Perivascular Tissue Research Articles

TIPIC syndrome in a patient following sorafenib treatment for acute myeloid leukemia: a rare case report

Transient Perivascular Inflammation of the\ Carotid Artery (TIPIC) syndrome is uncommon, and cases of TIPIC induced by the targeted drug, sorafenib, are extremely rare. This case report describes a patient with acute myeloid leukemia carrying an FMS‐like tyrosine kinase 3 mutation, who developed TIPIC syndrome, which may have been induced by sorafenib treatment. A 65-year-old woman diagnosed with acute myeloid leukemia experienced severe neck pain and sclerotic blisters on her palms and soles during sorafenib treatment. Carotid ultrasound revealed thickening of the right common carotid artery (RCCA) wall, and magnetic resonance imaging revealed perivascular tissue edema in the distal RCCA. Following clinical and imaging assessments, the patient was diagnosed with TIPIC syndrome. Treatment involved a one-week course of oral steroid therapy with dexamethasone and non-steroidal anti-inflammatory drugs, which led to complete clinical recovery. TIPIC syndrome involves transient nonspecific perivascular inflammation of the carotid adventitia; however, the precise underlying cause remains unclear. In this study, we report a rare case and explore the potential pathophysiological mechanisms through a review of the existing literature.

Predicting the macrovascular contribution to resting-state fMRI functional connectivity at 3 Tesla: A model-informed approach

Abstract Macrovascular biases have been a long-standing challenge for functional magnetic resonance imaging (fMRI), limiting its ability to detect spatially specific neural activity. Recent experimental studies, including our own, found substantial resting-state macrovascular blood-oxygenation level-dependent (BOLD) fMRI contributions from large veins and arteries, extending into the perivascular tissue at 3 T and 7 T. The objective of this study is to demonstrate the feasibility of predicting, using a biophysical model, the experimental resting-state BOLD fluctuation amplitude (RSFA) and associated functional connectivity (FC) values at 3 Tesla. We investigated the feasibility of both 2D and 3D infinite-cylinder Models as well as macrovascular anatomical networks (macro-VANs) derived from angiograms. Our results demonstrate that (1) with the availability of macro-VANs, it is feasible to model macrovascular BOLD FC using both the macro-VAN-based model and 3D infinite-cylinder Models, though the former performed better; (2) biophysical modelling can accurately predict the BOLD pair-wise correlation near to large veins (with R2 ranging from 0.53 to 0.93 across different subjects), but not near to large arteries; (3) compared with FC, biophysical modelling provided less accurate predictions for RSFA; (4) modelling of perivascular BOLD connectivity was feasible at close distances from veins (with R2 ranging from 0.08 to 0.57), but not arteries, with performance deteriorating with increasing distance. While our current study demonstrates the feasibility of simulating macrovascular BOLD in the resting state, our methodology may also apply to understanding task-based BOLD. Furthermore, these results suggest the possibility of correcting for macrovascular bias in resting-state fMRI and other types of fMRI using biophysical modelling based on vascular anatomy.

A Skeletal Muscle-Mediated Anticontractile Response on Vascular Tone: Unraveling the Lactate-AMPK-NOS1 Pathway in Femoral Arteries.

