Leiden University Medical Center

ABSTRACT Cardiac magnetic resonance perfusion imaging (CMR) and computed tomography angiography (CTA) are widely used to assess heart disease. CMR is used to measure the global and regional myocardial function and to evaluate the presence of ischemia; CTA is used for diagnosing coronary artery disease, such as coronary stenoses.

The extracellular adherence protein (Eap), a broad-spectrum adhesin secreted by Staphylococcus aureus, was previously shown to curb acute inflammatory responses, presumably through its binding to endothelial cell (EC) ICAM-1. Examining the effect of Eap on endothelial function in more detail, we here show that, in addition, Eap functions as a potent angiostatic agent. Concomitant treatment of EC with purified Eap resulted in the complete blockage of the mitogenic and sprouting responses elicited by vascular endothelial growth factor (VEGF) 165 or basic fibroblast growth factor (bFGF). Moreover, the induction of tissue factor and decay-accelerating factor were repressed by Eap, as determined by qRT-polymerase chain reaction (qRT-PCR), with a corresponding reduction in Egr-1 protein up-regulation seen. This angiostatic activity was accompanied by a corresponding inhibition in ERK1/2 phosphorylation, while activation of p38 was not affected. Inhibition occurred downstream of tyrosine kinase receptor activation, as comparable effects were seen on TPA-induced ERK1/2 phosphorylation.

Inside-out signaling regulation of the ␤2integrin leukocyte function-associated antigen-1 (LFA-1) by different cytoplasmic proteins, including 14-3-3 proteins, is essential for adhesion and migration of immune cells. Here, we identify a new pathway for the regulation of LFA-1 activity by Cbl-b, an adapter molecule and ubiquitin ligase that modulates several signaling pathways. Cbl-b ؊/؊ mice displayed increased macrophage recruitment in thioglycollate-induced peritonitis, which was attributed to Cbl-b deficiency in macrophages, as assessed by bone marrow chimera experiments. In vitro, Cbl-b ؊/؊ bone marrow-derived mononuclear phagocytes (BMDMs) displayed increased adhesion to endothelial cells. Activation of LFA-1 in Cbl-bdeficient cells was responsible for their increased endothelial adhesion in vitro and peritoneal recruitment in vivo, as the phenotype of Cbl-b deficiency was reversed in Cbl-b ؊/؊ LFA-1 ؊/؊ mice. Consistently, LFA-1-mediated adhesion of BMDM to ICAM-1 but not VLA-4-mediated adhesion to VCAM-1 was enhanced by Cbl-b deficiency. Cbl-b deficiency resulted in increased phosphorylation of T758 in the ␤2-chain of LFA-1 and thereby in enhanced association of 14-3-3␤ protein with the ␤2chain, leading to activation of LFA-1. Consistently, disruption of the 14-3-3/␤2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b ؊/؊ BMDMs. In conclusion, Cbl-b deficiency activates LFA-1 and LFA-1mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 ␤-chain and 14-3-3 proteins. (Blood.

Postnatal neovascularization is triggered by tissue hypoxia and the hypoxia-inducible transcription factor dependent upregulation of vascular growth factors. At the same time hypoxia is associated with replication stress and can induce a cellular DNA repair response including the phosphorylation of histone H2AX. Recent findings point to a role of H2AX in endothelial cell proliferation under hypoxia and thereby in hypoxia-driven neovascularization.

Meiosis is a crucial process for the production of functional gametes. However, the biological significance of many genes expressed during the meiotic phase remains poorly understood, mainly because of the lethal phenotypes of the knockout mice. Functional analysis of such genes using the conditional knockout approach is hindered by the lack of suitable Cre transgenic lines. We describe here the generation of transgenic mice expressing Cre recombinase under the control of the meiotic Spo11 gene. Using LacZ-R26 loxP and EYFP-R26 loxP reporter mice, we show the specific expression and activity of Cre during meiosis in males and females. Spo11 Cre mice were then crossed with floxed Nbs1 and JAM-C mice to produce conditional knockouts. A strong reduction of Nbs1 and JAM-C protein levels was found in the testis. Although Nbs1-deleted mice developed minor gonadal abnormalities, JAM-C-knockout mice showed a spermiogenetic arrest, as previously described for the null mice. These results provide strong evidence that Spo11 Cre transgenic mice represent a powerful tool for deleting genes of interest specifically in meiotic and/or in postmeiotic germ cells.

Giant cell tumors deriving from synovium are classified into a localized (GCT of tendon sheath; GCT-TS) and diffuse form (diffuse-type GCT, Dt-GCT). We propose a multidisciplinary management based upon a systematic review and authors' opinion. Open excision for GCT-TS and open synovectomy (plus excision) for Dt-GCT is advised to reduce the relatively high recurrence risk. External beam radiotherapy should be considered in severe cases, as Dt-GCT commonly extends extra-articular. J. Surg. Oncol. 2013;107:433–445. © 2012 Wiley Periodicals, Inc.

