Murray Adams

The central nervous system (CNS) influences the immune system generally by regulating the systemic concentration of humoral substances (e.g., cortisol and epinephrine), whereas the peripheral nervous system (PNS) communicates specifically with the immune system according to local interactions/connections. An imbalance between the components of the PNS might contribute to pathogenesis and the further development of certain diseases. In this review, we have explored the “thread” (hardwiring) of the connections between the immune system (e.g., primary/secondary/tertiary lymphoid tissues/organs) and PNS (e.g., sensory, sympathetic, parasympathetic, and enteric nervous systems (ENS)) in health and disease in vitro and in vivo . Neuroimmune cell units provide an anatomical and physiological basis for bidirectional crosstalk between the PNS and the immune system in peripheral tissues, including lymphoid tissues and organs. These neuroimmune interactions/modulation studies might greatly contribute to a better understanding of the mechanisms through which the PNS possibly affects cellular and humoral-mediated immune responses or vice versa in health and diseases. Physical, chemical, pharmacological, and other manipulations of these neuroimmune interactions should bring about the development of practical therapeutic applications for certain neurological, neuroimmunological, infectious, inflammatory, and immunological disorders/diseases.

Anti-beta-2 glycoprotein 1 (anti-β2GP1) is an antiphospholipid antibody found in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Its presence commonly is associated with thrombosis; however, the mechanisms of interaction of anti-β2GP1 antibodies and platelets remain unclear. We investigated the effects of APS and SLE patient-derived IgG fractions on collagen-mediated platelet aggregation and examined the binding of patient-derived IgG to platelets before and after activation by collagen. IgG fractions, 150, 200, 300 or 350 µg/ml, isolated from 11 patients with APS and SLE were incubated with two sets of platelet-rich plasma (PRP) in the incubation wells of an aggregometer. The first set was activated by collagen and the other set was incubated for an additional 10 min. All platelets were collected by centrifugation and fixed in cell blocks. We assessed binding of IgG to platelets using immunocytochemistry (ICC). Patient-derived IgG fractions did not affect collagen-induced platelet aggregation. ICC staining using anti-human IgG antibodies demonstrated that patient-derived IgG fractions had greater affinity for non-activated platelets than those activated by 0.75 µg/ml collagen. Patient-derived IgG fractions bound to the surface of platelets and potentially could be internalized by platelets. IgG fractions from APS and SLE patients may sensitize non-activated platelets, which could increase platelet reactivity and thrombotic risk in patients. We did not detect secondary effects of patient-derived IgG fractions.

The ectopic overexpression of transient receptor potential vanilloid-1 (TRPV1) has been detected in numerous solid cancers, including breast, prostate, pancreatic, and tongue epithelium cancer. However, the expression of TRPV1 in hematological malignancies remains unknown. Here we show through in silico analysis that elevated TRPV1 mRNA expression occurs in a range of hematological malignancies and presents an optimized flow cytometry method to rapidly assess TRPV1 protein expression for both cell lines and primary patient samples. Three anti-TRPV1 antibodies were evaluated for intracellular TRPV1 detection using flow cytometry resulting in an optimized protocol for the evaluation of TRPV1 in hematological malignant cell lines and patients’ peripheral blood mononuclear cells (PBMC). Overexpression of TRPV1 was observed in THP-1 (acute monocytic leukemia) and U266B1 (multiple myeloma, MM), but not U937 (histiocytic lymphoma) compared to healthy PBMC. TRPV1 was also detected in all 49 patients including B-cell non-Hodgkin’s lymphoma (B-NHL), MM, and others and 20 healthy controls. TRPV1 expression was increased in 8% of patients (MM = 2, B-NHL = 2). In conclusion, we provide an optimized flow cytometry method for routine expression analysis of clinical samples and show that TRPV1 is increased in a subset of patients with hematological malignancies.