The regulation of vascular tone by perivascular tissues is a complex interplay of various paracrine factors. Here, we investigate the anti-contractile effect of skeletal muscle surrounding the femoral and carotid arteries and its underlying mechanisms. Using male and female Wistar rats, we demonstrated that serotonin, phenylephrine, and U-46619 induced a concentration-dependent vasoconstrictor response in femoral artery rings. Interestingly, this response was diminished in the presence of surrounding femoral skeletal muscle, irrespective of sex. No anti-contractile effect was observed when the carotid artery was exposed to its surrounding skeletal muscle. The observed effect in the femoral artery persisted even in the absence of endothelium and when the muscle was detached from the artery. Furthermore, the skeletal muscle surrounding the femoral artery was able to promote an anti-contractile effect in three other vascular beds (basilar, mesenteric, and carotid arteries). Using inhibitors of lactate dehydrogenase and the 1/4 monocarboxylate transporter, we confirmed the involvement of lactate, as both inhibitors were able to abolish the anti-contractile effect. However, lactate did not directly promote vasodilation; rather, it exerted its effect by activating 5' AMP-activated protein kinase (AMPK) and neuronal nitric oxide synthase (NOS1) in the skeletal muscle. Accordingly, Nω-propyl L-arginine, a specific inhibitor of NOS1, prevented the anti-contractile effect, as well as lactate-induced phosphorylation of NOS1 at the stimulatory serine site (1417) in primary skeletal muscle cells. Phosphorylation of NOS1 was reduced in the presence of Bay-3827, a selective AMPK inhibitor. In conclusion, femoral artery-associated skeletal muscle is a potent paracrine and endocrine organ that influences vascular tone in both sexes. Mechanistically, the anti-contractile effect involves muscle fiber type and/or its anatomical location but not the type of artery or its related vascular endothelium. Finally, the femoral artery anti-contractile effect is mediated by the lactate-AMPK-phospho-NOS1Ser1417-NO signaling axis.

Editorial Comment: CT Surveillance for Local Recurrence After Pancreatic Cancer Resection-Focus on Perivascular Soft Tissue in the Surgical Bed.

Editorial Comment: CT Surveillance for Local Recurrence After Pancreatic Cancer Resection-Focus on Perivascular Soft Tissue in the Surgical Bed.

Long-term efficacy of drug-coated balloon-only angioplasty for IgG4-related coronary artery disease: A case report

Abstract Background Although coronary artery involvement in patients with IgG4-related disease (IgG4-RD) is rare, emergency revascularisation is recommended for managing acute coronary syndrome. However, coronary aneurysm formation and stent migration after sirolimus-eluting stent implantation have been reported for this disease. Thus, new treatment modalities are warranted for the management of coronary artery disease in this vasculitis. Case summary A 70-year-old male who experienced progressive chest discomfort for 1 month underwent cardiac examination. Coronary computed tomography angiography (CCTA) revealed right coronary artery hypoplasia, coronary artery aneurysm with severely calcified stenosis in the proximal left anterior descending artery (LAD), and subtotal obstruction in the mid-LAD. The left circumflex artery (LCX) also had stenosis and dilated lesions. Additionally, diffuse perivascular soft tissue thickening was observed in the mid-LCX. Percutaneous coronary intervention was performed for the proximal- and mid-LAD lesions. Rotational atherectomy with low-pressure drug-coated balloon (DCB) dilation was considered for these lesions owing to suspicion of vasculitis. The patient was later diagnosed with Sjögren's syndrome and IgG4-RD overlap syndrome. Oral steroids and immunosuppressive drugs were initiated. In a follow-up at 7 and 26 months, late lumen enlargement was observed in the treated area of the LAD, without enlargement of the adjacent aneurysm. CCTA performed after 26 months revealed resolution of the diffuse perivascular soft tissue thickening in the mid-LCX. Discussion To our knowledge, this is the first case report demonstrating favourable outcomes for treatment of a coronary artery lesion attributed to IgG4-RD with DCB, leaving nothing implanted in the coronary artery tree.

Vγ6/Vδ1+ γδ T cells protect from angiotensin II effects on blood pressure and endothelial function in mice.

