Venous Thromboembolism: Classification, Risk Factors, Diagnosis, and Management

Venous thromboembolism (VTE) is categorised as deep venous thrombosis (DVT) and pulmonary embolism (PE). VTE is associated with high morbidity and causes a huge financial burden on patients, hospitals, and governments. Both acquired and hereditary risks factors contribute to VTE. To diagnose VTE, noninvasive cost-effective diagnostic algorithms including clinical probability assessment and D-dimer measurement may be employed followup by compression ultrasonography for suspected DVT patients and multidetector computed tomography angiography for suspected PE patients. There are pharmacological and mechanical interventions to manage and prevent VTE. The pharmacological approaches mainly target pathways in coagulation cascade nonspecifically: conventional anticoagulants or specifically: new generation of anticoagulants. Excess bleeding is one of the major risk factors for pharmacological interventions. Hence, nonpharmacological or mechanical approaches such as inferior vena cava filters, graduated compression stockings, and intermittent pneumatic compression devices in combination with pharmacological interventions or alone may be a good approach to manage VTE

Key role of dysregulated airway epithelium in response to respiratory viral infections in asthma

A differentiated air–liquid interface model shows that the airway epithelium plays a key role in response to respiratory viral infections in people with asthma https://bit.ly/3yDgiX

Effect of Exposure of Human Monocyte-Derived Macrophages to High, versus Normal, Glucose on Subsequent Lipid Accumulation from Glycated and Acetylated Low-Density Lipoproteins

During atherosclerosis monocyte-derived macrophages accumulate cholesteryl esters from low-density lipoproteins (LDLs) via lectin-like oxidised LDL receptor-1 (LOX-1) and class AI and AII (SR-AI, SR-AII) and class B (SR-BI, CD36) scavenger receptors. Here we examined the hypothesis that hyperglycaemia may modulate receptor expression and hence lipid accumulation in macrophages. Human monocytes were matured into macrophages in 30 versus 5 mM glucose and receptor expression and lipid accumulation quantified. High glucose elevated LOX1 mRNA, but decreased SR-AI, SR-BI, LDLR, and CD36 mRNA. SR-BI and CD36 protein levels were decreased. Normo- and hyperglycaemic cells accumulated cholesteryl esters from modified LDL to a greater extent than control LDL, but total and individual cholesteryl ester accumulation was not affected by glucose levels. It is concluded that, whilst macrophage scavenger receptor mRNA and protein levels can be modulated by high glucose, these are not key factors in lipid accumulation by human macrophages under the conditions examined

Effect of a polyunsaturated fatty acid mimetic on the development of atherosclerosis in the apoE deficient mouse.

Atheroma, heart attacks and strokes continue to be a major cause of morbidity and mortality in our community. Atherosclerosis is a chronic inflammatory vascular disease, characterised by thickening of the vascular wall due to lipid accumulation, infiltration by circulating monocytes and T cells and proliferation of smooth muscle cells. Leukocyte adherence to the blood vessel wall is promoted by the up-regulation of cell adhesion molecules (CAM) by atherogenic substances such as tumour necrosis factor (TNF-α) and oxidised low density lipoprotein (oxidised-LDL). Recently our group has synthesised a novel polyunsaturated fatty acid, β-oxa 23:4n-6 which inhibits CAM up-regulation in blood vessel walls. It was therefore the objective of this thesis to determine whether this fatty acid protects against atherosclerosis. Advantage was taken of an experimental model of this disease, the apoE deficient mouse (apoE [superscript -/-]) which spontaneously develop atherosclerosis. To assist our studies on MP3, we established an appropriate classification of different stages of atherosclerotic lesions and defined the kinetics of development of the disease in this model. By examining of the sections at the level of aortic roots the atherosclerotic lesions were classified into six categories. This classification was based on the histological characteristics of the plaque component including the degree of macrophage infiltration and foam cells formation, the presence of cholesterol clefts and confluent lipid cores, calcification and ossification, the composition of the fibrous cap, the media involvement and the incipient/actual aneurysm formation and inflammation, including neutrophils. Kinetics of plaque development under the influence of a high fat and high cholesterol diet followed an exponential relationship of y= -e [ superscript -x ]. The asymptotic characteristic of this lesion development was however a function of compensatory aortic enlargement which accompanied the increase in lesion development and size. Thus it is concluded that the level of atherosclerosis needs to be gauged by the size of the lesion per se. This may be particularly important for the assessment of anti-atherogenic effects of drugs. Therefore attempts to develop a quantitative system to assess plaques revealed that expression of plaque size as % of occupation of blood vessel had limitations. Using this model we were able to demonstrate that injections of the novel polyunsaturated fatty acid, MP3 led to a significant reduction/inhibition (70%) of plaque area and a corresponding 60% inhibition of aortic size. As expected this inhibition was not as evident when results were expressed as % of aortic lumen size. The results also suggested that protection by MP3 was dependent on conditions which promoted increased uptake into tissues by, for example, preloading animals with MP3 prior to commencing the high fat high cholesterol diet. The protective effects of MP3 are consistent with a role for the activation of the transcriptional factor, NFkB and up-regulation of cell adhesion molecules in this disease, and the ability of MP3 to inhibit these targets. Thus the objective of this research has been achieved and the hypothesis proven.Thesis (M.Med.Sc.)--University of Adelaide, School of Paediatrics & Reproductive Health, 2005

