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Brain Research May 2024Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus...
Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus coeruleus-norepinephrine (LC-NE) system is a critical regulator of arousal levels and higher executive processes affected by TBI including attention, working memory, and decision making. LC-NE axon injury and impaired signaling within the prefrontal cortex (PFC) is a potential contributor to the neuropsychiatric symptoms after single, moderate to severe TBI. The majority of TBIs are mild, yet long-term cognitive deficits and increased susceptibility for further injury can accumulate after each repetitive mild TBI. As a potential treatment for restoring cognitive function and daytime sleepiness after injury psychostimulants, including methylphenidate (MPH) that increase levels of NE within the PFC, are being prescribed "off-label". The impact of mild and repetitive mild TBI on the LC-NE system remains limited. Therefore, we determined the extent of LC-NE and arousal dysfunction and response to therapeutic doses of MPH in rats following experimentally induced single and repetitive mild TBI. Microdialysis measures of basal NE efflux from the medial PFC and arousal measures were significantly lower after repetitive mild TBI. Females showed higher baseline PFC-NE efflux than males following single and repetitive mild TBI. In response to MPH challenge, males exhibited a blunted PFC-NE response and persistent arousal levels following repetitive mild TBI. These results provide critical insight into the role of catecholamine system dysfunction associated with cognitive deficits following repeated injury, outcome differences between sex/gender, and lack of success of MPH as an adjunctive therapy to improve cognitive function following injury.
PubMed: 38815643
DOI: 10.1016/j.brainres.2024.149040 -
Diabetologia May 2024Hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) enzymes regulate adaptive cellular responses to low oxygen concentrations. Inhibition of HIF-P4Hs leads to...
AIMS/HYPOTHESIS
Hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) enzymes regulate adaptive cellular responses to low oxygen concentrations. Inhibition of HIF-P4Hs leads to stabilisation of hypoxia-inducible factors (HIFs) and activation of the HIF pathway affecting multiple biological processes to rescue cells from hypoxia. As evidence from animal models suggests that HIF-P4H inhibitors could be used to treat metabolic disorders associated with insulin resistance, we examined whether roxadustat, an HIF-P4H inhibitor approved for the treatment of renal anaemia, would have an effect on glucose metabolism in primary human myotubes.
METHODS
Primary skeletal muscle cell cultures, established from biopsies of vastus lateralis muscle from men with normal glucose tolerance (NGT) (n=5) or type 2 diabetes (n=8), were treated with roxadustat. Induction of HIF target gene expression was detected with quantitative real-time PCR. Glucose uptake and glycogen synthesis were investigated with radioactive tracers. Glycolysis and mitochondrial respiration rates were measured with a Seahorse analyser.
RESULTS
Exposure to roxadustat stabilised nuclear HIF1α protein expression in human myotubes. Treatment with roxadustat led to induction of HIF target gene mRNAs for GLUT1 (also known as SLC2A1), HK2, MCT4 (also known as SLC16A4) and HIF-P4H-2 (also known as PHD2 or EGLN1) in myotubes from donors with NGT, with a blunted response in myotubes from donors with type 2 diabetes. mRNAs for LDHA, PDK1 and GBE1 were induced to a similar degree in myotubes from donors with NGT or type 2 diabetes. Exposure of myotubes to roxadustat led to a 1.4-fold increase in glycolytic rate in myotubes from men with NGT (p=0.0370) and a 1.7-fold increase in myotubes from donors with type 2 diabetes (p=0.0044), with no difference between the groups (p=0.1391). Exposure to roxadustat led to a reduction in basal mitochondrial respiration in both groups (p<0.01). Basal glucose uptake rates were similar in myotubes from donors with NGT (20.2 ± 2.7 pmol mg min) and type 2 diabetes (25.3 ± 4.4 pmol mg min, p=0.4205). Treatment with roxadustat enhanced insulin-stimulated glucose uptake in myotubes from donors with NGT (1.4-fold vs insulin-only condition, p=0.0023). The basal rate of glucose incorporation into glycogen was lower in myotubes from donors with NGT (233 ± 12.4 nmol g h) than in myotubes from donors with type 2 diabetes (360 ± 40.3 nmol g h, p=0.0344). Insulin increased glycogen synthesis by 1.9-fold (p=0.0025) in myotubes from donors with NGT, whereas roxadustat did not affect their basal or insulin-stimulated glycogen synthesis. Insulin increased glycogen synthesis by 1.7-fold (p=0.0031) in myotubes from donors with type 2 diabetes. While basal glycogen synthesis was unaffected by roxadustat, pretreatment with roxadustat enhanced insulin-stimulated glycogen synthesis in myotubes from donors with type 2 diabetes (p=0.0345).
