Acute Insult Research Articles

Functional MRI evaluation of hyperbaric oxygen therapy’s effect on hand motor recovery in a chronic post-stroke patient: a case report and physiological discussion

The objective of the case report was to evaluate a specific HBOT protocol as an effective treatment for stroke rehabilitation, specifically improving hand motor function in chronic post-stroke patients. Stroke is the second leading cause of long-term disability worldwide. About 80% of individuals with acute stroke present upper-limb motor impairment, and 50–60% will have persistent disability or weakness at the chronic phase. Impaired upper-limb motor function is highly associated with low self-care ability, limited mobility and poor quality of life. In recent years, there has been evidence of the neuroplasticity effects of HBOT, and HBOT was found to induce neuroplasticity in chronic stages, even years after brain injury. While the healthcare system is primarily focused on teaching patients to live with their impairments, this case report evaluates the effect of a specific hyperbaric oxygen therapy (HBOT) protocol on true stroke rehabilitation, specifically, improving upper-limb function. This case report studied motor task functional MRI (fMRI) activation and resting-state functional connectivity (rsFC) in a 61-year-old right-handed male patient who suffered hemiparesis and physical weakness in the right upper limb two years after his acute insult, pre- and post-treatment of 60 daily HBOT sessions. Motor functions were assessed at baseline and after the treatment using the Fugl–Meyer assessment (FMA) and the handgrip maximum voluntary contraction (MVC). Following the HBOT protocol, the patient’s FMA score improved from 17 (severe impairment) to 31 (moderate impairment), and there was an increase in fMRI activation in both the supplementary motor cortex (SMA) and the premotor cortex (PMA) bilaterally during trials involving the right hand. The lateralization index (LI) decreased from 1 to 0.63, demonstrating the recruitment of the contralesional hemisphere. The region of interest, ROI-to-ROI, analysis revealed increased post-intervention inter-hemispheric connectivity (P = 0.002) and a between-network connectivity increase (z-score: 0.35 ± 0.21 to 0.41 ± 0.21, P < 0.0001). Seed-to-voxel-based rsFC analysis using the right SMA as seed showed increased connectivity to the left posterior parietal cortex, the left primary somatosensory cortex and the premotor cortex. This case report provides additional insights into HBOT-induced brain plasticity and functional improvement in chronic post-stroke patients, and shows HBOT’s potential as an effective, valuable treatment option for those suffering with lingering symptoms after a stroke. This work was conducted by a research team at the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center and Tel Aviv University, and published in Frontiers in Neurology. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical experience with bromocriptine for central hyperthermia after brain insult

ABSTRACT Introduction Bromocriptine is a dopamine receptor agonist used for central hyperthermia with limited data. We describe our single-center experience utilizing bromocriptine for central hyperthermia, including the population treated, most common dosing regimens, adverse events, and discontinuation reasons. Methods A retrospective study was conducted screening patients who were admitted to intensive care units for acute neurological insults and administered bromocriptine for central hyperthermia between April 2016 and September 2022. Baseline characteristics, disease severity markers, and bromocriptine doses were collected. Body temperatures prior to the first dose of bromocriptine, at the time of dose, and after each dose were recorded. Co-administration of additional hyperthermia management therapies was noted. Results Thirty patients were included. The most common diagnosis was traumatic brain injury (TBI) (N = 14). The most common reason for discontinuation was resolution of indication (N = 14). Discontinuation due to mild adverse effects occurred in four patients; hepatotoxicity was the most common. There was a paired mean difference of −0.37°C (p = 0.005) between temperatures before and after bromocriptine initiation. Conclusion Bromocriptine is a potential therapy for the management of central hyperthermia in patients with severe acute neurologic insults who have failed other therapies. Bromocriptine was well tolerated and associated with a low incidence of adverse events.

Delayed levodopa-responsive parkinsonism following acute midbrain injury

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

Parental obesity predisposes offspring to kidney dysfunction and increased susceptibility to ischemia-reperfusion injury in a sex-dependent manner.

