare the risk of stroke between groups. During 244 560 person‐years of follow‐up (median 8.7 years), 1206 strokes occurred. Compared with patients with neither AF nor cardiovascular comorbidities, we did not find an increased stroke risk (hazard ratio [HR], 1.23; 95% CI, 0.62–2.18 [P=0.511]) among participants with AF alone. Participants without AF but with cardiovascular comorbidities had both an elevated stroke risk (HR, 1.77; 95% CI, 1.48–2.18 [P<0.0001]) and an increased risk of cardioembolic stroke (HR, 2.34; 95% CI, 1.48–3.90 [P=0.0002]).
Conclusions
In this large cohort of participants with AF without cardiovascular comorbidities, we found that AF itself, without cardiovascular comorbidities, did not confer increased risk of stroke. Cardiovascular comorbidities, however, were associated with an increased risk of both stroke of any type and cardioembolic stroke, even in the absence of AF.
Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte–neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.
by
Chloé M. Martin;
Danyella Greene;
Jules P Harrell;
Denée Thomas Mwendwa;
Carla D Williams;
Sara Horton;
Melanie Cradle;
Briana D Hudson;
Teletia R Taylor
OBJECTIVE: Insomnia is a significant concern among African-American breast cancer survivors (BCS). Social constraints (SC)-receiving unsupportive or critical responses when expressing trauma-related emotions-and fear of recurrence (FOR) have been associated with insomnia. We examined FOR as a mediator in the relationship between SC and insomnia in African-American BCS. We hypothesized a direct effect of SC on insomnia, and an indirect effect of SC on insomnia through FOR. METHODS: Sixty-four African-American BCS completed a questionnaire assessing demographics, clinical characteristics, SC, FOR, and insomnia. Participants were an average of M = 8.41 (SD = 5.8) year survivors. The mediation was tested using PROCESS for SPSS. RESULTS: The direct effect of SC on insomnia was significant (direct effect = .17, SE = .08, P = .04). Moreover, the indirect effect of SC on insomnia through FOR was significant (indirect effect = .19, SE = .10, 95% CI = .05, .41). CONCLUSIONS: Experiencing SC from family and friends could produce cognitions that impact sleep for BCS, and FOR could be one of those cognitions. Family-based models of care that emphasize the emotional needs of survivors and families could be a relevant strategy to address the SC that impacts sleep.
The complement system is an evolutionarily ancient arm of the innate immune system. It is composed of over 40 proteins, receptors and regulators that interact in a cascade manner to protect the host against pathogens (1). The soluble circulating complement proteins are mainly produced by hepatocytes. However, it is now well established that complement factors are expressed throughout the body, including in the central nervous system (CNS). In recent years, complement factors have been shown to control major aspects of CNS development, health, injury and disease (2–4). This Research Topic gathers the latest contributions to how complement factors interact with the nervous system, providing new mechanistic insight into neurodevelopment, cognitive function, myelination, and CNS infection. Review articles highlight roles for complement in development and degeneration of the visual system, and also the status of translation and clinical trials for complement-targeted therapeutics.
Objective.
Electrical nerve block offers the ability to immediately and reversibly block peripheral nerve conduction and would have applications in the emerging field of bioelectronics. Two modalities of electrical nerve block have been investigated—kilohertz frequency alternating current (KHFAC) and direct current (DC). KHFAC can be safely delivered with conventional electrodes, but has the disadvantage of having an onset response, which is a period of increased neural activation before block is established and currently limits clinical translation. DC has long been known to block neural conduction without an onset response but creates damaging reactive species. Typical electrodes can safely deliver DC for less than one second, but advances in high capacitance electrodes allow DC delivery up to 10 s without damage. The present work aimed to combine DC and KHFAC into a single waveform, named the combined reduced onset waveform (CROW), which can initiate block without an onset response while also maintaining safe block for long durations. This waveform consists of a short, DC pre-pulse before initiating KHFAC.
Approach.
