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Biomolecules Jun 2024Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of...
Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4 T cells, CD8 T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.
Topics: Animals; Angiotensin II; Aortic Aneurysm, Abdominal; Mice; Male; Sulfonamides; Apolipoproteins E; Phosphate-Binding Proteins; Disease Models, Animal; Mice, Inbred C57BL; Macrophages; Indoles; Mice, Knockout, ApoE; Gasdermins
PubMed: 38927129
DOI: 10.3390/biom14060726 -
BMC Pediatrics Jun 2024Guillain‒Barre syndrome (GBS) is an acute inflammatory peripheral neuropathy caused by autoimmunity. Gangliosides and sulfatides are important components of peripheral...
BACKGROUND
Guillain‒Barre syndrome (GBS) is an acute inflammatory peripheral neuropathy caused by autoimmunity. Gangliosides and sulfatides are important components of peripheral nerves. Anti-sulfatide antibody-mediated complement is associated with acute sensorimotor peripheral neuropathy in GBS, which is characterized by pain and paresthesias.
CASE PRESENTATION
The child was a 7-year-old girl with headache and abdominal pain, followed by limb numbness and pain. Cranial imaging showed ventricular dilatation, peripheral nerve function conduction examination showed polyradiculopathy, and cerebrospinal fluid tests showed normal cell counts but elevated protein levels, all of which led to the diagnosis of GBS. After treatment with intravenous immunoglobulin (400 mg/kg × 5 days), the symptoms did not improve, and muscle strength progressively worsened, accompanied by paroxysmal complexion flushing, heart rate fluctuation, hyperhidrosis, and a progressive increase in cerebrospinal fluid protein (up to 3780.1 mg/L). On the basis of these findings combined with serum anti-sulfatide IgM positivity, anti-sulfatide antibody-related GBS was considered, and treatment with low-dose prednisolone (1 mg/kg/d) led to symptom improvement.
CONCLUSIONS
Anti-sulfatide antibody-associated GBS is associated with small fiber peripheral neuropathy. The main manifestations are pain, paresthesias and autonomic dysfunction. In addition to the dysfunction of spinal nerve root absorption caused by increased cerebrospinal fluid protein, autonomic dysfunction may be involved in pain. When the therapeutic effect of immunoglobulin is not satisfactory, a low dose and short course of corticosteroids can be considered, and the prognosis is good.
Topics: Humans; Female; Child; Guillain-Barre Syndrome; Abdominal Pain; Headache; Sulfoglycosphingolipids; Autoantibodies; Prednisolone
PubMed: 38926645
DOI: 10.1186/s12887-023-04287-5 -
Scientific Reports Jun 2024The study of muscle mass as an imaging-derived phenotype (IDP) may yield new insights into determining the normal and pathologic variations in muscle mass in the...
The study of muscle mass as an imaging-derived phenotype (IDP) may yield new insights into determining the normal and pathologic variations in muscle mass in the population. This can be done by determining 3D abdominal muscle mass from 12 distinct abdominal muscle regions and groups using computed tomography (CT) in a racially diverse medical biobank. To develop a fully automatic technique for assessment of CT abdominal muscle IDPs and preliminarily determine abdominal muscle IDP variations with age and sex in a clinically and racially diverse medical biobank. This retrospective study was conducted using the Penn Medicine BioBank (PMBB), a research protocol that recruits adult participants during outpatient visits at hospitals in the Penn Medicine network. We developed a deep residual U-Net (ResUNet) to segment 12 abdominal muscle groups including the left and right psoas, quadratus lumborum, erector spinae, gluteus medius, rectus abdominis, and lateral abdominals. 110 CT studies were randomly selected for training, validation, and testing. 