Smoking Status and Outcomes following Lung Resection.

BACKGROUND: Surgical resection is the gold standard treatment for the management of early-stage lung cancer. Several modifiable factors may significantly influence postoperative morbidity and mortality. We examined the outcomes of patients following lung resection based upon preoperative smoking status to quantify the impact on postoperative outcomes. METHODS: Data from consecutive lung resections from January 1, 2012 to June 11, 2021 were included. Biopsies for interstitial lung disease and resections for emphysematous lung or bullae were excluded. Patients were divided into three cohorts: current smokers (those who smoked within 4 weeks of surgery), ex-smokers (those who stopped smoking prior to 4 weeks leading up to surgery), and nonsmokers (those who have never smoked). Patient's preoperative variables, postoperative complications, length of stay, and mortality were examined. RESULTS: A total of 2,426 patients were included in the study. A total of 502 patients (20.7%) were current smokers, 1,445 (59.6%) were ex-smokers and 479 patients (19.7%) nonsmokers. Of those smoking immediately prior to surgery 36.9% developed postoperative complications. Lower respiratory tract infections (18.1%) and prolonged air leak (17.1%), in particular, were significant higher in smokers. 90-day mortality (5.8%) was higher in the current smokers when compared with ex- and nonsmokers (5.3 and 1%, respectively). Median length of hospital stay, readmissions, and cost of hospital stay was also higher in the current smoker cohort. CONCLUSION: Smoking immediately prior to surgery is associated with an increase in morbidity, mortality, and length of stay. Not only does this have a significant individual impact, but it is also associated with a significant financial burden to the National Health Service.

Aortic Dissection in a Case of Peripartum Cardiomyopathy.

Management of acute Type A aortic dissection can be complicated by patient comorbidities. We describe the case of a 29-year-old female with preexisting peripartum cardiomyopathy who developed a Type A dissection. Surgery was performed and venoarterial extracorporeal membrane oxygenation (ECMO) was instituted. She left hospital on the 71st postoperative day. It is extremely rare for a patient with cardiomyopathy to develop an aortic dissection. Deferring this patient's surgery to an ECMO center was crucial for her survival.

Turn down of acute aortic syndrome cases during COVID-19: Results from UK multicentre studies.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has restructured the healthcare systems, prioritizing resources to treat COVID-19 patients. The aim of this study was to establish if patients affected by acute aortic syndrome (AAS) had unrestricted access to emergency treatment and evaluate outcome of these patients during the peak of the pandemic. METHODS: This is a retrospective analysis of prospectively collected data between March and June 2020 from 19 participating cardiac surgery centers in the United Kingdom. RESULTS: Among 95 patients who presented with an AAS in the participating centers; 85 (89%) underwent surgery, 7 (7%) were turned down for surgery because of their profile of comorbidities, and 3 (3%) died on transfer. Among the patients treated conservatively, three of them (43%) were alive at 30 days. We observed no significant restriction in access to treatment for AAS during the early months of the pandemic. CONCLUSION: Services for life-threatening aortic surgery patients were maintained during the COVID-19 period through patient selection and timing of surgery. The rate of surgical turn-down was comparable to published figures despite the challenges faced during the COVID-19 pandemic.

The Wythenshawe Hybrid Circuit for lung transplantation: a previously undescribed circuit for lung transplant.

Extracorporeal membrane oxygenation is a safe modality of cardiorespiratory support for lung transplantation, with a reduction in coagulopathy and transfusion requirement when compared with cardiopulmonary bypass. In some scenarios, in lung transplantation, there are advantages to the use of cardiopulmonary bypass, which allows cardiac decompression, filtering of embolic air, easy addition and removal of volume, and a means to immediately reintroduce lost blood into circulation. We describe a novel circuit which allows safe and easy switch between modalities without prolonged interruption of flow. This circuit offers a safety net during surgery to minimise the risks influencing the use of extracorporeal membrane oxygenation.

Bomb blast shrapnel trauma to the main pulmonary artery: learning points to achieve a safe outcome.