Simulations of this novel waveform were carried out in the axonal simulation environment NEURON to test feasibility and gain insight into the mechanisms of action. Two sets of acute experiments were then conducted in adult Sprague–Dawley rats to determine the effectiveness of the waveform in mitigating the onset response.
Main results.
The CROW reduced the onset response both in silico and in vivo. The onset area was reduced by over 90% with the tested parameters in the acute experiments. The amplitude of the DC pulse was shown to be particularly important for effective onset mitigation, requiring amplitudes 6–8 times the DC block threshold.
Significance.
This waveform can reliably reduce the onset response due to KHFAC and could allow for wider clinical implementation of electrical nerve block.
Morbidly obese obstetric patients undergoing anesthesia present many unique challenges. Previous caesarean sections (CSs) further complicate their management. We present the successful anesthetic management of a super morbidly obese obstetric patient with body mass index (BMI) of 109 kg/m2 who underwent her fourth CS. As per our review, this patient has the highest recorded BMI in the obstetric anesthesia literature.
A 27-year-old female, G4P3003, presented for fourth repeat CS at 38 weeks’ gestation. She had obstructive sleep apnea, hypertension, atrial fibrillation, and type 2 diabetes. Her first CS was emergent under general anesthesia (GA), and the other two were performed under neuraxial anesthesia, with the most recent one complicated by intraoperative cardiac arrest requiring cardiopulmonary resuscitation. Preoperative preparation involved multidisciplinary preparation, planning, and risk stratification. Although neuraxial anesthesia is preferred over GA for CS, she refused neuraxial anesthesia due to her prior traumatic experience and the potential that it caused her prior cardiac arrest. In addition, her inability to position for a block or lay flat, poor anatomical landmarks, unknown length of surgery, plan for periumbilical incision, uncertain placental status, and risk of massive hemorrhage convinced us to consider GA. Surprisingly, her airway examination was reassuring. Two 18G peripheral intravenous lines and an arterial line were obtained prior to induction. With optimum patient positioning and preoxygenation, modified rapid sequence induction with mask ventilation and endotracheal intubation with direct laryngoscopy were performed. A healthy baby was delivered without significant intraoperative complications. Intraoperative lung-protective strategy with recruitment maneuvers, multimodal analgesia, and elective postoperative continuous positive airway pressure aided in successful extubation. Postoperatively, pulmonary toilet, early mobilization, physical therapy, and venous thromboembolism prophylaxis were employed. Her postoperative course was complicated by severe preeclampsia and pulmonary embolism, which were managed successfully in the intensive care unit. She was discharged initially to outpatient rehabilitation followed by home. This case highlights the complexities and significance of an individualized approach in managing super morbidly obese obstetric patients.
Gastric hemangiomas (GHs) are extremely rare vascular lesions of mesodermal origin that may occur in isolation or in conjunction with underlying congenital pathology. Due to the scarcity of these tumors, there is no standardized diagnostic method; however, many have found the combination of endoscopic investigation and radiographic imaging to be most effective, with the presence of phleboliths on computerized tomography as being pathognomonic for GHs. Surgical treatment for symptomatic lesions is curative with no reports of recurrence. We describe a 21-year-old woman who presented with epigastric pain and one episode of 250 mL hematemesis earlier that morning. Under the impression of an upper gastrointestinal bleed due to peptic ulcer disease, esophagogastroduodenoscopy was performed which revealed a 5-cm blood clot-like mass similar in appearance to that of a II-b peptic ulcer, but the presence of a bridging fold led to the suspicion of a possible submucosal tumor. Dynamic computerized tomography scan showed similar findings, and the patient was referred for surgical intervention. Laparoscopic distal gastrectomy was performed with the final diagnosis of cavernous GH made via histological evaluation. The patient was discharged 9 days later with no complications. This case puts emphasis on the importance of considering cavernous GH as a potential cause of severe upper GI bleeding especially in those with atypical demographic profile and history.