Although obesity is recognized as a risk factor for cardiorenal and metabolic diseases, the impact of parental obesity on the susceptibility of their offspring to renal injury at adulthood is unknown. We examined the impact of parental obesity on offspring kidney function, morphology, and markers of kidney damage after acute kidney injury (AKI). Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were fed N (HN) or H diet (HH) after weaning. All offspring groups were submitted to bilateral AKI by clamping the left and right renal pedicles for 30 min. Compared with male NH and NN offspring from lean parents, male HH and HN offspring from obese parents exhibited higher kidney injury markers such as urinary, renal osteopontin, plasma creatinine, urinary albumin excretion, and neutrophil gelatinase-associated lipocalin (NGAL) levels, and worse histological injury score at 22 wk of age. Only albumin excretion and NGAL were elevated in female HH offspring from obese parents compared with lean and obese offspring from lean parents. We also found an increased mortality rate and worse kidney injury scores after AKI in male offspring from obese parents, regardless of the diet consumed after weaning. Female offspring were protected from major kidney injury after AKI. These results indicate that parental obesity leads to increased kidney injury in their offspring after ischemia-reperfusion in a sex-dependent manner, even when their offspring remain lean.NEW & NOTEWORTHY Offspring from obese parents are more susceptible to kidney injury and worse outcomes following an acute ischemia-reperfusion insult. Male, but not female, offspring from obese parents exhibit increased blood pressure early in life. Female offspring are partially protected against major kidney injury induced by ischemia-reperfusion.

Made to order: emergency myelopoiesis and demand-adapted innate immune cell production.

Definitive haematopoiesis is the process by which haematopoietic stem cells, located in the bone marrow, generate all haematopoietic cell lineages in healthy adults. Although highly regulated to maintain a stable output of blood cells in health, the haematopoietic system is capable of extensive remodelling in response to external challenges, prioritizing the production of certain cell types at the expense of others. In this Review, we consider how acute insults, such as infections and cytotoxic drug-induced myeloablation, cause molecular, cellular and metabolic changes in haematopoietic stem and progenitor cells at multiple levels of the haematopoietic hierarchy to drive accelerated production of the mature myeloid cells needed to resolve the initiating insult. Moreover, we discuss how dysregulation or subversion of these emergency myelopoiesis mechanisms contributes to the progression of chronic inflammatory diseases and cancer.

86 Evaluation of dietary Saccharomyces cerevisiae fermentation product on markers of joint inflammation in young, exercising horses following an intra-articular lipopolysaccharide challenge

Abstract Including Saccharomyces cerevisiae fermentation product (SCFP) into the diets of young, exercising horses may prolong their performance career by optimizing the intra-articular environment. Our objective was to evaluate the effect of dietary SCFP on joint inflammation in yearlings undergoing regular exercise, challenged with intra-articular lipopolysaccharide (LPS). Thirty Quarter Horse yearlings (374 ± 25 kg BW; 562 ± 16 d of age; 15 fillies and 15 geldings) were used in a 60-d study to test the hypothesis that dietary SCFP (TruEquine C, Diamond V Mills, Inc.) ameliorates joint inflammation following an acute inflammatory insult. Horses were stratified by BW, age, sex, and randomly assigned to dietary treatments (n = 10/treatment): Control (0), 46, or 92 mg/kg BW SCFP. Treatments were top-dressed onto a custom-formulated concentrate void of added microbials offered at 1% BW/d (as-fed) every 12 h. Horses were individually stalled (3.6 m × 7.3 m) and offered ad libitum Coastal bermudagrass hay. Using a free-stall exerciser, horses were exercised following a progressive workload regimen for 30 min/d, 5 d/wk. On d 46, all horses underwent an intra-articular LPS challenge where each horse had one radial carpal joint randomly assigned to receive either 0.8 mL of a 0.5 ng LPS solution or sterile lactated Ringer’s solution (LRS) as a contralateral control. Synovial fluid samples were obtained pre-injection (h 0) and at 6, 12, 24, and 336 h post-injection and analyzed for prostaglandin E2 (PGE2), a pro-inflammatory prostaglandin via commercial ELISA, and for chemokine-concentration (signaling proteins that direct immune cells; CCL2, and CCL11) and cytokines (inflammatory mediators; TNFα and IL-10) using a multiplex platform via commercial laboratory. Non-normal data (PGE2, IL-10, and CCL2) were log transformed, and all markers were analyzed using MIXED procedure of SAS v9.4. Mean separation was achieved with orthogonal contrasts, and contralateral control carpi were used as a covariate across all hours. There was no effect of SCFP on synovial logPGE2 (P = 0.42), logCCL2 (P = 0.90), CCL11 (P = 0.26), or logIL-10 (P = 0.23). However, there was a treatment × hour interaction for CCL11 (P = 0.04) where the Control had increased concentrations compared with SCFP treatment groups at 6 h post-injection. Furthermore, logIL-10 also had a treatment × hour interaction (P = 0.05) where the 46mg/kg BW group had decreased concentrations at h 12 compared with the Control and 92mg/kg BW group. The main effect of treatment for TNFα (P = 0.04) revealed that the 92mg/kg BW group had less concentrations than the 46mg/kg BW group and tended to have less concentrations than the Control group across all hours. Results indicate that SCFP may help mitigate inflammation markers following an acute intra-articular inflammatory insult.