A 47-year-old patient was injured in a bomb blast and sustained trauma due to multiple fragments of shrapnel from a terrorist explosive device. We report on the surgery required to safely remove a piece of shrapnel from the anterior wall of the main pulmonary artery (PA). A chest X-ray revealed a left-sided haemothorax. A computed tomography scan confirmed the trajectory and position of a metal bolt that had lodged between the main PA and the aortic arch. At surgery, a limited left anterior thoracotomy was performed initially. A significant quantity of blood was observed in the pericardium, and the incision was extended to perform a hemi-clamshell incision with a transverse division of the sternum. Cardiopulmonary bypass (CPB) was initiated before prizing the shrapnel from a haematoma involving the front wall of the main PA. The use of the CPB prevented uncontrolled haemorrhage, and the injury to the wall was successfully repaired. The patient subsequently developed acute respiratory distress syndrome and required a prolonged period of ventilation but made a full recovery after multiple further surgeries to remove the shrapnel from his neck and legs, having been injured by 11 pieces of the shrapnel in total.

Pathogenicity Determinants of the Human Malaria Parasite Plasmodium falciparum Have Ancient Origins.

Plasmodium falciparum, the most deadly of the human malaria parasites, is a member of the Laverania subgenus that also infects African Great Apes. The virulence of P. falciparum is related to cytoadhesion of infected erythrocytes in microvasculature, but the origin of dangerous parasite adhesion traits is poorly understood. To investigate the evolutionary history of the P. falciparum cytoadhesion pathogenicity determinant, we studied adhesion domains from the chimpanzee malaria parasite P. reichenowi. We demonstrate that the P. reichenowi var gene repertoire encodes cysteine-rich interdomain region (CIDR) domains which bind human CD36 and endothelial protein C receptor (EPCR) with the same levels of affinity and at binding sites similar to those bound by P. falciparum. Moreover, P. reichenowi domains interfere with the protective function of the activated protein C-EPCR pathway on endothelial cells, a presumptive virulence trait in humans. These findings provide evidence for ancient evolutionary origins of two key cytoadhesion properties of P. falciparum that contribute to human infection and pathogenicity. IMPORTANCE Cytoadhesion of P. falciparum-infected erythrocytes in the microcirculation is a major virulence determinant. P. falciparum is descended from a subgenus of parasites that also infect chimpanzees and gorillas and exhibits strict host species specificity. Despite their high genetic similarity to P. falciparum, it is unknown whether ape parasites encode adhesion properties similar to those of P. falciparum or are as virulent in their natural hosts. Consequently, it has been unclear when virulent adhesion traits arose in P. falciparum and how long they have been present in the parasite population. It is also unknown whether cytoadhesive interactions pose a barrier to cross-species transmission. We show that parasite domains from the chimpanzee malaria parasite P. reichenowi bind human receptors with specificity similar to that of P. falciparum. Our findings suggest that parasite adhesion traits associated with both mild and severe malaria have much earlier origins than previously appreciated and have important implications for virulence evolution in a major human pathogen.

Feasibility of hybrid off pump artery bypass grafting and transaortic transcatheter aortic valve implantation: A case series.

INTRODUCTION: Patients with complex coronary artery disease and severe aortic stenosis unsuitable for conventional cardiac surgery pose a significant treatment challenge. This is especially difficult for patients where percutaneous revascularization is technically very challenging and/or would not offer as complete revascularisation compared to surgical revascularisation. In addition, patients who are unsuitable for transfemoral transcatheter aortic valve implantation (TAVI) pose an additional technical challenge, particularly with dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI). As a potential solution we describe the first case series of hybrid off-pump coronary artery bypass grafting (CABG) combined with transaortic TAVI. METHODS AND RESULTS: Over a ten-month-period, four patients underwent hybrid off-pump CABG combined with transaortic TAVI. A full sternotomy allowed off-pump arterial and vein graft anastomosis to significantly stenosed coronaries. The first three patients had severe aorto-iliac disease precluding femoral access; the fourth patient was deemed unsuitable for PCI. Transaortic TAVI using Edwards Sapien 3 valves were performed without complication in all four patients. CONCLUSION: The hybrid off-pump CABG and transaortic TAVI procedure allows for more complete coronary revascularization, negates the need for DAPT, and minimizes treatment delay of a TAVI procedure, particularly in patients unsuitable for transfemoral access. We propose this as an important treatment option for the heart team to consider. © 2016 Wiley Periodicals, Inc.

Thrombin Cleavage of Plasmodium falciparum Erythrocyte Membrane Protein 1 Inhibits Cytoadherence.