γδ T cells mediate angiotensin II (AngII)-induced hypertension and vascular injury. γδ T cells expressing specific T-cell receptor (TCR) variable (V) γ chains develop in several waves in the thymus and migrate to specific or diverse tissues. We hypothesized that γδ T cells expressing specific Vγ subtypes in perivascular tissue mediate AngII hypertensive effects. C57BL/6J male mice were infused or not with AngII (490 ng/kg/min, subcutaneously) for 14 days. γδ T-cell Vγ subtypes were profiled by flow cytometry in the spleen, descending thoracic aorta with adherent perivascular adipose tissue (DTAo/PVAT) and mesenteric vessels (MV)/PVAT. Other sets of AngII-infused mice were injected with control or specific anti-Vγ6 or Vγ4 antibodies. Blood pressure (BP) was determined by telemetry, and mesenteric artery function and remodeling by pressurized myography. Vγ6/Vδ1+ γδ T cells represented more than 50% of the γδ T-cell Vγ subtypes in DTAo/PVAT and MV/PVAT, whereas Vγ1/2+, Vγ4+ and Vγ6/Vδ1+ γδ T cells were the most abundant Vγ subtypes in the spleen. The frequency of Vγ6/Vδ1+ γδ T cells was increased at least 1.5-fold in the spleen and DTAo/PVAT, and tended to increase in MV/PVAT by AngII. A majority of Vγ6/Vδ1+ γδ T cells were activated in perivascular tissues. Vγ6/Vδ1+ γδ T-cell neutralization caused a steeper BP elevation and greater mesenteric artery endothelial dysfunction in mice infused with AngII. This was associated with more than three-fold increase in activated Vγ6/Vδ1- γδ T cells in perivascular tissues. Depletion of Vγ4+ γδ T cells did not alter AngII detrimental effects. Vγ6/Vδ1+ γδ T cells reduce the BP elevation and endothelial dysfunction induced by AngII infusion.

Abstract 32: Vγ6 + γδ T cells protect against angiotensin II-induced hypertension and vascular injury in male mice

Background: γδ T cells mediate angiotensin II (AngII)-induced blood pressure (BP) elevation, vascular injury and activated T cell infiltration in mesenteric vessels with adherent perivascular adipose tissue (MV/PVAT). γδ T cells expressing specific T cell receptor (TCR) variable (V) chain γ develop in several waves in the thymus and migrate to diverse tissues. We hypothesized that γδ T cells expressing specific Vγ subtypes in perivascular tissue are implicated in AngII detrimental hypertensive effects. Methods: C57BL/6J male mice were infused or not with AngII (490 ng/kg/min, SC) for 14 days. Vγ1 and Vγ2 (Vγ1/2) + , Vγ4 + , Vγ5 + , Vγ6 + , and Vγ7 + γδ T cell frequencies and T cell phenotypes were determined by flow cytometry in the spleen, descending thoracic aorta (DTAo)/PVAT, and MV/PVAT (n=7-13). Other sets of AngII-infused mice were injected with control or anti-Vγ6 (n=7-12) or Vγ4 antibodies (n=5-8). BP was determined by telemetry, mesenteric artery (MA) function and remodeling by pressurized myography, and T cell phenotypes by flow cytometry. Results: In DTAo/PVAT and MV/PVAT, respectively, 43±5% and 51%±6% of γδ T cells were Vγ6 + , and 17±2% and 23±4% Vγ4 + , whereas in the spleen, 36±2% of the γδ T cells were Vγ1/2 + , 32±1% Vγ4 + and 24±1% Vγ6 + . AngII increased the frequency of Vγ6 + γδ T cells in the spleen (0.8±0.1 vs 0.5±0.0% of CD3, P <0.001) and DTAo/PVAT (5.9±0.8 vs 3.6±0.5% of CD3, P <0.05), and tended to increase their frequency in MV/PVAT. The majority of Vγ6 + γδ T cells were activated (CD69 + ) in DTAo/PVAT (75±5%) and MV/PVAT (84±2%). Vγ6 + γδ T cell depletion caused a steeper BP elevation ( P <0.05) and worsened MA endothelial dysfunction (maximal acetylcholine relaxation response: 28±3 vs 55±8%, P <0.05) in mice infused with AngII. This was associated with increased CD69 + non-Vγ6 + γδ T cells in DTAo/PVAT (3.0±0.7 vs 0.8±0.4% of CD3, P <0.01) and MV/PVAT (15.2±2.6 vs 4.9±1.0% of CD3, P <0.01). Depletion of Vγ4 + γδ T cells in perivascular tissues, did not alter the AngII detrimental effects. Conclusions: Vγ6 + γδ T cells are the most abundant γδ T cell Vγ subtype in perivascular tissues. AngII increased Vγ6 + γδ T cells in the spleen and perivascular tissue. Vγ6 + γδ T cell depletion in AngII-infused mice induced a steeper BP elevation, worsened MA endothelial dysfunction, and activated non-Vγ6 + γδ T cells. Vg6 + γδ T cells may play a protective role in AngII-induced hypertension and vascular injury.