Human hepatocytes response to pathological shifts in liver fibrosis

Protracted liver assault results in hepatic fibrosis, frequently advancing into cirrhosis, hepatic failure, portal hypertension and hepatocellular carcinoma or degeneration. Hepatic fibrosis emanates from the wound-healing response of the liver to persistent assault. Following acute liver insult, such as viral hepatitis, parenchymal cells regenerate and substitute the necrotic or apoptotic cells. A salient proportion of the affected population of NAFLD advances to nonalcoholic steatohepatitis, NASH, and is characterised by inflammation, hepatocellular swelling, with ensuing eruption of deteriorating fibrosis. An untreated or persistent NASH can progressively culminate in liver cirrhosis and hepatocellular carcinoma. Chronic liver derangement results in pathologic ECM protein or liver fibrosis aggregation. In essence, the encompassing characterisation of human ECM molecular composition provides for excursions into mechanisms of liver disease or hepatocellular degeneration. Hepatocytes are characterized by elevated mitochondrial concentrations. The difference between NASH and fibrosis is evident that the progression of NASH to cirrhosis commences as inflamed liver tissue evolves into scar tissue or fibrosis that is capable of obliterating the liver from optimum functionality. A third or more of persons presenting with NASH develop cirrhosis , and also elevates and accelerates the risk in the development of liver cancer. The hepatic stellate cells are responsible for liver fibrosis as they are substantially involved in the initiation, progression, and regression of liver fibrosis via the secretion of fibrogenic factors which promote portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts in the formation of collagen, and consequential propagation of fibrosis.

Comparison of a Novel Score “NOD−ACLF” to Other Established Prognostic Scores for Prediction of Mortality in APASL−ACLF Patients: A Cohort Study from a Tertiary Care Center of North India

Commonly used prognostic scores for acute on-chronic liver failure (ACLF) have complex calculations. We tried to compare the simple counting of numbers and types of organ dysfunction to these scores, to predict mortality in ACLF patients. In this prospective cohort study, ACLF patients diagnosed on the basis of Asia Pacific Association for Study of the Liver (APASL) definition were included. Severity scores were calculated. Prognostic factors for outcome were analysed. A new score, the Number of Organ Dysfunctions in Acute-on-Chronic Liver Failure (NOD-ACLF) score was developed. Among 80 ACLF patients, 74 (92.5%) were male, and 6 were female (7.5%). The mean age was 41.0±10.7 (18-70) years. Profile of acute insult was; alcohol 48 (60%), sepsis 30 (37.5%), variceal bleeding 22 (27.5%), viral 8 (10%), and drug-induced 3 (3.8%). Profiles of chronic insults were alcohol 61 (76.3%), viral 20 (25%), autoimmune 3 (3.8%), and non-alcoholic steatohepatitis 2 (2.5%). Thirty-eight (47.5%) were discharged, and 42 (52.5%) expired. The mean number of organ dysfunction (NOD-ACLF score) was ->4.5, simple organ failure count (SOFC) score was >2.5, APASL ACLF Research Consortium score was >11.5, Model for End-Stage Liver Disease-Lactate (MELD-LA) score was >21.5, and presence of cardiovascular and respiratory dysfunctions were significantly associated with mortality. NOD-ACLF and SOFC scores had the highest area under the receiver operating characteristic to predict mortality among all these. The NOD-ACLF score is easy to calculate bedside and is a good predictor of mortality in ACLF patients performing similar or better to other scores.