UNLABELLED: Plasmodium falciparum malaria remains one of the most deadly infections worldwide. The pathogenesis of the infection results from the sequestration of infected erythrocytes (IRBC) in vital organs, including the brain, with resulting impairment of blood flow, hypoxia, and lactic acidosis. Sequestration occurs through the adhesion of IRBC to host receptors on microvascular endothelium by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a large family of variant surface antigens, each with up to seven extracellular domains that can bind to multiple host receptors. Consequently, antiadhesive therapies directed at single endothelial adhesion molecules may not be effective. In this study, we demonstrated that the serine protease thrombin, which is pivotal in the activation of the coagulation cascade, cleaved the major parasite adhesin on the surface of IRBC. As a result, adhesion under flow was dramatically reduced, and already adherent IRBC were detached. Thrombin cleavage sites were mapped to the Duffy binding-like δ1 (DBLδ1) domain and interdomains 1 and 2 in the PfEMP1 of the parasite line IT4var19. Furthermore, we observed an inverse correlation between the presence of thrombin and IRBC in cerebral malaria autopsies of children. We investigated a modified (R67A) thrombin and thrombin inhibitor, hirugen, both of which inhibit the binding of substrates to exosite I, thereby reducing its proinflammatory properties. Both approaches reduced the barrier dysfunction induced by thrombin without affecting its proteolytic activity on PfEMP1, raising the possibility that thrombin cleavage of variant PfEMP1 may be exploited as a broadly inhibitory antiadhesive therapy. IMPORTANCE: Plasmodium falciparum malaria is the third leading cause of mortality due to a pathogen, with 214 million people infected and 438,000 deaths annually. The adhesion of Plasmodium falciparum-infected erythrocytes (IRBC) to microvascular endothelium is a major pathological process in severe malaria. While the recent implementation of artemisinin-based antimalarial therapy for severe malaria improves patient survival by targeting all parasite stages, antiparasite drugs alone may not immediately reverse pathophysiological processes in occluded vessels. Here we show that thrombin, an enzyme intimately involved in the clotting process, cleaves the main parasite adhesin expressed on the surface of IRBC, thereby preventing and reversing the binding of IRBC to endothelial cells. This beneficial effect of thrombin can be achieved by modified thrombins that cause significantly less clotting and vessel leakage while preserving the ability to cleave the parasite protein. Our results provide the basis for using modified thrombins as adjunctive therapy in severe malaria.

Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum-Infected Erythrocytes to Endothelial Cells.

UNLABELLED: Intercellular adhesion molecule 1 (ICAM-1) and the endothelial protein C receptor (EPCR) are candidate receptors for the deadly complication cerebral malaria. However, it remains unclear if Plasmodium falciparum parasites with dual binding specificity are involved in cytoadhesion or different parasite subpopulations bind in brain microvessels. Here, we investigated this issue by studying different subtypes of ICAM-1-binding parasite lines. We show that two parasite lines expressing domain cassette 13 (DC13) of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family have dual binding specificity for EPCR and ICAM-1 and further mapped ICAM-1 binding to the first DBLß domain following the PfEMP1 head structure in both proteins. As PfEMP1 head structures have diverged between group A (EPCR binders) and groups B and C (CD36 binders), we also investigated how ICAM-1-binding parasites with different coreceptor binding traits influence P. falciparum-infected erythrocyte binding to endothelial cells. Whereas levels of binding to tumor necrosis factor alpha (TNF-α)-stimulated endothelial cells from the lung and brain by all ICAM-1-binding parasite lines increased, group A (EPCR and ICAM-1) was less dependent than group B (CD36 and ICAM-1) on ICAM-1 upregulation. Furthermore, both group A DC13 parasite lines had higher binding levels to brain endothelial cells (a microvascular niche with limited CD36 expression). This study shows that ICAM-1 is a coreceptor for a subset of EPCR-binding parasites and provides the first evidence of how EPCR and ICAM-1 interact to mediate parasite binding to both resting and TNF-α-activated primary brain and lung endothelial cells. IMPORTANCE: Cerebral malaria is a severe neurological complication of P. falciparum infection associated with infected erythrocyte (IE) binding in cerebral vessels. Yet little is known about the mechanisms by which parasites adhere in the brain or other microvascular sites. Here, we studied parasite lines expressing group A DC13-containing PfEMP1 variants, a subset that has previously been shown to have high brain cell- and other endothelial cell-binding activities. We show that DC13-containing PfEMP1 variants have dual EPCR- and ICAM-1-binding activities and that both receptors are involved in parasite adherence to lung and brain endothelial cells. As both EPCR and ICAM-1 are implicated in cerebral malaria, these findings suggest the possibility that parasites with dual binding activities are involved in parasite sequestration to microvascular beds with low CD36 expression, such as the brain, and we urge more research into the multiadhesive properties of PfEMP1 variants.