O47 THE ROLE OF IL-33 AND ST2 IN THE MODULATION OF TARGET ORGAN DAMAGE IN ANGIOTENSIN II-DEPENDENT HYPERTENSION

Introduction: Hypertension is associated with a chronic inflammatory state and aberrant immune system activity. Interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) signalling axis is important in the modulation of atherosclerosis and cardiovascular fibrosis. We aimed to evaluate the modulation of IL-33 and ST2 in hypertensive mouse models and patients. Methods and Results: Hypertension was induced by a 14-day infusion of Ang-II (490ng/min/kg) in 12-week-old WT C57BL/6, ST2KO, IL33KO mice. IL-33 and ST2 mRNA and protein were evaluated using qPCR and Western blot in WT mice. Ang II-infusion significantly increased IL-33 and ST2 protein expression in target organs related to hypertension, particularly the aorta (1.0±0.1 vs 2.8±0.2, p<0.0001, and 0.963±0.068 vs 2.094±0.231, p=0.002, respectively). Further, mRNA expression of IL-33 and ST2 was elevated in hypertensive aortas when compared with control (1.0±0.053 vs 1.76±0.271, p=0.0185 and 1.0±0.039 vs 1.978±0.221, p=0.0039, respectively). IHC from WT mice illustrated the localisation of IL-33 and ST2 in Ang-II aortas in ECs and SMCs. Further in human hypertensive mammary arteries, the localisation was. In-vivo, IL33KO and ST2KO mice showed no altered BP at baseline or after 14 days of Ang-II compared to WT littermates. ST2KO Ang-II mice showed protection against endothelial dysfunction compared to WT Ang-II mice through isometric tension studies (p=0.0317). Additionally, Ang-II-induced IL33KO and ST2KO mice worsen cardiac fibrosis compared to WT littermates (p=0.0005,p<0.0001, respectively). Conclusion: Both IL-33 and its receptor, ST2 are increased in the vascular and perivascular tissues in hypertension. Additionally, the IL-33/ST2 axis has a role in regulating cardiac fibrosis.

B cells in perivascular and peribronchiolar granuloma-associated lymphoid tissue and B-cell signatures identify asymptomatic Mycobacterium tuberculosis lung infection in Diversity Outbred mice.

Because most humans resist Mycobacterium tuberculosis infection, there is a paucity of lung samples to study. To address this gap, we infected Diversity Outbred mice with M. tuberculosis and studied the lungs of mice in different disease states. After a low-dose aerosol infection, progressors succumbed to acute, inflammatory lung disease within 60 days, while controllers maintained asymptomatic infection for at least 60 days, and then developed chronic pulmonary tuberculosis (TB) lasting months to more than 1 year. Here, we identified features of asymptomatic M. tuberculosis infection by applying computational and statistical approaches to multimodal data sets. Cytokines and anti-M. tuberculosis cell wall antibodies discriminated progressors vs controllers with chronic pulmonary TB but could not classify mice with asymptomatic infection. However, a novel deep-learning neural network trained on lung granuloma images was able to accurately classify asymptomatically infected lungs vs acute pulmonary TB in progressors vs chronic pulmonary TB in controllers, and discrimination was based on perivascular and peribronchiolar lymphocytes. Because the discriminatory lesion was rich in lymphocytes and CD4 T cell-mediated immunity is required for resistance, we expected CD4 T-cell genes would be elevated in asymptomatic infection. However, the significantly different, highly expressed genes were from B-cell pathways (e.g., Bank1, Cd19, Cd79, Fcmr, Ms4a1, Pax5, and H2-Ob), and CD20+ B cells were enriched in the perivascular and peribronchiolar regions of mice with asymptomatic M. tuberculosis infection. Together, these results indicate that genetically controlled B-cell responses are important for establishing asymptomatic M. tuberculosis lung infection.