Efficacy of Jiuzao polysaccharides in ameliorating alcoholic fatty liver disease and modulating gut microbiota

Jiuzao, the residue from Baijiu production, has shown radical scavenging properties in prior investigations, suggesting its potential as a hepatoprotective agent against acute liver damage. This study reveals that Jiuzao polysaccharides ameliorated liver morphological damage in zebrafish larvae afflicted with alcoholic fatty liver disease (AFLD), as evidenced by Oil red O, H&E, and Nile red staining. These polysaccharides notably modulated antioxidant enzyme levels and lipid peroxidation components. The real-time quantitative polymerase chain reactions analyses illustrated the significant impact of Jiuzao polysaccharides on genes integral to ethanol and lipid metabolism. The 16 S rRNA results showed that Jiuzao polysaccharides could improve the intestinal flora in zebrafish larvae exposed to ethanol. In summary, Jiuzao polysaccharides efficaciously mitigate liver lipid accumulation, enhance ethanol metabolism, and reduce oxidative stress by downregulating genes involved in AFLD development. They also regulate the changes in gut microbiota, providing further protection against acute alcoholic liver insult in zebrafish larvae.

Examining B-cell dynamics and responsiveness in different inflammatory milieus using an agent-based model.

B-cells are essential components of the immune system that neutralize infectious agents through the generation of antigen-specific antibodies and through the phagocytic functions of naïve and memory B-cells. However, the B-cell response can become compromised by a variety of conditions that alter the overall inflammatory milieu, be that due to substantial, acute insults as seen in sepsis, or due to those that produce low-level, smoldering background inflammation such as diabetes, obesity, or advanced age. This B-cell dysfunction, mediated by the inflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α), increases the susceptibility of late-stage sepsis patients to nosocomial infections and increases the incidence or severity of recurrent infections, such as SARS-CoV-2, in those with chronic conditions. We propose that modeling B-cell dynamics can aid the investigation of their responses to different levels and patterns of systemic inflammation. The B-cell Immunity Agent-based Model (BCIABM) was developed by integrating knowledge regarding naïve B-cells, short-lived plasma cells, long-lived plasma cells, memory B-cells, and regulatory B-cells, along with their various differentiation pathways and cytokines/mediators. The BCIABM was calibrated to reflect physiologic behaviors in response to: 1) mild antigen stimuli expected to result in immune sensitization through the generation of effective immune memory, and 2) severe antigen challenges representing the acute substantial inflammation seen during sepsis, previously documented in studies on B-cell behavior in septic patients. Once calibrated, the BCIABM was used to simulate the B-cell response to repeat antigen stimuli during states of low, chronic background inflammation, implemented as low background levels of IL-6 and TNF-α often seen in patients with conditions such as diabetes, obesity, or advanced age. The levels of immune responsiveness were evaluated and validated by comparing to a Veteran's Administration (VA) patient cohort with COVID-19 infection known to have a higher incidence of such comorbidities. The BCIABM was successfully able to reproduce the expected appropriate development of immune memory to mild antigen exposure, as well as the immunoparalysis seen in septic patients. Simulation experiments then revealed significantly decreased B-cell responsiveness as levels of background chronic inflammation increased, reproducing the different COVID-19 infection data seen in a VA population. The BCIABM proved useful in dynamically representing known mechanisms of B-cell function and reproduced immune memory responses across a range of different antigen exposures and inflammatory statuses. These results elucidate previous studies demonstrating a similar negative correlation between the B-cell response and background inflammation by positing an established and conserved mechanism that explains B-cell dysfunction across a wide range of phenotypic presentations.

P-31 GLP1 receptor agonist in end-stage kidney disease: Are they safe and effective?