Long-Term Survival After Off-Pump Coronary Artery Bypass Grafting.

BACKGROUND: The aim of this study was to compare the long-term survival rates of patients undergoing isolated first-time coronary artery bypass grafting (CABG) by off-pump CABG with the long-term survival rates in patients undergoing CABG using cardioplegic cardiopulmonary bypass techniques. METHODS: All patients undergoing isolated CABG at a single center (Manchester Heart Centre, Manchester, United Kingdom) between 2000 and 2014 were included. Propensity score matching was performed on the basis of on demographic variables. The in-hospital morbidity and long-term all-cause mortality rates for matched patients were compared. RESULTS: A total of 8,055 patients were identified, with a median follow-up of 7.0 years. With patients matched for preoperative patient characteristics, there was no significant difference in long-term survival between cardiopulmonary bypass and off-pump CABG (n = 2,082 each; 11.5 years vs 11.3 years; p = 0.178). In the off-pump CABG group, there were significantly fewer in-hospital cerebrovascular complications (0.5% vs 1.1%; p = 0.017), and mean length of stay was shorter (7.6 days vs 8.1 days; p < 0.0001). Arterial conduit use was significantly higher in the off-pump group, with more right mammary artery grafts (16.3% vs 4.3%; p < 0.0001) and sequential grafts (27.1% vs 13.5%; p < 0.0001). The mean number of grafts was higher in the on-pump group (3.28 ± 0.94 vs 3.10 ± 1.10; p < 0.0001). CONCLUSIONS: Long-term survival after off-pump CABG is not inferior to long-term survival after on-pump CABG despite a lower mean number of grafts. A statistically significant difference in cerebrovascular complications may be related to conduit choice and reduced aortic manipulation.

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass.

The interplay between cellular and molecular determinants that lead to severe malaria in adults is unexplored. Here, we analyzed parasite virulence factors in an infected adult population in India and investigated whether severe malaria isolates impair endothelial protein C receptor (EPCR), a protein involved in coagulation and endothelial barrier permeability. Severe malaria isolates overexpressed specific members of the Plasmodium falciparum var gene/PfEMP1 (P. falciparum erythrocyte membrane protein 1) family that bind EPCR, including DC8 var genes that have previously been linked to severe pediatric malaria. Machine learning analysis revealed that DC6- and DC8-encoding var transcripts in combination with high parasite biomass were the strongest indicators of patient hospitalization and disease severity. We found that DC8 CIDRα1 domains from severe malaria isolates had substantial differences in EPCR binding affinity and blockade activity for its ligand activated protein C. Additionally, even a low level of inhibition exhibited by domains from two cerebral malaria isolates was sufficient to interfere with activated protein C-barrier protective activities in human brain endothelial cells. Our findings demonstrate an interplay between parasite biomass and specific PfEMP1 adhesion types in the development of adult severe malaria, and indicate that low impairment of EPCR function may contribute to parasite virulence.

A meta-analysis of computerized tomography scan for reducing complications following repeat sternotomy for cardiac surgery.

Cardiac reoperation carries additional risks compared with surgery in patients who are sternotomy-naïve. To identify if preoperative computerized tomography (CT) can reduce this risk, we performed a systematic review of the literature and meta-analysis. Literature search identified 178 studies of which 4 retrospective cohort studies incorporating 900 patients met inclusion criteria. There were no statistically significant differences in the risk of death, re-entry injury, renal failure or perfusion/ischaemic times. CT scan reduced the risk of stroke by 0.42 [95% confidence interval (CI): 0.19-0.93, P = 0.03] and a composite of major complications by 0.65 (95% CI: 0.47-0.88, P = 0.006). The use of preoperative cross-sectional imaging to reduce the risk of complications following cardiac reoperation is advocated.