CONCLUSIONS/INTERPRETATION
Roxadustat increases glycolysis and inhibits mitochondrial respiration in primary human myotubes regardless of diabetes status. Roxadustat may also improve insulin action on glycogen synthesis in myotubes from donors with type 2 diabetes.
PubMed: 38814443
DOI: 10.1007/s00125-024-06185-6 -
Revista Do Colegio Brasileiro de... 2024Trauma primarily affects the economically active population, causing social and economic impact. The non-operative management of solid organ injuries aims to preserve...
INTRODUCTION
Trauma primarily affects the economically active population, causing social and economic impact. The non-operative management of solid organ injuries aims to preserve organ function, reducing the morbidity and mortality associated with surgical interventions. The aim of study was to demonstrate the epidemiological profile of patients undergoing non-operative management in a trauma hospital and to evaluate factors associated with mortality in these patients.
METHODS
This is a historical cohort of patients undergoing non-operative management for solid organ injuries at a Brazilian trauma reference hospital between 2018 and 2022. Included were patients with blunt and penetrating trauma, analyzing epidemiological characteristics, blood transfusion, and association with the need for surgical intervention.
RESULTS
A total of 365 patients were included in the study. Three hundred and forty-three patients were discharged (93.97%), and the success rate of non-operative treatment was 84.6%. There was an association between mortality and the following associated injuries: hemothorax, sternal fracture, aortic dissection, and traumatic brain injury. There was an association between the need for transfusion and surgical intervention. Thirty-eight patients required some form of surgical intervention.
CONCLUSION
The profile of patients undergoing non-operative treatment consists of young men who are victims of blunt trauma. Non-operative treatment is safe and has a high success rate.
Topics: Humans; Male; Female; Adult; Brazil; Middle Aged; Young Adult; Wounds, Nonpenetrating; Adolescent; Retrospective Studies; Blood Transfusion; Wounds, Penetrating; Aged; Trauma Centers
PubMed: 38808820
DOI: 10.1590/0100-6991e-20243734-en -
Brain Sciences Apr 2024Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence...
Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence.
PubMed: 38790410
DOI: 10.3390/brainsci14050431 -
Ethiopian Journal of Health Sciences Nov 2023Temporal bone fracture is usually a sequel of significant blunt head injury. Fracture of the temporal bone is mainly classified according to the orientation of the...
BACKGROUND
Temporal bone fracture is usually a sequel of significant blunt head injury. Fracture of the temporal bone is mainly classified according to the orientation of the fracture plane and whether there is involvement of the otic capsule. Despite its frequent occurrence, there is limited research on the frequency and pattern of temporal bone fractures in our setup.
METHODS
Retrospective cross-sectional hospital - based study of 60 patients who underwent computed tomography of the head for head trauma at Tikur Anbessa Specialized Hospital during the study period from October 2020 - October 2022.
RESULTS
Among the 60 patients enrolled in the study, the mean age of presentation was 31.1 years with a male-to-female ratio of 4:1. There were 69 temporal bone fractures, 9(15%) were bilateral and 51(85%) unilateral The longitudinal fracture pattern was the most common fracture pattern, occurring in 40(78.4%) of unilateral cases, 15(83.3%) of bilateral cases. Otic capsule sparing fractures accounted for 49(96.07%) of unilateral fracture cases, and all patients with bilateral involvement had an otic capsule sparing fracture. Among the 42 patients for whom data regarding post-traumatic hearing outcome was available, 4 patients had post-traumatic hearing impairment. Anatomically, the squamous portion of the temporal bone was involved in 30(43.5%) of cases.
CONCLUSIONS
Fractures affecting the squamous portion of the temporal bone, longitudinal fracture patterns, and otic capsule sparing were the most frequent forms. The majority of temporal bone fractures were associated with other bone fractures and intracranial injuries.
Topics: Humans; Temporal Bone; Male; Ethiopia; Female; Adult; Cross-Sectional Studies; Retrospective Studies; Skull Fractures; Middle Aged; Tomography, X-Ray Computed; Young Adult; Adolescent; Craniocerebral Trauma; Child; Aged
PubMed: 38784483
DOI: 10.4314/ejhs.v33i6.8 -
Initial Hemorrhage Control Procedure for Splenic Injuries May Affect Risk of Venous Thromboembolism.The Journal of Surgical Research May 2024Venous thromboembolism (VTE) continues to be a major cause of morbidity in trauma. It is unclear whether the type of hemorrhage control procedure (i.e., splenectomy...
INTRODUCTION
Venous thromboembolism (VTE) continues to be a major cause of morbidity in trauma. It is unclear whether the type of hemorrhage control procedure (i.e., splenectomy versus angioembolization) is associated with an increased risk of VTE. We hypothesize that hemodynamically stable patients undergoing angioembolization for blunt high-grade splenic injuries have lower rates of VTE compared to those undergoing splenectomy.