44 of the 110 CT studies were selected to enrich the dataset with representative cases of intra-abdominal and abdominal wall pathology. The studies were divided into non-overlapping training, validation and testing sets. Model performance was evaluated using the Sørensen-Dice coefficient. Volumes of individual muscle groups were plotted to distribution curves. To investigate associations between muscle IDPs, age, and sex, deep learning model segmentations were performed on a larger abdominal CT dataset from PMBB consisting of 295 studies. Multivariable models were used to determine relationships between muscle mass, age and sex. The model's performance (Dice scores) on the test data was the following: psoas: 0.85 ± 0.12, quadratus lumborum: 0.72 ± 0.14, erector spinae: 0.92 ± 0.07, gluteus medius: 0.90 ± 0.08, rectus abdominis: 0.85 ± 0.08, lateral abdominals: 0.85 ± 0.09. The average Dice score across all muscle groups was 0.86 ± 0.11. Average total muscle mass for females was 2041 ± 560.7 g with a high of 2256 ± 560.1 g (41-50 year old cohort) and a change of - 0.96 g/year, declining to an average mass of 1579 ± 408.8 g (81-100 year old cohort). Average total muscle mass for males was 3086 ± 769.1 g with a high of 3385 ± 819.3 g (51-60 year old cohort) and a change of - 1.73 g/year, declining to an average mass of 2629 ± 536.7 g (81-100 year old cohort). Quadratus lumborum was most highly correlated with age for both sexes (correlation coefficient of - 0.5). Gluteus medius mass in females was positively correlated with age with a coefficient of 0.22. These preliminary findings show that our CNN can automate detailed abdominal muscle volume measurement. Unlike prior efforts, this technique provides 3D muscle segmentations of individual muscles. This technique will dramatically impact sarcopenia diagnosis and research, elucidating its clinical and public health implications. Our results suggest a peak age range for muscle mass and an expected rate of decline, both of which vary between genders. Future goals are to investigate genetic variants for sarcopenia and malnutrition, while describing genotype-phenotype associations of muscle mass in healthy humans using imaging-derived phenotypes. It is feasible to obtain 3D abdominal muscle IDPs with high accuracy from patients in a medical biobank using fully automated machine learning methods. Abdominal muscle IDPs showed significant variations in lean mass by age and sex. In the future, this tool can be leveraged to perform a genome-wide association study across the medical biobank and determine genetic variants associated with early or accelerated muscle wasting.
Topics: Humans; Female; Male; Tomography, X-Ray Computed; Middle Aged; Adult; Phenotype; Retrospective Studies; Aged; Abdominal Muscles; Biological Specimen Banks; Age Factors; Sex Factors; Aged, 80 and over
PubMed: 38926479
DOI: 10.1038/s41598-024-64603-6 -
The Journal of Clinical Investigation Jun 2024Aortic aneurysm is a life-threatening disease with limited interventions, closely related to vascular smooth muscle cells (VSMCs) phenotypic switching. SLC44A2, a member...
Aortic aneurysm is a life-threatening disease with limited interventions, closely related to vascular smooth muscle cells (VSMCs) phenotypic switching. SLC44A2, a member of solute carrier series 44 (SLC44) family, remains under-characterized in the context of cardiovascular diseases. Venn diagram analysis based on microarray and single-cell RNA sequencing identified SLC44A2 as a major regulator of VSMCs phenotypic switching in aortic aneurysm. Screening for Slc44a2 amongst aortic cell lineages demonstrated its predominant location in VSMCs. Elevated levels of SLC44A2 were evidenced in the aorta of both abdominal aortic aneurysm patients and angiotensin II (Ang II)-infused Apoe-/- mice. In vitro, SLC44A2 silencing promoted VSMCs towards a synthetic phenotype, while SLC44A2 overexpression attenuated VSMCs phenotypic switching. VSMCs-specific SLC44A2 knockout mice were more susceptible to aortic aneurysm under Ang II infusion, while SLC44A2 overexpression showed protective effects. Mechanistically, SLC44A2 interaction with NRP1 and ITGB3 activates TGF-β/SMAD signaling, thereby promoting contractile genes expression. Elevated SLC44A2 in aortic aneurysm is associated with upregulated runt-related transcription factor 1 (RUNX1). Furthermore, low dose of lenalidomide (LEN) suppressed aortic aneurysm progression by enhancing SLC44A2 expression. These findings reveal SLC44A2/NRP1/ITGB3 complex is a major regulator of VSMCs phenotypic switching and provide potential therapeutic approach (LEN) for aortic aneurysm treatment.