Heterogeneous stiffness of the bone marrow microenvironment regulates the fate decision of haematopoietic stem and progenitor cells.

The bone marrow (BM) niches are the complex microenvironments that surround cells, providing various external stimuli to regulate a range of haematopoietic stem cell (HSC) behaviours. Recently, it has been proposed that the fate decision of HSCs is often correlated with significantly altered biophysical signals of BM niches. To thoroughly elucidate the effect of mechanical microenvironments on cell fates, we constructed 2D and 3D cell culture hydrogels using polyacrylamide to replicate the mechanical properties of heterogeneous sub-niches, including the inherent rigidity of marrow adipose tissue (2 kPa), perivascular tissue (8 kPa) and endosteum region (35 kPa) in BM. Our observations suggest that HSCs can respond to the mechanical heterogeneity of the BM microenvironment, exhibiting diversity in cell mechanics, haematopoietic pool maintenance and differentiated lineages. Hydrogels with higher stiffness promote the preservation of long-term repopulating HSCs (LT-HSCs), while those with lower stiffness support multi-potent progenitors (MPPs) viability in vitro. Furthermore, we established a comprehensive transcriptional profile of haematopoietic subpopulations to reflect the multipotency of haematopoietic stem and progenitor cells (HSPCs) that are modulated by niche-like stiffness. Our findings demonstrate that HSPCs exhibit completely distinct downstream differentiated preferences within hydrogel systems of varying stiffness. This highlights the crucial role of tissue-specific mechanical properties in HSC lineage decisions, which may provide innovative solutions to clinical challenges.

Toward a physiological model of vascular wall vibrations in the arteriovenous fistula.

The mechanism behind hemodialysis arteriovenous fistula (AVF) failure remains poorly understood, despite previous efforts to correlate altered hemodynamics with vascular remodeling. We have recently demonstrated that transitional flow induces high-frequency vibrations in the AVF wall, albeit with a simplified model. This study addresses the key limitations of our original fluid-structure interaction (FSI) approach, aiming to evaluate the vibration response using a more realistic model. A 3D AVF geometry was generated from contrast-free MRI and high-fidelity FSI simulations were performed. Patient-specific inflow and pressure were incorporated, and a three-term Mooney-Rivlin model was fitted using experimental data. The viscoelastic effect of perivascular tissue was modeled with Robin boundary conditions. Prescribing pulsatile inflow and pressure resulted in a substantial increase in vein displacement ( %) and strain ( %), with a higher maximum spectral frequency becoming visible above -42 dB (from 200 to 500 Hz). Transitioning from Saint Venant-Kirchhoff to Mooney-Rivlin model led to displacement amplitudes exceeding 10 micrometers and had a substantial impact on strain ( %). Robin boundary conditions significantly damped high-frequency displacement ( %). Incorporating venous tissue properties increased vibrations by 91%, extending up to 700 Hz, with a maximum strain of 0.158. Notably, our results show localized, high levels of vibration at the inner curvature of the vein, a site known for experiencing pronounced remodeling. Our findings, consistent with experimental and clinical reports of bruits and thrills, underscore the significance of incorporating physiologically plausible modeling approaches to investigate the role of wall vibrations in AVF remodeling and failure.

The impact of perivascular tissue preservation on 5-year patency of saphenous vein composite grafts.