Background Approximately one in five patients with giant cell tumor of bone presents with a pathologic fracture. However, recurrence rates after resection or curettage differ substantially in the literature and it is unclear when curettage is reasonable after fracture. Questions/Purposes We therefore determined: (1) local recurrence rates after curettage with adjuvants or en bloc resection; (2) complication rates after both surgical techniques and whether fracture healing occurred after curettage with adjuvants; and (3) function after both treatment modalities for giant cell tumor of bone with a pathologic fracture. Methods We retrospectively reviewed 48 patients with fracture from among 422 patients treated between 1981 and 2009. The primary treatment was resection in 25 and curettage with adjuvants in 23 patients. Minimum followup was 27 months (mean, 101 months; range, 27–293 months). Results Recurrence rate was higher after curettage with adjuvants when compared with resection (30% versus 0%). Recurrence risk appears higher with soft tissue extension. The complication rate was lower after curettage with adjuvants when compared with resection (4% versus 16%) and included aseptic loosening of prosthesis, allograft failure, and pseudoarthrosis. Tumor and fracture characteristics did not increase complication risk. Fracture healing occurred in 24 of 25 patients. Mean Musculoskeletal Tumor Society score was higher after curettage with adjuvants (mean, 28; range, 23–30; n = 18) when compared with resection (mean, 25; range, 13–30; n = 25). Conclusions Our observations suggest curettage with adjuvants is a reasonable option for giant cell tumor of bone with pathologic fractures. Resection should be considered with soft tissue extension, fracture through a local recurrence, or when structural integrity cannot be regained after reconstruction. Level of Evidence Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Giant cell tumours (GCT) of the synovium and tendon sheath can be classified into two forms: localised (giant cell tumour of the tendon sheath, or nodular tenosynovitis) and diffuse (diffuse-type giant cell tumour or pigmented villonodular synovitis). The former principally affects the small joints. It presents as a solitary slow-growing tumour with a characteristic appearance on MRI and is treated by surgical excision. There is a significant risk of multiple recurrences with aggressive diffuse disease. A multidisciplinary approach with dedicated MRI, histological assessment and planned surgery with either adjuvant radiotherapy or systemic targeted therapy is required to improve outcomes in recurrent and refractory diffuse-type GCT.

Giant cell tumours (GCTs) of the small bones of the hands and feet are rare. Small case series have been published but there is no consensus about ideal treatment. We performed a systematic review, initially screening 775 titles, and included 12 papers comprising 91 patients with GCT of the small bones of the hands and feet. The rate of recurrence across these publications was found to be 72% (18 of 25) in those treated with isolated curettage, 13% (2 of 15) in those treated with curettage plus adjuvants, 15% (6 of 41) in those treated by resection and 10% (1 of 10) in those treated by amputation.

Background: It has been suggested that, when a patient has a giant cell tumor, subchondral bone involvement close to articular cartilage and a hyperthermic reaction from polymethylmethacrylate (PMMA) are risk factors for the development of osteoarthritis. We determined the prevalence, risk factors, and clinical relevance of osteoarthritis on radiographs after curettage and application of PMMA for the treatment of giant cell tumors around the knee.

Purpose We aimed to ascertain the feasibility of crowdsourcing via Facebook for medical research purposes; by investigating surgical, oncological and functional outcome and quality-of-life (QOL) in patients with pigmented villonodular synovitis (PVNS) enrolled in a Facebook community (1112 members). Methods Patients completed online open surveys on demographics, surgery and clinical outcomes (group 1); and patient-reported outcome measures (PROMs) including knee-injury osteoarthritis outcome score (KOOS), hipdisability osteoarthritis outcome score (HOOS), Toronto extremity salvage score (TESS) and SF-36 (group 2). Mean follow-up was 70 months (12-374). Consistency checks were performed with Cohen's kappa statistic for intra-rater agreement. The first survey was completed by 272 patients (group 1) and 72 patients completed the second (group 2). In group 1, recurrence-rate was 58 % (69/118) after arthroscopic, 36 % (35/97) after open and 50 % (5/10) after combined synovectomy (p = 0.003). In group 2, recurrence-rate was 67 % (26/39) after arthroscopic and 51 % (17/33) after open synovectomy (p = 0.19). Recurrence-risk was increased for diffuse disease (OR = 16; 95%CI = 3.2-85; p < 0.001). Mean function and QOL did not differ after arthroscopic or open synovectomy: KOOS 49 vs. 58 (p = 0.24), HOOS 62 vs. 53 (p = 0.56), TESS 78 vs. 82 (p = 0.86), SF-36 61 vs. 66 (p = 0.41). Cohen's kappa statistic for intra-rater agreement was good to outstanding (κ = 0.68-0.95; p < 0.001). Conclusion Local recurrence-risk was higher for diffusetype disease and arthroscopic synovectomy. Functional outcome and QOL were comparable for both types of surgery. Gathering data via crowdsourcing seems a promising and innovative way of evaluating rare diseases including PVNS. Crowdsourcing . Diffuse-type giant cell tumor . Facebook . Functional outcome . Pigmented villonodular synovitis . PVNS . Quality of life * Lizz van der Heijden