METHODS
The American College of Surgeons Trauma Quality Program dataset from 2017 to 2019 was queried to identify all patients with American Association for the Surgery of Trauma grade 3-5 blunt splenic injuries. Outcomes including VTE rates were compared between those who were managed with splenectomy versus angioembolization. Propensity score matching (1:1) was performed adjusting for age, sex, initial vital signs, Injury Severity Score, and splenic injury grade.
RESULTS
The analysis included 4698 matched patients (splenectomy [n = 2349] and angioembolization [n = 2349]). The median (interquartile range) age was 41 (27-58) years and 69% were male. Patients were well matched between groups. Angioembolization was associated with significantly lower VTE than splenectomy (2.2% versus 3.4%, P = 0.010) despite less use of VTE chemoprophylaxis (70% versus 80%, P < 0.001), as well as a relative delay in initiation of chemoprophylaxis (44 h versus 33 h, P < 0.001). Hospital and intensive care unit length of stay and mortality were also significantly lower in the angioembolization group.
CONCLUSIONS
Angioembolization is associated with a significantly lower incidence of VTE than splenectomy. Thus, angioembolization should be considered for initial management of hemodynamically stable patients with high-grade blunt splenic injuries in whom laparotomy is not otherwise indicated.
PubMed: 38781735
DOI: 10.1016/j.jss.2024.04.034 -
Radiographics : a Review Publication of... Jun 2024Acute diaphragmatic abnormalities encompass a broad variety of relatively uncommon and underdiagnosed pathologic conditions, which can be subdivided into nontraumatic... (Review)
Review
Acute diaphragmatic abnormalities encompass a broad variety of relatively uncommon and underdiagnosed pathologic conditions, which can be subdivided into nontraumatic and traumatic entities. Nontraumatic abnormalities range from congenital hernia to spontaneous rupture, endometriosis-related disease, infection, paralysis, eventration, and thoracoabdominal fistula. Traumatic abnormalities comprise both blunt and penetrating injuries. Given the role of the diaphragm as the primary inspiratory muscle and the boundary dividing the thoracic and abdominal cavities, compromise to its integrity can yield devastating consequences. Yet, diagnosis can prove challenging, as symptoms may be vague and findings subtle. Imaging plays an essential role in investigation. Radiography is commonly used in emergency evaluation of a patient with a suspected thoracoabdominal process and may reveal evidence of diaphragmatic compromise, such as abdominal contents herniated into the thoracic cavity. CT is often superior, in particular when evaluating a trauma patient, as it allows rapid and more detailed evaluation and localization of pathologic conditions. Additional modalities including US, MRI, and scintigraphy may be required, depending on the clinical context. Developing a strong understanding of the acute pathologic conditions affecting the diaphragm and their characteristic imaging findings aids in efficient and accurate diagnosis. Additionally, understanding the appearance of diaphragmatic anatomy at imaging helps in differentiating acute pathologic conditions from normal variations. Ultimately, this knowledge guides management, which depends on the underlying cause, location, and severity of the abnormality, as well as patient factors. RSNA, 2024 Supplemental material is available for this article.
Topics: Humans; Diaphragm; Diagnosis, Differential; Acute Disease; Female; Hernias, Diaphragmatic, Congenital
PubMed: 38781091
DOI: 10.1148/rg.230110 -
Social Cognitive and Affective... May 2024Aberrant levels of reward sensitivity have been linked to substance use disorder and are characterized by alterations in reward processing in the ventral striatum (VS)....
Aberrant levels of reward sensitivity have been linked to substance use disorder and are characterized by alterations in reward processing in the ventral striatum (VS). Less is known about how reward sensitivity and subclinical substance use relate to striatal function during social rewards (e.g., positive peer feedback). Testing this relation is critical for predicting risk for development of substance use disorder. In this pre-registered study, participants (N=44) underwent fMRI while completing well-matched tasks that assess neural response to reward in social and monetary domains. Contrary to our hypotheses, aberrant reward sensitivity blunted the relationship between substance use and striatal activation during receipt of rewards, regardless of domain. Moreover, exploratory whole-brain analyses showed unique relations between substance use and social rewards in temporoparietal junction. Psychophysiological interactions demonstrated that aberrant reward sensitivity is associated with increased connectivity between the VS and ventromedial prefrontal cortex during social rewards. Finally, we found that substance use was associated with decreased connectivity between the VS and dorsomedial prefrontal cortex for social rewards, independent of reward sensitivity. These findings demonstrate nuanced relations between reward sensitivity and substance use, even among those without substance use disorder, and suggest altered reward-related engagement of cortico-VS responses as potential predictors of developing disordered behavior.
PubMed: 38779870
DOI: 10.1093/scan/nsae033 -
Frontiers in Cardiovascular Medicine 2024Endothelial-to-mesenchymal transition (EndMT) is a transdifferentiation process in which endothelial cells (ECs) adopt a mesenchymal-like phenotype. Over the past few...