Urgent resection of a giant left atrial appendage aneurysm and mitral valve replacement in a complex case of Hurler-Scheie syndrome.

Hurler-Scheie syndrome is a rare lysosomal storage disease affecting the cardiovascular system. Besides the cardiac manifestations, it presents with complications from abnormal proteoglycan deposition in soft tissues in many locations, resulting in joint contractures, paraplegia, impaired vision, airway narrowing and restrictive lung function, to name a few. There are very few reports of surgical management of valvular heart disease due to mucopolysaccharidosis (MPS). We describe the successful management of a patient with an extremely challenging case of mitral valve stenosis and a giant left atrial appendage aneurysm due to MPS type 1 (Hurler-Scheie syndrome). The patient underwent mitral valve replacement and excision of the giant left atrial appendage aneurysm; a similar case has not been previously reported.

Plasmodium falciparum adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor.

Cytoadhesion of Plasmodium falciparum-infected erythrocytes to endothelial protein C receptor (EPCR) is associated with severe malaria. It has been postulated that parasite binding could exacerbate microvascular coagulation and endothelial dysfunction in cerebral malaria by impairing the protein C-EPCR interaction, but the extent of binding inhibition has not been fully determined. Here we expressed the cysteine-rich interdomain region (CIDRα1) domain from a variety of domain cassette (DC) 8 and DC13 P. falciparum erythrocyte membrane protein 1 proteins and show they interact in a distinct manner with EPCR resulting in weak, moderate and strong inhibition of the activated protein C (APC)-EPCR interaction. Overall, there was a positive correlation between CIDRα1-EPCR binding activity and APC blockade activity. In addition, our analysis from a combination of mutagenesis and blocking antibodies finds that an Arg81 (R81) in EPCR plays a pivotal role in CIDRα1 binding, but domains with weak and strong APC blockade activity were distinguished by their sensitivity to inhibition by anti-EPCR mAb 1535, implying subtle differences in their binding footprints. These data reveal a previously unknown functional heterogeneity in the interaction between P. falciparum and EPCR and have major implications for understanding the distinct clinical pathologies of cerebral malaria and developing new treatment strategies.

Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial pathogenesis.

Plasmodium falciparum-infected erythrocytes (IRBC) expressing the domain cassettes (DC) 8 and 13 of the cytoadherent ligand P. falciparum erythrocyte membrane protein 1 adhere to the endothelial protein C receptor (EPCR). By interfering with EPCR anti-coagulant and pro-endothelial barrier functions, IRBC adhesion could promote coagulation and vascular permeability that contribute to the pathogenesis of cerebral malaria. In this study, we examined the adhesion of DC8- and DC13-expressing parasite lines to endothelial cells from different microvasculature, and the consequences of EPCR engagement on endothelial cell function. We found that IRBC from IT4var19 (DC8) and IT4var07 (DC13) parasite lines adhered to human brain, lung and dermal endothelial cells under shear stress. However, the relative contribution of EPCR to parasite cytoadherence on different types of endothelial cell varied. We also observed divergent functional outcomes for DC8 cysteine-rich interdomain region (CIDR)α1.1 and DC13 CIDRα1.4 domains. IT4var07 CIDRα1.4 inhibited generation of activated protein C (APC) on lung and dermal endothelial cells and blocked the APC-EPCR binding interaction on brain endothelial cells. IT4var19 CIDRα1.1 inhibited thrombin-induced endothelial barrier dysfunction in lung endothelial cells, whereas IT4var07 CIDRα1.4 inhibited the protective effect of APC on thrombin-induced permeability. Overall, these findings reveal a much greater complexity of how CIDRα1-expressing parasites may modulate malaria pathogenesis through EPCR adhesion.

Identification of a novel HIV-1 inhibitor targeting Vif-dependent degradation of human APOBEC3G protein.