PubMed: 38916960
DOI: 10.1172/JCI173690 -
Annals of Translational Medicine Jun 2024The abdominal donor site is the most common flap used for breast reconstruction, with flap necrosis a feared complication. The technique of surgical 'delay' involves the... (Review)
Review
BACKGROUND
The abdominal donor site is the most common flap used for breast reconstruction, with flap necrosis a feared complication. The technique of surgical 'delay' involves the inducing of relative ischemia to promote neovascularisation, amongst other metabolic adaptations, and has been used to augment flap vascularity and reduce this complication. There is significant variability in the manner in which flap surgery and surgical delay may be performed, such as the vessels ligated, the presence and degree of flap elevation, and the decision to harvest muscle with the flap, amongst other factors. A formal review of techniques, however, has not yet been performed, and there is no consensus as to the optimal technique for surgical delay.
METHODS
A scoping review of the current literature was undertaken to determine the optimal surgical delay technique in abdominal-based flap surgery. A literature search was conducted across PubMed, Embase, Cochrane, and Medline databases. Data regarding the type of flap surgery, delay techniques, and corresponding clinical outcomes was collected and categorised by technique type.
RESULTS
Nine studies met the inclusion criteria and were included for review. Levels of evidence and rates of complications were compared. The range of surgical delay techniques reported in the literature was described. Surgical delay was found to reduce overall complication rates, and the available data suggests it may be particularly beneficial in high-risk patients.
CONCLUSIONS
The current data support delay as a viable method for reducing rates of complications. Further studies and data are required to compare surgical delay techniques and determine the benefit delay may pose to patients with risk factors.
PubMed: 38911569
DOI: 10.21037/atm-23-306 -
Drug Design, Development and Therapy 2024We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain... (Randomized Controlled Trial)
Randomized Controlled Trial
Esketamine Combined with Dexmedetomidine to reduce Visceral Pain During elective Cesarean Section Under Combined Spinal-Epidural Anesthesia: A double-Blind Randomized Controlled Study.
PURPOSE
We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain during elective cesarean section under combined spinal-epidural anesthesia (CSEA).
PATIENTS AND METHODS
A total of 269 parturients scheduled for elective cesarean section under CSEA between May 2023 and August 2023 were assessed. The parturients were randomly allocated to receiving either intravenous infusion of 0.3-mg/kg esketamine combined with 0.5-μg/kg dexmedetomidine (group ED, n=76), 0.5-μg/kg dexmedetomidine (group D, n=76), or normal saline (group C, n=76) after umbilical cord clamping. The primary outcome was intraoperative visceral pain. Secondary outcomes included the visual analog scale (VAS) score for pain evaluation and other intraoperative complications.
RESULTS
The incidence of visceral pain was lower in group ED [9 (12.7%)] than in group D [32 (43.8%)] and group C [36 (48.6%), <0.0001]. The VAS score was also lower in group ED when exploring abdominal cavity [0 (0), <0.0001] and suturing the muscle layer [0 (0), =0.036]. The mean arterial pressure was higher in group D [83 (9) mmHg] and group ED [81 (11) mmHg] than in group C [75 (10) mmHg, <0.0001] after solution infusion. The heart rate after infusion of the solution was lower in group D [80 (12) bpm] than in group C [86 (14) bpm] and group ED [85 (12) bpm, = 0.016]. The incidence of transient neurologic or mental symptoms was higher in group ED compared to group C and group D (76.1% vs 18.9% vs 23.3%, <0.0001).
CONCLUSION
During cesarean section, 0.3-mg/kg esketamine combined with 0.5-μg/kg dexmedetomidine can alleviate visceral traction pain and provide stable hemodynamics. Parturients receiving this regimen may experience transient neurologic or mental symptoms that can spontaneously resolve at the end of the surgery.