Abstract Introduction The novel antidiabetic therapies have been showing promising results in cardiovascular and renal protection besides diabetes treatment. GLP-1 receptor agonists (GLP-1RA) are well tolerated drugs with few side effects, but they are only approved for a glomerular filtration rate (GFR) higher than 15 mL/min. Anecdotal reports have been made of therapy with GLP-1RA in patients undergoing hemodialysis and intermittent hemodialysis with good results. Clinical Case A sixty-five-year-old male patient with stage 4 chronic kidney disease in the setting of hypertensive and diabetic nephropathy is accompanied at our Endocrinology Department due to non-insulin treated type 2 diabetes. His past-history was notable for atrial fibrillation, obstructive sleep apnea and chronic obstructive pulmonary disease. In what diabetes is concerned, he was under empagliflozin 10mg daily and dulaglutide 1.5mg weekly with excellent glycemic control. Despite optimized treatment and Nephrology follow-up, GFR continued to decay, standing currently at 11 mL/min, without any acute insult, acidosis or hyperkalemia. The patient is starting preparation for hemodialysis with construction of an arteriovenous fistula. At last appointment, despite the lower GFR he maintained an excellent glycemic control with HbA1c of 6% without hypoglycemia and remained clinically asymptomatic without nausea, vomiting, or abdominal pain. A pharmacokinetics study revealed a similar exposure to semaglutide independent of renal function (including severe renal impairment [10 patients] and end-stage kidney disease [10 patients]) with the drug being well tolerated in both subgroups without the need for dose adjustments. In our case, the patient maintained the weekly treatment, without reported and/or documented hypoglycemia and possible advantageous cardiovascular profile. In the future, GLP1RA may be a treatment option independently of the patient renal function.

Transitional care for older adults with chronic illness: Aqualitative inquiry.

Improved public health strategies and medical advancements have expanded older adults' survival after acute insults from chronic diseases. The resultant increase in disability and care requirements among older adults is significant. However, transitional care interventions to support the efficient transition from acute care settings to home are primitive in developing countries like India. This qualitative survey aimed to estimate the transitional care requirements of older adults with chronic illness discharged from acute care facilities. Descriptive phenomenological approach was utilised for this qualitative study. The older adult-family caregiver dyads fulfilling the inclusion criteria were interviewed until the achievement of information saturation. The transcribed narratives between the researcher, older adults and their caregivers were thematically analysed. Consolidated Criteria for Reporting Qualitative Research (COREQ) served as the framework for reporting this research. Thirteen older adult-caregiver dyads participated in the semi-structured interview, which yielded six themes. Older adults have a hidden self with characteristics ranging between a continuum of 'insistence' to 'giving up'. Caregiver attributes identified from this inquiry were exhaustion, engagement and empowerment. The remaining four themes which constitute the framework for the 'transitional care progression' model include 'complications are mature when identified among older adults', 'medication knowledge is proportionate with its compliance', 'ignorance of supportive care increases caregiver burden' and 'deficient follow-up practices compromise health'. Transitional care for older adults with chronic illness is premature in developing countries. However, the needs of older adults with chronic disease and their caregivers evolved from the present study align with global perspectives. Themes generated from the current qualitative interview, blended with evidence-based interventions, yielded the transitional care progression model, which serves as the only available framework for implementing transitional care in the region. Future research to establish the feasibility and validity of the 'transitional care progression model' is forecasted. The model requires inclusion within the healthcare curriculum. Professional nurses prepared to implement coordinated transitional care pathways are recommended.

Utility of magnetic resonance imaging of brain in neurocritically ill children in pediatric intensive care unit: A single-center retrospective observational study

Abstract Background: Brain magnetic resonance imaging (MRI) was increasingly performed in children admitted in pediatric intensive care unit (PICU) with acute nontraumatic neurological disorders. The study aimed to describe neuroimaging findings and contribution of brain MRI in children admitted with acute encephalopathy admitted in PICU as well as adverse events during procedure. Subjects and Methods: Retrospective chart of all children with nontraumatic acute brain insults required MRI of brain admitted in PICU from January 2019 to December 2021. Demographic, clinical diagnosis, ICU therapies, and pertinent neurodiagnostic data were collected into a structured data collection sheet. The neurodiagnostic findings, contribution in the clinical management either as diagnostic, therapeutic, or prognostic as well as any adverse events during procedure and transport were also collected. All transport and procedure was done by pediatric intensive care team. Appropriate descriptive and analytical statistical tests were applied. Results: Eight two had brain MRI during the study period. The median age (year) was 3.0 (2 mo.-16 years) the most common admitting diagnoses were central nervous system infections in 39 (47.5%) and Status epilepticus in 7 (8%) cases. Neurodiagnostic categories of MRI were inflammatory in 34 (41.5%) and vascular/ischemia in 23 (28%) cases. Brain MRI was contributory in 57 (69.5%) cases in management of child as diagnostic in 41 (71.9%), prognostic in 15 (26%) therapeutic in 1 (1.7%) while noncontributory in 25 (30%) cases. No adverse events were reported during MRI. Conclusions: Brain MRI was helpful for the diagnosis as well as prognosis for acute neurocritically ill children in PICU and associated with very few minor adverse events.