This retrospective study was conducted to evaluate the impact of saphenous vein (SV) harvesting with versus without perivascular tissue on the 5-year angiographic patency in coronary artery bypass grafting. Among the 944 patients who received coronary artery bypass grafting between 2010 and 2015, 579 patients who received off-pump coronary artery bypass grafting using 1 SV as a Y-composite graft based on the in situ left internal thoracic artery were enrolled. SV harvesting was performed using no-touch technique without perivascular tissue (the NoPVT group) in 342 patients and with perivascular tissue (the PVT group) in 237 patients. Follow-up duration was 84.0 months (interquartile range 66.5-105.4). Propensity score matching was performed, and long-term clinical outcomes and angiographic patency were compared. The average number of distal anastomoses per patient was comparable between the groups, although more SV grafts were anastomosed to left anterior descending territory in the PVT group than in the NoPVT group. Overall survival and cumulative incidence of cardiac death were comparable between the groups, whereas cumulative incidence of target vessel revascularization (1.3% vs 4.3% at 5 year, P = 0.009) and that of major adverse cardiac events (7.3% vs 9.9% at 5 year, P = 0.035) were lower in the PVT group than in the NoPVT group. One-year and 5-year angiographic patency rates of the SV grafts were higher in the PVT group than in the NoPVT group [97.0% vs 91.7% (P = 0.004) and 96.3% vs 89.9% (P = 0.007), respectively]. SV grafts harvested using no-touch technique with perivascular tissue further improved the 5-year patency of SV composite grafts compared with those without perivascular tissue.

No-touch saphenous vein: current understanding of the conduit 'less handled'.

The no-touch technique is an established method to harvest the saphenous vein (NT-SV), which is the most commonly used conduit in coronary artery bypass grafting. Herein, we summarize the foundational evidence, as well as highlight recent innovations and ongoing clinical trials involving NT-SV. Through preservation of perivascular tissue for atraumatic handling and omission of manual distension, the NT-SV maintains endothelial nitrous oxide synthase levels and experiences less vascular smooth muscle cell activation, which translates to slower progression of atherosclerosis and less size mismatch of the graft and target vessel. These biomolecular advantages allow NT-SV to provide superior graft patency compared to conventional skeletonized saphenous vein and approximating that of the radial artery. Nonetheless, the clinical benefits of NT-SV for mortality and reduction in major adverse cardiac and cerebrovascular events are insufficiently studied in the long-term. The drawback of NT-SV is the short-term harvest site complications, which may potentially be addressed by the advent of endoscopic no-touch technique. NT-SV is a promising conduit, and its role will be further clarified in upcoming clinical trials and as follow-up lengthens. However, conduit selection and harvest technique should ultimately be personalized to the individual patient.

A Rare Case of Lemierre’s Syndrome due to Veillonella Parvula: A Dangerous and Forgotten Complication of a Septic Condition

This clinical case presents an unusual case of Lemierre’s syndrome (LS) in a young woman of 38-year-old. She arrived in the Emergency Department with a high fever and pharyngology resistant to antibiotic therapy with clarithromycin, ceftriaxone, and cortisone for two weeks. At the blood sampling, there is a marked leucocytosis, and the advice of the otolaryngologist is required given the strong pain in the throat. Due to the tonsillar abscess, a neck CT with a contrast medium is necessary for the otolaryngologist’s opinion. The CT shows thrombosis of the jugular vein and left subclavian, with thickening of soft perivascular tissues; these findings suggest Lemierre’s syndrome: a septic thrombophlebitis of the jugular vein that occurs as a complication of a peritonsillar abscess. The diagnostic process is then completed with a chest HR-CT, which reveals lung density and excavation areas suggesting tuberculosis. Blood culture reveals the presence of Veillonella Parvula (an anaerobic gram-negative coccus), sputum culture reveals the presence of some colonies of Enterobacter cloacae complex, real-time PCR examination on sputum reveals the presence of Streptococcus Pneumoniae and the borderline presence of rhinovirus. Microbiologists, after these results and neck and chest CT with a contrast agent, agree with the diagnosis of suspected LS at an early stage: a septic dissemination fortunately limited only to the neck and lungs region.