OBJECTIVE
Endothelial-to-mesenchymal transition (EndMT) is a transdifferentiation process in which endothelial cells (ECs) adopt a mesenchymal-like phenotype. Over the past few years, it became clear that EndMT can contribute to several cardiovascular pathologies. However, the molecular pathways underlying the development of EndMT remain incompletely understood. Since the epigenetic enzyme Enhancer of Zeste Homolog 2 (EZH2) and its concomitant mark H3K27Me3 have been shown to be elevated in many cardiovascular diseases that associate with EndMT, we hypothesized that H3K27Me3 is a determinant for the susceptibility of EndMT.
METHODS
To study the association between H3K27Me3 and EndMT, a knockdown model of EZH2 in human endothelial cells (HUVEC) was utilized to reduce H3K27Me3 abundance, followed by induction of EndMT using TGFβ1. The expression of molecular markers of EndMT and fibrogenesis were analysed.
RESULTS
In cultured HUVECs, a reduction of H3K27Me3 abundance facilitates EndMT but mitigates fibrogenesis as shown by a decreased expression of collagen I and III. In HUVEC, H3K27Me3 abundance directly affects the expression of miR29c, a collagen-targeting miRNA. Additionally, knockdown of miR-29c in HUVEC with low H3K27Me3 abundance partly restored the expression of collagen I and III. Expectedly, in rats with perivascular fibrosis an increased abundance of H3K27Me3 associated with a decreased expression of miR-29c.
CONCLUSION
our data shows that endothelial fibrogenesis underlies an epigenetic regulatory pathway and we demonstrate that a decreased abundance of H3K27Me3 in ECs blunts fibrogenesis in part in a miR-29c dependent manner. Therefore, a reduction of H3K27Me3 could serve as a novel therapeutical strategy to mitigate fibrogenesis and may prove to be beneficial in fibrogenic diseases including atherosclerosis, cardiac fibrosis, and PAH.
PubMed: 38774662
DOI: 10.3389/fcvm.2024.1373279 -
PloS One 2024Recent research suggests that endothelial activation plays a role in coronavirus disease 2019 (COVID-19) pathogenesis by promoting a pro-inflammatory state. However, the...
INTRODUCTION
Recent research suggests that endothelial activation plays a role in coronavirus disease 2019 (COVID-19) pathogenesis by promoting a pro-inflammatory state. However, the mechanism by which the endothelium is activated in COVID-19 remains unclear.
OBJECTIVE
To investigate the mechanism by which COVID-19 activates the pulmonary endothelium and drives pro-inflammatory phenotypes.
HYPOTHESIS
The "inflammatory load or burden" (cytokine storm) of the systemic circulation activates endothelial NADPH oxidase 2 (NOX2) which leads to the production of reactive oxygen species (ROS) by the pulmonary endothelium. Endothelial ROS subsequently activates pro-inflammatory pathways.
METHODS
The inflammatory burden of COVID-19 on the endothelial network, was recreated in vitro, by exposing human pulmonary microvascular endothelial cells (HPMVEC) to media supplemented with serum from COVID-19 affected individuals (sera were acquired from patients with COVID-19 infection that eventually died. Sera was isolated from blood collected at admission to the Intensive Care Unit of the Hospital of the University of Pennsylvania). Endothelial activation, inflammation and cell death were assessed in HPMVEC treated with serum either from patients with COVID-19 or from healthy individuals. Activation was monitored by measuring NOX2 activation (Rac1 translocation) and ROS production; inflammation (or appearance of a pro-inflammatory phenotype) was monitored by measuring the induction of moieties such as intercellular adhesion molecule (ICAM-1), P-selectin and the NLRP3 inflammasome; cell death was measured via SYTOX™ Green assays.
RESULTS
Endothelial activation (i.e., NOX2 activation and subsequent ROS production) and cell death were significantly higher in the COVID-19 model than in healthy samples. When HPMVEC were pre-treated with the novel peptide PIP-2, which blocks NOX2 activation (via inhibition of Ca2+-independent phospholipase A2, aiPLA2), significant abrogation of ROS was observed. Endothelial inflammation and cell death were also significantly blunted.
CONCLUSIONS
The endothelium is activated during COVID-19 via cytokine storm-driven NOX2-ROS activation, which causes a pro-inflammatory phenotype. The concept of endothelial NOX2-ROS production as a unifying pathophysiological axis in COVID-19 raises the possibility of using PIP-2 to maintain vascular health.
Topics: Humans; COVID-19; Reactive Oxygen Species; Endothelial Cells; SARS-CoV-2; NADPH Oxidase 2; Signal Transduction; Endothelium, Vascular; Lung; Peptides; Intercellular Adhesion Molecule-1
PubMed: 38771750
DOI: 10.1371/journal.pone.0289854