Topics: Humans; Dexmedetomidine; Ketamine; Double-Blind Method; Cesarean Section; Female; Adult; Visceral Pain; Anesthesia, Spinal; Pregnancy; Anesthesia, Epidural; Drug Therapy, Combination; Elective Surgical Procedures
PubMed: 38911034
DOI: 10.2147/DDDT.S460924 -
Poultry Science Jun 2024As an anti-myogenic factor, the myostatin (MSTN) gene was mainly considered as a genetic marker to improve meat production. Moreover, an additional effect of the MSTN...
As an anti-myogenic factor, the myostatin (MSTN) gene was mainly considered as a genetic marker to improve meat production. Moreover, an additional effect of the MSTN mutation on reducing fat deposition in various farm animals suggested a potential application of the MSTN gene on regulating fat deposition in poultry species. Although increase in muscle mass resulted from muscle hyperplasia in the MSTN mutant quail, cellular mechanism behind the decrease in fat deposition was not investigated in the quail model. In the current study, to investigate sexual dimorphic association between fat deposition and Mstn mutation in quail, leg and abdominal fat pads from 4-month-old male and female quail were histologically analyzed. Interestingly, abdominal and leg fat pad weights were significantly decreased by the MSTN mutation only in female quail, but not in male quail, showing sexual dimorphism in regulating fat deposition by the MSTN mutation in quail. Histological analysis also revealed that fat cell sizes of leg and abdominal fats were significantly reduced only in female groups aligning with the decreased fat pad weights. Sexual dimorphic effect of the MSTN mutation on fat cell hypotrophy and reduced fat pad weights in quail provided an important scientific finding to be considered on the usage of the MSTN gene as a genetic marker to reduce fat deposition in poultry species.
PubMed: 38909511
DOI: 10.1016/j.psj.2024.103951 -
Biomaterials Jun 2024Biohybrid tissue-engineered vascular grafts (TEVGs) promise long-term durability due to their ability to adapt to hosts' needs. However, the latter calls for sensitive...
Biohybrid tissue-engineered vascular grafts (TEVGs) promise long-term durability due to their ability to adapt to hosts' needs. However, the latter calls for sensitive non-invasive imaging approaches to longitudinally monitor their functionality, integrity, and positioning. Here, we present an imaging approach comprising the labeling of non-degradable and degradable TEVGs' components for their in vitro and in vivo monitoring by hybrid H/F MRI. TEVGs (inner diameter 1.5 mm) consisted of biodegradable poly(lactic-co-glycolic acid) (PLGA) fibers passively incorporating superparamagnetic iron oxide nanoparticles (SPIONs), non-degradable polyvinylidene fluoride scaffolds labeled with highly fluorinated thermoplastic polyurethane (F-TPU) fibers, a smooth muscle cells containing fibrin blend, and endothelial cells. H/F MRI of TEVGs in bioreactors, and after subcutaneous and infrarenal implantation in rats, revealed that PLGA degradation could be faithfully monitored by the decreasing SPIONs signal. The F signal of F-TPU remained constant over weeks. PLGA degradation was compensated by cells' collagen and α-smooth-muscle-actin deposition. Interestingly, only TEVGs implanted on the abdominal aorta contained elastin. XTT and histology proved that our imaging markers did not influence extracellular matrix deposition and host immune reaction. This concept of non-invasive longitudinal assessment of cardiovascular implants using H/F MRI might be applicable to various biohybrid tissue-engineered implants, facilitating their clinical translation.
PubMed: 38906013
DOI: 10.1016/j.biomaterials.2024.122669 -
Frontiers in Cardiovascular Medicine 2024In hypertension (HTN), biomechanical stress may drive matrix remodeling through dysfunctional VSMC activity. Prior evidence has indicated VSMC tension-induced signaling...
INTRODUCTION
In hypertension (HTN), biomechanical stress may drive matrix remodeling through dysfunctional VSMC activity. Prior evidence has indicated VSMC tension-induced signaling through the serum and glucocorticoid inducible kinase-1 (SGK-1) can impact cytokine abundance. Here, we hypothesize that SGK-1 impacts production of additional aortic pathologic markers (APMs) representing VSMC dysfunction in HTN.