Background: High estradiol (E2) levels are linked to an increased risk of venous thromboembolism; however, the underlying molecular mechanism(s) remain poorly understood. We previously identified an E2-responsive microRNA (miR), miR-494–3p, that downregulates protein S expression, and posited additional coagulation factors, such as tissue factor, may be regulated in a similar manner via miRs. Objectives: To evaluate the coagulation capacity of cohorts with high physiological E2, and to further characterize novel E2-responsive miR and miR regulation on tissue factor in E2-related hypercoagulability. Methods: Ceveron Alpha thrombin generation assay (TGA) was used to assess plasma coagulation profile of three cohorts. The effect of physiological levels of E2, 10 nM, on miR expression in HuH-7 cells was compared using NanoString nCounter and validated with independent assays. The effect of tissue factor-interacting miR was confirmed by dual-luciferase reporter assays, immunoblotting, flow cytometry, biochemistry assays, and TGA. Results: Plasma samples from pregnant women and women on the contraceptive pill were confirmed to be hypercoagulable (compared with sex-matched controls). At equivalent and high physiological levels of E2, miR-365a-3p displayed concordant E2 downregulation in two independent miR quantification platforms, and tissue factor protein was upregulated by E2 treatment. Direct interaction between miR-365a-3p and F3-3′UTR was confirmed and overexpression of miR-365a-3p led to a decrease of (1) tissue factor mRNA transcripts, (2) protein levels, (3) activity, and (4) tissue factor-initiated thrombin generation. Conclusion: miR-365a-3p is a novel tissue factor regulator. High E2 concentrations induce a hypercoagulable state via a miR network specific for coagulation factors.

Zadow, EK, Edwards, KH, Kitic, CM, Fell, JW, Adams, MJ, Singh, I, Kundur, A, Johnstone, ANB, Crilly, J, Bulmer, AC, Halson, SL, and, and Wu, SSX. Compression socks reduce running-induced intestinal damage. J Strength Cond Res 36(9): 2461–2464, 2022—Exercise is associated with a reduction in splanchnic blood flow that leads to the disruption of intestinal epithelium integrity, contributing to exercise-induced gastrointestinal syndrome. Strategies that promote intestinal blood flow during exercise may reduce intestinal damage, which may be advantageous for subsequent recovery and performance. This study aimed to explore if exercise-associated intestinal damage was influenced by wearing compression garments, which may improve central blood flow. Subjects were randomly allocated to wear compression socks (n = 23) or no compression socks (control, n = 23) during a marathon race. Blood samples were collected 24 hours before and immediately after marathon and analyzed for intestinal fatty acid–binding protein (I-FABP) concentration as a marker of intestinal damage. The magnitude of increase in postmarathon plasma I-FABP concentration was significantly greater in control group (107%; 95% confidence interval [CI], 72–428%) when compared with runners wearing compression socks (38%; 95% CI, 20–120%; p = 0.046; d = 0.59). Wearing compression socks during a marathon run reduced exercise-associated intestinal damage. Compression socks may prove an effective strategy to minimize the intestinal damage component of exercise-induced gastrointestinal syndrome.

The proinflammatory cytokine storm associated with coronavirus disease 2019 (COVID-19) negatively affects the hematological system, leading to coagulation activation and endothelial dysfunction and thereby increasing the risk of venous and arterial thrombosis. Coagulopathy has been reported as associated with mortality in people with COVID-19 and is partially reflected by enhanced D-dimer levels. Poor vascular health, which is associated with the cardiometabolic health conditions frequently reported in people with severer forms of COVID-19, might exacerbate the risk of coagulopathy and mortality. Sedentary lifestyles might also contribute to the development of coagulopathy, and physical activity participation has been inherently lowered due to at-home regulations established to slow the spread of this highly infectious disease. It is possible that COVID-19, coagulation, and reduced physical activity may contribute to generate a “perfect storm,” where each fuels the other and potentially increases mortality risk. Several pharmaceutical agents are being explored to treat COVID-19, but potential negative consequences are associated with their use. Exercise is known to mitigate many of the identified side effects from the pharmaceutical agents being trialled but has not yet been considered as part of management for COVID-19. From the limited available evidence in people with cardiometabolic health conditions, low- to moderate-intensity exercise might have the potential to positively influence biochemical markers of coagulopathy, whereas high-intensity exercise is likely to increase thrombotic risk. Therefore, low- to moderate-intensity exercise could be an adjuvant therapy for people with mild-to-moderate COVID-19 and reduce the risk of developing severe symptoms of illness that are associated with enhanced mortality.