Multimodal imaging of acute fovealitis with angular sign of Henle fiber layer hyperreflectivity (ASHH): Report of a case and review of the literature

Acute retinal pigment epitheliitis (ARPE) is a rare and transient macular disorder that was first described by Krill and Deutman in 1972. Later, Gerardo Ledesma-Gil and Spaide described a novel disease named acute fovealitis in 2022. According to them, this entity was different from ARPE on the basis of distinct features found in high-resolution optical coherence tomography (OCT) imaging. Angular sign of Henle fiber layer hyperreflectivity (ASHH) is a newly described terminology that is caused by an acute insult to photoreceptor compartments. In this article, we report a case that has both the ophthalmoscopic and OCT features of acute fovealitis as described in the literature, with the presence of ASHH in the acute stage, which resolves on its own rapidly along with the symptoms without any intervention.

Central activation of the fatty acid sensor GPR120 suppresses microglia reactivity and alleviates sickness- and anxiety-like behaviors

G protein-coupled receptor 120 (GPR120, Ffar4) is a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs) known for beneficial effects on inflammation, metabolism, and mood. GPR120 mediates the anti-inflammatory and insulin-sensitizing effects of n-3 PUFAs in peripheral tissues. The aim of this study was to determine the impact of GPR120 stimulation on microglial reactivity, neuroinflammation and sickness- and anxiety-like behaviors by acute proinflammatory insults. We found GPR120 mRNA to be enriched in both murine and human microglia, and in situ hybridization revealed GPR120 expression in microglia of the nucleus accumbens (NAc) in mice. In a manner similar to or exceeding n-3 PUFAs, GPR120 agonism (Compound A, CpdA) strongly attenuated lipopolysaccharide (LPS)-induced proinflammatory marker expression in primary mouse microglia, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inhibited nuclear factor-ĸB translocation to the nucleus. Central administration of CpdA to adult mice blunted LPS-induced hypolocomotion and anxiety-like behavior and reduced TNF-α, IL-1β and IBA-1 (microglia marker) mRNA in the NAc, a brain region modulating anxiety and motivation and implicated in neuroinflammation-induced mood deficits. GPR120 agonist pre-treatment attenuated NAc microglia reactivity and alleviated sickness-like behaviors elicited by central injection TNF-α and IL-1β. These findings suggest that microglial GPR120 contributes to neuroimmune regulation and behavioral changes in response to acute infection and elevated brain cytokines. GPR120 may participate in the protective action of n-3 PUFAs at the neural and behavioral level and offers potential as treatment target for neuroinflammatory conditions.

SORCS2 activity in pancreatic α-cells safeguards insulin granule formation and release from glucose-stressed β-cells

Sorting receptor SORCS2 is a stress-response factor protecting neurons from acute insults, such as during epilepsy. SORCS2 is also expressed in the pancreas, yet its action in this tissue remains unknown. Combining metabolic studies in SORCS2-deficient mice with exvivo functional analyses and single-cell transcriptomics of pancreatic tissues, we identified a role for SORCS2 in protective stress response in pancreatic islets, essential to sustain insulin release. We show that SORCS2 is predominantly expressed in isletalpha cells. Loss of expression coincides with inability of these cells to produce osteopontin, a secreted factor that facilitates insulin release from stressed beta cells. In line with diminished osteopontin levels, beta cells in SORCS2-deficient islets show gene expression patterns indicative of aggravated cell stress, and exhibit defects in insulin granule maturation and a blunted glucose response. These findings corroborate a function for SORCS2 in protective stress response that extends to metabolism.

