Thrombospondin mediates the cytoadherence of Plasmodium falciparum- infected red cells to vascular endothelium in shear flow conditions

Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

B-type natriuretic peptide levels in obese patients with advanced heart failure.

Although recent studies show that obesity, or elevated body mass index (BMI), is associated with lower levels of B-type natriuretic peptide (BNP), it is unknown whether BMI affects the prognostic value of BNP in heart failure (HF). This study confirms the relationship between high BMI and low BNP in patients with advanced systolic HF. Despite relatively lower levels of BNP in overweight and obesity, BNP predicts worse symptoms, impaired hemodynamics, and higher mortality in HF at all levels of BMI.OBJECTIVES: This study aimed to examine the influence of obesity on the predictive value of the B-type natriuretic peptide (BNP) assay in heart failure (HF). BACKGROUND: Recent studies show that obesity, or elevated body mass index (BMI), is associated with lower circulating levels of BNP both in the general population and in patients with HF. METHODS: We analyzed data from 316 systolic HF (left ventricular ejection fraction [LVEF] < or =40%) patients [age, 53 +/- 13 years; mean LVEF, 24 +/- 7%; 48% ischemic] followed up at a university HF center. Patients were divided into categories of BMI: lean (BMI <25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI > or =30 kg/m2). RESULTS: The BNP levels were significantly lower in overweight and obese compared with lean patients (p = 0.0001); median BNP (interquartile range) for the lean (n = 131), overweight (n = 99), and obese (n = 86) groups was 747 (272 to 1,300), 380 (143 to 856), and 332 (118 to 617) pg/ml, respectively. In each BMI category, elevated BNP was significantly associated with worse symptoms and higher pulmonary capillary wedge pressure. Higher BNP was also a significant independent predictor of survival independent of BMI. Optimal BNP cutoff for prediction of death or urgent transplant in lean, overweight, and obese HF patients was 590, 471, and 342 pg/ml, respectively. CONCLUSIONS: Although BNP levels are relatively lower in overweight and obese HF patients, BNP predicts worse symptoms, impaired hemodynamics, and higher mortality at all levels of BMI.     

Normal synthesis and expression of endothelial IIb/IIIa in Glanzmann's thrombasthenia

Glanzmann's thrombasthenia is a bleeding disorder, inherited in an autosomal recessive way and characterized by an absence or deficiency of the platelet glycoprotein (GP) IIb/IIIa complex. Recently, we and others demonstrated that cultured human umbilical vein endothelial cells synthesized a membrane protein complex similar to the platelet GP IIb/IIIa complex. In this article, we demonstrate that endothelial cells isolated from the umbilical vein of a newborn with Glanzmann's thrombasthenia, as compared with normal endothelial cells, show no difference in their ability to synthesize and express this GP IIb/IIIa complex. Our results indicate that Glanzmann's thrombasthenia is not accompanied by an "endotheliopathy."     

Wnt8a and Wnt3a cooperate in the axial stem cell niche to promote mammalian body axis extension

Background: Vertebrate body axis extension occurs in a head‐to‐tail direction from a caudal progenitor zone that responds to interacting signals. Wnt/β‐catenin signaling is critical for generation of paraxial mesoderm, somite formation, and maintenance of the axial stem cell pool. Body axis extension requires Wnt8a in lower vertebrates, but in mammals Wnt3a is required, although the anterior trunk develops in the absence of Wnt3a. Results: We examined mouse Wnt8a^–/– and Wnt3a^–/– single and double mutants to explore whether mammalian Wnt8a contributes to body axis extension and to determine whether a posterior growth function for Wnt8a is conserved throughout the vertebrate lineage. We find that caudal Wnt8a is expressed only during early somite stages and is required for normal development of the anterior trunk in the absence of Wnt3a. During this time, we show that Wnt8a and Wnt3a cooperate to maintain Fgf8 expression and prevent premature Sox2 up‐regulation in the axial stem cell niche, critical for posterior growth. Similar to Fgf8, Wnt8a requires retinoic acid (RA) signaling to restrict its caudal expression boundary and possesses an upstream RA response element that binds RA receptors. Conclusions: These findings provide new insight into interaction of caudal Wnt‐FGF‐RA signals required for body axis extension. Developmental Dynamics 244:797–807, 2015. © 2015 Wiley Periodicals, Inc.     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Randomized Controlled Trial of Online Acceptance and Commitment Therapy for Fibromyalgia

In this study, 67 participants (95% female) with fibromyalgia (FM) were randomly assigned to an online acceptance and commitment therapy (online ACT)?and?treatment as usual (TAU; ACT + TAU) protocol or a TAU control condition. Online ACT?+?TAU participants were asked to complete 7 modules over an 8-week period. Assessments were completed at pre-treatment, post-treatment, and 3-month follow-up periods and included measures of FM impact (primary outcome), depression, pain, sleep, 6-minute walk, sit to stand, pain acceptance (primary process variable), mindfulness, cognitive fusion, valued living, kinesiophobia, and pain catastrophizing. The results indicated that online ACT?+?TAU participants significantly improved in FM impact, relative to TAU (P?<.001), with large between condition effect sizes at post-treatment (1.26) and follow-up (1.59). Increases in pain acceptance significantly mediated these improvements (P?=?.005). Significant improvements in favor of online ACT?+?TAU were also found on measures of depression (P?=?.02), pain (P?=?.01), and kinesiophobia (P?=?.001). Although preliminary, this study highlights the potential for online ACT to be an efficacious, accessible, and cost-effective treatment for people with FM and other chronic pain conditions.