P2Y₁₂ receptor:Platelet thrombus formation and medical interventions

Platelets express a wide range of receptors and proteins that play essential roles in thrombus formation. Among these, the P2Y12 receptor, a member of the G protein-coupled receptor family, has attracted a significant amount of attention. Stimulation of the P2Y12 receptor by ADP results in activation of various signaling pathways involved in amplification of platelet activation and aggregation. There have been extensive attempts to design an ideal antithrombotic agent to block P2Y12, which shows selective expression, as an intervention for cardiovascular disease. Current inhibitors of the P2Y12 receptor include indirect inhibitor members of the thienopyridine family (ticlopidine, clopidogrel, and prasugrel), and direct P2Y12 inhibitors (ticagrelor, cangrelor and elinogrel). Of these, clopidogrel is the most commonly prescribed P2Y12 blocker; however, this product does not fulfill the ideal therapeutic requirements. The main limitations of clopidogrel administration include slow onset, prevention of recovery of platelet functions, and interindividual variability. Hence, advanced studies have been carried out to achieve more efficient and safer P2Y12 blockade. In this review, we provide a brief but comprehensive report on P2Y12, its role on platelet thrombus formation, and the targeting of this receptor as an intervention for cardiovascular disease, for the benefit of basic science and clinical researchers

Distinct Effects of Respiratory Viral Infection Models on miR-149-5p, IL-6 and p63 Expression in BEAS-2B and A549 Epithelial Cells

Respiratory viruses cause airway inflammation, resulting in epithelial injury and repair. miRNAs, including miR-149-5p, regulate different pathological conditions. We aimed to determine how miR-149-5p functions in regulating pro-inflammatory IL-6 and p63, key regulators of airway epithelial wound repair, in response to viral proteins in bronchial (BEAS-2B) and alveolar (A549) epithelial cells. BEAS-2B or A549 cells were incubated with poly (I:C, 0.5 µg/mL) for 48 h or SARS-CoV-2 spike protein-1 or 2 subunit (S1 or S2, 1 μg/mL) for 24 h. miR-149-5p was suppressed in BEAS-2B challenged with poly (I:C), correlating with IL-6 and p63 upregulation. miR-149-5p was down-regulated in A549 stimulated with poly (I:C); IL-6 expression increased, but p63 protein levels were undetectable. miR-149-5p remained unchanged in cells exposed to S1 or S2, while S1 transfection increased IL-6 expression in BEAS-2B cells. Ectopic over-expression of miR-149-5p in BEAS-2B cells suppressed IL-6 and p63 mRNA levels and inhibited poly (I:C)-induced IL-6 and p63 mRNA expressions. miR-149-5p directly suppressed IL-6 mRNA in BEAS-2B cells. Hence, BEAS-2B cells respond differently to poly (I:C), S1 or S2 compared to A549 cells. Thus, miR-149-5p dysregulation may be involved in poly (I:C)-stimulated but not S1- or S2-stimulated increased IL-6 production and p63 expression in BEAS-2B cells

Distinct Effects of Respiratory Viral Infection Models on miR-149-5p, IL-6 and p63 Expression in BEAS-2B and A549 Epithelial Cells

Respiratory viruses cause airway inflammation, resulting in epithelial injury and repair. miRNAs, including miR-149-5p, regulate different pathological conditions. We aimed to determine how miR-149-5p functions in regulating pro-inflammatory IL-6 and p63, key regulators of airway epithelial wound repair, in response to viral proteins in bronchial (BEAS-2B) and alveolar (A549) epithelial cells. BEAS-2B or A549 cells were incubated with poly (I:C, 0.5 µg/mL) for 48 h or SARS-CoV-2 spike protein-1 or 2 subunit (S1 or S2, 1 μg/mL) for 24 h. miR-149-5p was suppressed in BEAS-2B challenged with poly (I:C), correlating with IL-6 and p63 upregulation. miR-149-5p was down-regulated in A549 stimulated with poly (I:C); IL-6 expression increased, but p63 protein levels were undetectable. miR-149-5p remained unchanged in cells exposed to S1 or S2, while S1 transfection increased IL-6 expression in BEAS-2B cells. Ectopic over-expression of miR-149-5p in BEAS-2B cells suppressed IL-6 and p63 mRNA levels and inhibited poly (I:C)-induced IL-6 and p63 mRNA expressions. miR-149-5p directly suppressed IL-6 mRNA in BEAS-2B cells. Hence, BEAS-2B cells respond differently to poly (I:C), S1 or S2 compared to A549 cells. Thus, miR-149-5p dysregulation may be involved in poly (I:C)-stimulated but not S1- or S2-stimulated increased IL-6 production and p63 expression in BEAS-2B cells