Effect of resistance exercise on secondary inflammatory insult in Alzheimer’s disease models

AbstractBackgroundPhysical exercise improves cognition in human and animal studies associated with Alzheimer’s Disease (AD). However, resistance‐type regimes remain poorly investigated. Acute illness or injury can influence the rate AD progression and trigger accelerated cognitive decline.MethodTo evaluate the role of RE in modulating pre‐existing cognitive impairment, female 3xTg and 5xFAD mice underwent a five‐week RE training protocol. An acute systemic inflammatory insult: laparotomy or intraperitoneally‐injected LPS, was performed to investigate the effect of RE under these challenges. Behavior tests was used to probe for cognition and learning. Brain homogenates were harvested for western blot analysis, qPCR, or post‐fixed in neutral‐buffered formalin solution for immuno‐histochemical exploration.ResultRE showed improved cognitive function, reduced P‐S396‐tau, decreased ionized calcium‐binding adapter molecule 1 (Iba‐1), and decreased inflammatory cytokine transcripts compared to sedentary controls. RE significantly reduced anxiety‐like behavior and cognitive deficit stimulated by acute systemic inflammation episode.ConclusionRE attenuates exaggerated cellular responses and improves cognitive functions in AD and accelerated cognitive impairment triggered by secondary inflammation insult.

Acute Events Significantly Increase Risk for Long-Term End-Organ Sequelae in Sickle Cell Disease - a Retrospective Cohort Study Using Optum Electronic Health Records

Introduction: Sickle cell disease (SCD) is a hereditary red blood cell disorder characterized by hemolytic anemia and vaso-occlusive crisis (VOC), which are associated with acute organ insults and cumulative end-organ damage. However, real-world data (RWD) are lacking for a host of acute events and rates of long-term organ damage in people with SCD, including priapism and leg ulcers. The objective of this study was to use RWD from US patients to comprehensively assess the rates of acute and long-term SCD events, and to explore the association between acute events and the potential implications for long-term organ damage. Methods: This was a retrospective, non-interventional cohort study using Optum US-based Electronic Health Records data from January 1, 2007, to June 30, 2022. The index date followed a 183-day baseline period after initial diagnosis of SCD in the database. Patients with ≥1 inpatient or 2 outpatient SCD ICD-9-CM or ICD-10-CM codes ≥30 days apart were included. Follow-up for acute events and long-term organ damage started at the index date and continued until a patient was censored for lack of database activity, death, or the study period ended. The prevalences of acute events and long-term organ damage were estimated. Cox regression models were used to determine if acute events were associated with long-term organ damage. Acute events reported 1, 2, 3, and ≥4 times were captured and evaluated for their association with outcomes of long-term organ damage. Exposure was time-varying as patients contributed to the unexposed risk group prior to exposure (acute events) and then to subsequent risk groups after exposures accumulated. Hazard ratios (HR) for long-term organ damage between exposed acute event individuals and unexposed individuals with SCD were estimated. Results: A total of 19,214 patients with SCD were included in this study; median (range) age was 29 (0-88) years, 59% were women, and 81% were African American. The most common acute events were VOC episodes assessed through medical utilization (MU) in 39% of patients, acute chest syndrome (ACS) in 15%, and ischemic stroke and seizures, each in 8% of patients. The most common long-term events of organ damage were heart failure (HF) in 7% of patients, neurocognitive deficit in 6%, and pulmonary hypertension (PH) and chronic kidney disease in 5% of patients each (Table 1). After adjusting for age and sex, patients who at any time had an ischemic stroke had an increased risk of a recurrent event (HR=29.86, 95% CI 26.07-34.21), neurocognitive deficit (HR=8.67, 95% CI 7.22-10.40), and paralysis/hemiparesis (HR=21.19, 95% CI 17.25-26.04) compared with those with no pre-existing ischemic stroke event. Patients with ACS at any time had an increased risk of PH (HR=5.39, 95% CI 4.38-6.35), HF (HR=3.88, 95% CI 3.33-4.52), and oxygen dependency (HR=5.25, 95% CI 4.30-6.41) compared with those with no pre-existing ACS event. Patients who had leg ulcers at any time had an increased risk of amputation (HR=16.70, 95% CI 8.24-33.88) and osteomyelitis (HR=15.17, 95% CI 10.83-21.24) compared with those with no pre-existing leg ulcer event. In a similar manner, the risks were higher for long-term organ damage in corresponding organs among patients with an event of hemorrhagic stroke, avascular necrosis of the humerus or femur, gross hematuria, proteinuria, or priapism, than in patients with no pre-existing events. The risk of developing long-term organ damage following one or multiple acute events was assessed (Table 2). For all the HRs, both the upper and lower bounds of the 95% CI were greater than 1. Conclusions: Acute events remain common among patients with SCD, particularly for VOC episodes assessed via MU, ACS, ischemic stroke, and seizure. Compared with patients who never had acute events, those who had any acute events were at higher risk of long-term organ damage in the same organ. Despite improvements in clinical care, RWD in this study suggest patients with SCD who continue to experience a high rate of acute insults are at higher risk of long-term complications that can lead to organ damage. A limitation of this study is the results have not been corrected for hemoglobin (Hb), despite the known correlation between lower Hb levels and higher rates for some types of organ damage. With the development of new therapeutic interventions, it is critical to understand the impact of these new therapies on acute events and rates of long-term organ damage in patients with SCD.