APOBEC3G (A3G) is a cellular cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA and by deamination-independent mechanisms. HIV-1 Vif binds to A3G, resulting in its degradation via the 26 S proteasome. Therefore, this interaction represents a potential therapeutic target. To identify compounds that inhibit interaction between A3G and HIV-1 Vif in a high throughput format, we developed a homogeneous time-resolved fluorescence resonance energy transfer assay. A 307,520 compound library from the NIH Molecular Libraries Small Molecule Repository was screened. Secondary screens to evaluate dose-response performance and off-target effects, cell-based assays to identify compounds that attenuate Vif-dependent degradation of A3G, and assays testing antiviral activity in peripheral blood mononuclear cells and T cells were employed. One compound, N.41, showed potent antiviral activity in A3G(+) but not in A3G(-) T cells and had an IC50 as low as 8.4 µM and a TC50 of >100 µM when tested against HIV-1Ba-L replication in peripheral blood mononuclear cells. N.41 inhibited the Vif-A3G interaction and increased cellular A3G levels and incorporation of A3G into virions, thereby attenuating virus infectivity in a Vif-dependent manner. N.41 activity was also species- and Vif-dependent. Preliminary structure-activity relationship studies suggest that a hydroxyl moiety located at a phenylamino group is critical for N.41 anti-HIV activity and identified N.41 analogs with better potency (IC50 as low as 4.2 µM). These findings identify a new lead compound that attenuates HIV replication by liberating A3G from Vif regulation and increasing its innate antiviral activity.

DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.

During blood stage infection, Plasmodium falciparum infected erythrocytes (IE) bind to host blood vessels. This virulence determinant enables parasites to evade spleen-dependent killing mechanisms, but paradoxically in some cases may reduce parasite fitness by killing the host. Adhesion of infected erythrocytes is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1), a family of polymorphic adhesion proteins encoded by var genes. Whereas cerebral binding and severe malaria are associated with parasites expressing DC8 and DC13 var genes, relatively little is known about the non-brain endothelial selection on severe malaria adhesive types. In this study, we selected P. falciparum-IEs on diverse endothelial cell types and demonstrate that DC8 and DC13 var genes were consistently among the major var transcripts selected on non-brain endothelial cells (lung, heart, bone marrow). To investigate the molecular basis for this avid endothelial binding activity, recombinant proteins were expressed from the predominant upregulated DC8 transcript, IT4var19. In-depth binding comparisons revealed that multiple extracellular domains from this protein bound brain and non-brain endothelial cells, and individual domains largely did not discriminate between different endothelial cell types. Additionally, we found that recombinant DC8 and DC13 CIDR1 domains exhibited a widespread endothelial binding activity and could compete for DC8-IE binding to brain endothelial cells, suggesting they may bind the same host receptor. Our findings provide new insights into the interaction of severe malaria adhesive types and host blood vessels and support the hypothesis that parasites causing severe malaria express PfEMP1 variants with a superior ability to adhere to diverse endothelial cell types, and may therefore endow these parasites with a growth and transmission advantage.

Severe malaria is associated with parasite binding to endothelial protein C receptor.

Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.

A restricted subset of var genes mediates adherence of Plasmodium falciparum-infected erythrocytes to brain endothelial cells.

Cerebral malaria (CM) is a deadly complication of Plasmodium falciparum infection, but specific interactions involved in cerebral homing of infected erythrocytes (IEs) are poorly understood. In this study, P. falciparum-IEs were characterized for binding to primary human brain microvascular endothelial cells (HBMECs). Before selection, CD36 or ICAM-1-binding parasites exhibited punctate binding to a subpopulation of HBMECs and binding was CD36 dependent. Panning of IEs on HBMECs led to a more dispersed binding phenotype and the selection of three var genes, including two that encode the tandem domain cassette 8 (DC8) and were non-CD36 binders. Multiple domains in the DC8 cassette bound to brain endothelium and the cysteine-rich interdomain region 1 inhibited binding of P. falciparum-IEs by 50%, highlighting a key role for the DC8 cassette in cerebral binding. It is mysterious how deadly binding variants are maintained in the parasite population. Clonal parasite lines expressing the two brain-adherent DC8-var genes did not bind to any of the known microvascular receptors, indicating unique receptors are involved in cerebral binding. They could also adhere to brain, lung, dermis, and heart endothelial cells, suggesting cerebral binding variants may have alternative sequestration sites. Furthermore, young African children with CM or nonsevere control cases had antibodies to HBMEC-selected parasites, indicating they had been exposed to related variants during childhood infections. This analysis shows that specific P. falciparum erythrocyte membrane protein 1 types are linked to cerebral binding and suggests a potential mechanism by which individuals may build up immunity to severe disease, in the absence of CM.