Antibeta-2-glycoprotein 1 (antiβ2GP1) antibodies are associated with increased risk of thrombosis in patients with systemic lupus erythematosus (SLE). The specific effect(s) of antiβ2GP1 antibodies on platelets are unclear. Platelet activation in response to antiplatelet antibodies has been shown to induce shedding of the ectodomain of the platelet collagen receptor, glycoprotein VI (GPVI), releasing soluble GPVI (sGPVI). The aim of this study was to therefore determine whether antiβ2GP1 antibodies, and/or purified IgG fractions, from patients with SLE shed sGPVI from platelets. We determined sGPVI levels in platelet poor plasma from SLE patients with/without antiβ2GP1 antibodies (n = 37), as well as in platelet-rich plasma from healthy donors treated with either SLE-derived IgG fractions containing antiβ2GP1, animal-derived antiβ2GP1, or isotype control antibodies. Levels of sGPVI were higher in three SLE-derived platelet poor plasma with antiβ2GP1 antibodies (103.52 ± 12.32 ng/ml) compared with those without (28.11 ± 12.73 ng/ml). Neither SLE-derived IgG fractions containing antiβ2GP1 antibodies, nor animal-derived antiβ2GP1 antibodies induced significant shedding of sGPVI from healthy donor platelets compared with isotype controls. These results suggest that antiβ2GP1 antibodies do not affect shedding of sGPVI, and therefore collagen-mediated platelet signalling pathways. The shedding activity in SLE patients may be due to factors other than antiβ2GP1 antibodies, for example, metalloproteinases.

Background Laboratory analyses of blood samples are essential for diagnostics and therapy monitoring of patients with bleeding and thromboembolic diseases. Following publication of the core curriculum for clinical thrombosis and hemostasis, the International Society on Thrombosis and Haemostasis (ISTH) recognized that thrombosis and hemostasis laboratory specialists require distinct competencies that differ from medical doctors working clinically with patients. To address this gap the ISTH formed a working group of international hemostasis and thrombosis laboratory specialists to develop an evidence‐based core curriculum for laboratory specialists. Objective This research sought consensus from the international community on core competencies required for laboratory specialists in thrombosis and hemostasis. Methods A draft list of 64 competencies was developed and an online stakeholder survey was circulated electronically to 15 302 ISTH members and contacts in the wider international community. The results were analyzed and used to develop the final approved core curriculum. Results Three hundred and thirty responses contained meaningful data, with broad international representation of specialists. No draft competencies were excluded, and 58 were rated as “does” or “shows how.” The Leik measure of consensus for most competences was “moderate” (n = 30) or “fair” (n = 32). Conclusions The development of an international core curriculum for laboratory specialists provides a foundation for the development and enhancement of education and quality management of the laboratory. Although there is no formal designation for laboratory specialists, international governing bodies and regulatory organizations are encouraged to consider the diagnostic core curriculum for development and accreditation of more standardized educational programs and formal assessment across jurisdictions.

Whilst athletes are the epitome of health, venous thromboembolisms (VTE) including deep vein thrombosis and pulmonary embolism have been demonstrated to occur in well-trained athletes. VTE is frequently misdiagnosed and poorly treated within this population, often resulting in career or life-threatening ramifications. Furthermore, VTE risk rises with increasing age (> 40 years), potentially affecting masters athletes. A 44-year-old well-trained male cyclist volunteered to participate in a research project investigating the influence of exercise on haemostasis in well-trained athletes. The cyclist presented with elevated d-Dimer levels both pre- (2251 ng/mL) and post-exercise (2653 ng/mL). The cyclist reported constant mild-pain in the left mid-calf region, with a cold tingling sensation in their left foot. Diagnosis of DVT was confirmed via a DVT squeeze test and Doppler ultrasound, with the clot located in the left popliteal vein. During the research project, the cyclist was exposed to numerous thrombogenic risk factors including travel, dehydration, prolonged sitting and exercise. The DVT in the popliteal vein may have resulted from repetitive movements associated with cycling. Additionally, hypertrophy of the gastrocnemius muscle may have impinged the vein. When diagnosing DVT within a cycling population, PVES should not be overlooked as a contributing factor.

We investigated the incidence of ex vivo incompatibility between ovine maternal RBC and fetal plasma. Time-mated singleton pregnant ewes (n = 8) underwent cesarean delivery of the fetus; at the time of delivery, paired maternal and fetal blood samples were collected and subsequently separated for storage as packed RBC and fresh frozen plasma. Gel column crossmatching was performed 3 to 4 wk later. All fetus–dam crossmatches were considered major crossmatches, combining fetal (recipient) plasma with dam (donor) RBC. The plasma of 8 fetuses was cross-matched with RBC from 5 dams; all autologous controls were negative, and all but one crossmatch (1 of 40, 2.5%) were considered compatible. In addition, the plasma of 3 dams was crossmatched with RBC from 5 dams; all autologous controls were negative; however, significant incompatibility was noted. In total, 4 of 13 (30.8%) dam–dam crossmatches were considered incompatible. The results of this initial study suggest that when a single animal receives multiple blood-product transfusions, the risk of an immunologic transfusion reaction can be reduced by ensuring that the blood products are obtained from a single donor, performing a crossmatch prior to transfusion, and the use of synthetic products to increase the oxygen carrying capacity of fetal blood.