Neuroendocrine and cellular mechanisms in stress resilience: From hormonal influence in the CNS to mitochondrial dysfunction and oxidative stress.

Recent advancements in neuroendocrinology challenge the long-held belief that hormonal effects are confined to perivascular tissues and do not extend to the central nervous system (CNS). This paradigm shift, propelled by groundbreaking research, reveals that synthetic hormones, notably in anti-inflammatory medications, significantly influence steroid psychosis, behavioural, and cognitive impairments, as well as neuropeptide functions. A seminal development in this field occurred in 1968 with McEven's proposal that rodent brains are responsive to glucocorticoids, fundamentally altering the understanding of how anxiety impacts CNS functionality and leading to the identification of glucocorticosteroids and mineralocorticoids as distinct corticotropic receptors. This paper focuses on the intricate roles of the neuroendocrine, immunological, and CNS in fostering stress resilience, underscored by recent animal model studies. These studies highlight active, compensatory, and passive strategies for resilience, supporting the concept that anxiety and depression are systemic disorders involving dysregulation across both peripheral and central systems. Resilience is conceptualized as a multifaceted process that enhances psychological adaptability to stress through adaptive mechanisms within the immunological system, brain, hypothalamo-pituitary-adrenal axis, and ANS Axis. Furthermore, the paper explores oxidative stress, particularly its origin from the production of reactive oxygen species (ROS) in mitochondria. The mitochondria's role extends beyond ATP production, encompassing lipid, heme, purine, and steroidogenesis synthesis. ROS-induced damage to biomolecules can lead to significant mitochondrial dysfunction and cell apoptosis, emphasizing the critical nature of mitochondrial health in overall cellular function and stress resilience. This comprehensive synthesis of neuroendocrinological and cellular biological research offers new insights into the systemic complexity of stress-related disorders and the imperative for multidisciplinary approaches in their study and treatment.

REDISCOVER International Guidelines on the Perioperative Care of Surgical Patients With Borderline-resectable and Locally Advanced Pancreatic Cancer.

The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking. The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines. Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population ( https://rediscover.unipi.it/ ). The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population.

Microenvironment-differential Imaging of Demethylated Metabolites of Methionine for Identifying Ferroptosis Regional Preferences with Path-independent Equifinal Fluorescence Probes.

We realized the microenvironment-differential Imaging of demethylated metabolites of methionine and the regional regulation of ferroptosis.

Pathomorphological changes in sheep paramphistomatosis

The scientific article provides information on the pathomorphological changes caused by paramphistomes that develop in the digestive organs. The results of pathologoanatomical, pathogistological and histochemical changes in paramphistomatous digestive organs and parenchymatous organs are also written in detail. Pathomorphological changes are clearly explained in colourful pictures. Mutsicarmine, mucopolysaccharides, glycogen, polysaccharides and various pathomorphophysiological characteristics of adhesion were determined in epithelial cells and perivascular tissues by histochemical methods. The scientific article provides practical conclusions as well.

In Vitro Analysis of Dissolution of 18 HA-based Dermal Fillers with Tailored Hyaluronidase Dosing to Achieve Urgent Reversal of Vascular Complications