Pax protein depletion in proximal tubules triggers conserved mechanisms of resistance to acute ischemic kidney injury preventing transition to chronic kidney disease

Acute kidney injury (AKI) is a common condition that lacks effective treatments. In part, this shortcoming is due to an incomplete understanding of the genetic mechanisms that control pathogenesis and recovery. Identifying the molecular and genetic regulators unique to nephron segments that dictate vulnerability to injury and regenerative potential could lead to new therapeutic targets to treat ischemic kidney injury. Pax2 and Pax8 are homologous transcription factors with overlapping functions that are critical for kidney development and are re-activated in AKI. Here, we examined the role of Pax2 and Pax8 in recovery from ischemic AKI and found them upregulated after severe AKI and correlated with chronic injury. Surprisingly, proximal-tubule-selective deletion of Pax2 and Pax8 resulted in a less severe chronic injury phenotype. This effect was mediated by protection against the acute insult, similar to pre-conditioning. Prior to injury, Pax2 and Pax8 mutant mice develop a unique subpopulation of proximal tubule cells in the S3 segment that displayed features usually seen only in acute or chronic injury. The expression signature of these cells was strongly enriched with genes associated with other mechanisms of protection against ischemic AKI including caloric restriction, hypoxic pre-conditioning, and female sex. Thus, our results identified a novel role for Pax2 and Pax8 in mature proximal tubules that regulates critical genes and pathways involved in both the injury response and protection from ischemic AKI.

Abstract 15266: Inhibiting Endothelial Mammalian Sterile 20-Like Kinase 1 Attenuates Acute Lung Injury in Mice

Introduction: Lung endothelium plays a pivotal role in the orchestration of inflammatory and injury responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1), a mammalian homolog of Hippo, is a serine/threonine kinase that is ubiquitously expressed in many tissues and has been shown to play an important role in the regulation of complex biological processes, such as apoptosis, oncogenesis and organ growth. While Mst1 is highly expressed in the lung, its role in the endothelial response to pulmonary insults is largely unknown. Hypothesis: Mst1 regulates inflammatory responses in acute lung injury. Methods: Mst1 activity was assessed in lung endothelium by western blot and immunofluorescent staining. EC activation was measured by nuclear factor kappa B (NF-κB) dependent luciferase assay and the electrophoresis mobility shift assay. Mst1 knockout mice and pharmacological inhibitor were employed to assess the effects of Mst1 on homeostatic and lipopolysaccharide (LPS)-induced endothelial inflammation. Results: In this study, we found that Mst1 activation, as determined by Mst1 phosphorylation and nuclear translocation, was significantly increased in lung ECs after exposure to tumor necrosis factor-alpha (TNF-α) and in lungs of LPS-instilled mice as compared to the vehicle control. Overexpression of either full length Mst1 or its kinase domain promoted NF-κB activation by approximately 6.5-fold and 8-fold, respectively, whereas overexpression of the dominant negative forms of Mst1 attenuated endothelial inflammatory responses to both TNF-α and interleukin-1β stimulation. Consistent with these observations, endothelial specific deletion of Mst1 markedly attenuated LPS-induced acute lung injury in mice. Furthermore, we found that treatment of wild-type mice with Mst1 specific pharmacological inhibitor significantly prevented LPS-induced lung injury. Conclusion: Our findings identified Mst1 kinase as a key regulator in promoting lung EC activation and vascular inflammation, and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective for preventing inflammatory vascular diseases of the lung.