METHODS
Aortic VSMC expression of APMs was quantified by QPCR in cyclic biaxial stretch (Stretch) +/- AngiotensinII (AngII). APMs were selected to represent VSMC dedifferentiated transcriptional activity, specifically Interleukin-6 (IL-6), Cathepsin S (CtsS), Cystatin C (CysC), Osteoprotegerin (OPG), and Tenascin C (TNC). To further assess the effect of tension alone, abdominal aortic rings from C57Bl/6 WT mice were held in a myograph at experimentally derived optimal tension (OT) or OT + 30% +/-AngII. Dependence on SGK-1 was assessed by treating with EMD638683 (SGK-1 inhibitor) and APMs were measured by QPCR. Then, WT and smooth muscle cell specific SGK-1 heterozygous knockout (SMC-SGK-1KO) mice had AngII-induced HTN. Systolic blood pressure and mechanical stress parameters were assessed on Day 0 and Day 21. Plasma was analyzed by ELISA to quantify APMs. Statistical analysis was performed by ANOVA.
RESULTS
In cultured aortic VSMCs, expression of all APMs was increased in response to biomechanical stimuli (Stretch +/-AngII,). Integrating the matrix contribution to signal transduction in the aortic rings led to IL-6 and CysC demonstrating SGK-1 dependence in response to elevated tension and interactive effect with concurrent AngII stimulation. CtsS and TNC, on the other hand, primarily responded to AngII, and OPG expression was unaffected in aortic ring experimentation. Both mouse strains had >30% increase in blood pressure with AngII infusion, reduced aortic distensibility and increased PPV, indicating increased aortic stiffness. In WT + AngII mice, IL-6, CtsS, CysC, and TNC plasma levels were significantly elevated, but these APMs were unaffected by HTN in the SMC-SGK-1KO +AngII mice, suggesting SGK-1 plays a major role in VSMC biomechanical signaling to promote dysfunctional production of selected APMs.
CONCLUSION
In HTN, changes in the plasma levels of markers associated with aortic matrix homeostasis can reflect remodeling driven by mechanobiologic signaling in dysfunctional VSMCs, potentially through the activity of SGK-1. Further defining these pathways may identify therapeutic targets to reduce cardiovascular morbidity and mortality.
PubMed: 38903966
DOI: 10.3389/fcvm.2024.1359734 -
International Journal of Medical... 2024Glutamine (Gln), known as the most abundant free amino acid, is widely spread in human body. In this study, we demonstrated the protective effects of glutamine against...
Glutamine (Gln), known as the most abundant free amino acid, is widely spread in human body. In this study, we demonstrated the protective effects of glutamine against mouse abdominal aortic aneurysm (AAA) induced by both angiotensin II (AngII) and calcium phosphate (Ca(PO)) , which was characterized with lower incidence of mouse AAA. Moreover, histomorphological staining visually presented more intact elastic fiber and less collagen deposition in abdominal aortas of mice treated by glutamine. Further, we found glutamine inhibited the excessive production of reactive oxide species (ROS), activity of matrix metalloproteinase (MMP), M1 macrophage activation, and apoptosis of vascular smooth muscle cells (VSMCs) in suprarenal abdominal aortas of mice, what's more, the high expressions of MMP-2 protein, MMP-9 protein, pro-apoptotic proteins, and IL-6 as well as TNF-α in protein and mRNA levels in cells treated by AngII were down-regulated by glutamine. Collectively, these results revealed that glutamine protected against mouse AAA through inhibiting apoptosis of VSMCs, M1 macrophage activation, oxidative stress, and extracellular matrix degradation.
Topics: Animals; Aortic Aneurysm, Abdominal; Apoptosis; Mice; Glutamine; Angiotensin II; Macrophage Activation; Muscle, Smooth, Vascular; Humans; Myocytes, Smooth Muscle; Oxidative Stress; Reactive Oxygen Species; Disease Models, Animal; Male; Macrophages; Aorta, Abdominal; Matrix Metalloproteinase 9; Matrix Metalloproteinase 2; Tumor Necrosis Factor-alpha; Interleukin-6; Calcium Phosphates
PubMed: 38903916
DOI: 10.7150/ijms.96395