Introduction: Hyaluronidase (HYAL), a hyaluronic acid-degrading enzyme, is commonly used “off-label” as part of the gold standard management of hyaluronic acid (HA) dermal filler complications. It is paramount that injectors be cognizant to diagnose and treat filler complications, particularly vascular emboli, where there may be a narrow window for timely treatment. There is a paucity of studies, however, that provide HYAL dosage guidelines in the setting of acute vascular obstruction that are specific to each of the 18 reversible HA-based dermal fillers commercially available on the current US market. Differences in resistance to HYAL degradation is based on variation in cross-linking technique, concentration of HA, and cohesive properties that each filler may possess. This in vitro study investigates optimal dosage parameters of HYAL to achieve gross dissolution of every reversible HA-based filler commercially available to better improve outcomes after filler-induced vascular complications. Methods: Standardized in vitro analysis using 0.5-mL aliquots of all 18 commercially available HA-based fillers included all Restylane products (Lyft, Restylane-L, Silk, Refyne, Defyne, Kysse, Contour), Juvederm products (Volbella, Vollure, Voluma, Ultra XC, Ultra Plus XC), Revanesse products (Versa+, Lips+), Teoxane products (RHA 2, RHA 3, RHA 4), and Belotero. Hylenex, recombinant human HYAL, was used in 150 IU increments for total quantities of either 300, 450, 600, or 750 IU to achieve timed assessment of the gross dissolution of filler using photographic and videographic documentation. Inert dye was used to improve filler visibility against the HYAL. Mechanical integration of HYAL into the filler mimicked massage technique commonly implemented to incorporate HYAL into the perivascular soft tissue to help relieve a filler-induced vascular obstruction. Results: The cross-linking technology utilized by each HA-filler manufacturer played a significant role in the readiness of filler dissolution with HYAL. Fastest dissolution times ranged from 11 seconds to approximately 32 minutes, with a strong correlation with Restylane products dissolving the fastest, followed by Juvederm & Revanesse products. The slowest to achieve gross dissolution were Belotero and the RHA series. Discussion: All 18 HA-based fillers achieved complete gross dissolution within the first 32 minutes, however, due to differences in cross-linking technology and molecular properties, there was large variation in in vitro HYAL-induced degradation that can be extrapolated clinically to help reverse urgent vascular obstruction. This may also help beginner injectors strategically choose the HA-based dermal fillers that have the fastest degradation response to HYAL. Further in vivo studies are necessary to integrate these into clinical practice.

Alzheimer’s disease risk genes are differentially expressed upon Lipopolysaccharide stimulation in a myelogenic cell model

AbstractBackgroundLipopolysaccharides (LPS) is a molecule present in the outer membrane of Gram‐negative bacteria. Previous studies have shown that LPS treatment can lead to upregulated pro‐inflammatory and chemotactic cytokines, or elevate the expression of anti‐inflammatory factors in mouse or cell models. Inflammation is seen around amyloid plaques and around small cerebral vessels with Ab1‐40 deposits in AD brains. Increased levels of LPS have been found in the hippocampus of patients with Alzheimer’s disease, compared to age‐matched controls. Other studies demonstrated that LPS is also present and associated with white matter injury in AD and aging brains. Continued inflammation activates microglia and macrophages, which are ialso localized in perivascular tissue. However, to what extent the increased inflammation influences the expression of AD risk genes in myelogenic cells is not well known. Here we utilized RNA sequencing on THP‐1 derived macrophages using Aβ and LPS as stressors to further elucidate this.MethodWe performed RNA sequencing on THP1‐derived macrophages, with or without Aβ and LPS stimulation. 50 known AD risk genes were cross‐checked against the differentially expressed genes discovered. Furthermore, KEGG pathway analysis was performed on the Aβ versus the LPS and Aβ group.ResultOut of 50 AD risk genes, we identified a total of 24 genes in the various comparison groups (Figure 1). 14 AD risk genes were discovered in all the groups: TREM2, LILRB2, BIN1, TNIP1, CD2AP, CD33, CASS4, MS4A4A, NCK2, ADAMTS1, SPI1, RIN3, ECHDC3, AGRN (Figure 1 and2). KEGG pathway analysis pointed out TNF signaling pathway, lysosome, endocytosis and ubiquitin mediated proteolysis as enriched for cells stimulated by LPS with Aβ present (Figure 3).ConclusionOur study demonstrates that LPS activates inflammatory responses in myelogenic cells that further affects AD risk gene expression. Enriched pathways not only relate to Aβ uptake and clearance, but also reflect AD pathology. LPS and/or LPS induced inflammation may be a significant initiator or progressive contributor to inflammatory degeneration in AD.