[Lupus and thrombophilia : Antiphospholipid syndrome]. / Lupus und Thrombophilie : Antiphospholipidsyndrom.

Even early on thromboembolic events were observed in patients with systemic lupus erythematosus (SLE) until the antiphospholipid syndrome (APS) was described in the 1980s as an independent disorder. The APS is a systemic autoimmune disease often overlapping with SLE in which antiphospholipid autoantibodies, including lupus anticoagulant, can cause a hypercoagulation state, which clinically by definition is manifested as arterial and venous occlusions or pregnancy complications. The pathophysiology has not yet been entirely delineated and the clinical spectrum of associated concomitant manifestations is large. As the mortality is increased with SLE and simultaneous APS, focused diagnostics and risk assessment are indispensable. According to the recently published recommendations of the European League Against Rheumatism the therapeutic strategy comprises individualized secondary prevention of thromboembolic complications by means of anticoagulation (with unaltered importance of vitamin K antagonists) and thrombocyte aggregation inhibition, usually lifelong. Statins and antimalarial drugs are recommended for vascular protection while immunosuppressive treatment has not so far been sufficiently proven for APS but remains the subject of current research.

Lysosome-Related Effector Vesicles in T Lymphocytes and NK Cells.

Lysosome-related secretory organelles combine metabolic functions of conventional lysosomes with an inducible secretory potential. Specialized variants of such bi-functional organelles are present in several haematopoietic cell types that store, mobilize and/or secrete effector proteins, for example in mast cells, macrophages or cytotoxic effector cells. In the case of T lymphocytes and NK cells, it was believed that secretory lysosomes serve as a common storage and transport compartment for the most relevant cytotoxic effector proteins including FasL, perforin, granzymes and granulysin. However, recent observations suggest that cytotoxic effector cells might be able to mobilize two distinct lysosomal entities in order to react to differential stimulation with either FasL surface appearance or degranulation-associated release of perforin and granzymes. This assumption is supported by the proteomic characterization of enriched organelles from T and NK cells. FasL-associated light lysosomes biochemically segregate from morphologically distinct heavy lysosomes that preferentially contain granzymes, perforin and mature granulysin. Here, we briefly summarize the current knowledge about cargo proteins that are stored and transported in secretory vesicles and how these vesicles might be generated and mobilized. In addition, we describe common features and major differences of the two distinct effector organelles and discuss how these observations might expand existing models of cytotoxic effector function.

Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications.

The activating natural killer group 2 member D (NKG2D) receptor is expressed on NK cells, cytotoxic T cells and additional T cell subsets. Ligands for human NKG2D comprise two groups of MHC class I-related molecules, the MHC class I chain-related proteins A and B (MICA/B) and 6 UL16-binding proteins (ULBP1-6). While NKG2D ligands are absent from most normal cells, expression is induced upon stress and malignant transformation. In fact, most solid tumours and leukaemia/lymphomas constitutively express at least one NKG2D ligand and thereby are susceptible to NKG2D-dependent immunosurveillance. However, soluble NKG2D ligands are released from tumour cells and can down-modulate NKG2D activation as a means of tumour immune escape. In some tumour entities, levels of soluble NKG2D ligands in the serum correlate with tumour progression. NKG2D ligands can be proteolytically shed from the cell surface or liberated from the membrane by phospholipase C in the case of glycosylphosphatidylinositol (GPI)-anchored molecules. Moreover, NKG2D ligands can be secreted in exosomal microvesicles together with other tumour-derived molecules. Depending on the specific tumour/immune cell setting, these various forms of soluble and/or exosome-bound NKG2D ligands can exert multiple effects on NKG2D/NKG2D ligand interactions. In this review, we focus on the role of various proteases in the shedding of human NKG2D ligands from tumour cells and discuss the not completely unanimous reported functional implications of soluble and exosome-secreted NKG2D ligands for immunosurveillance.

3-T contrast-enhanced MR angiography with parallel imaging in cerebral venous and sinus thrombosis.

BACKGROUND AND PURPOSE: Contrast-enhanced (CE) 3D magnetic resonance venography (MRV) and CE 3D magnetization prepared rapid acquisition of gradient echo (MP-RAGE) sequences are increasingly commonly used methods for evaluation of the intracranial venous system. Our aim was to compare CE MRV, 2D time-of-flight (TOF) MRV and MP-RAGE sequences at 3 T for visualization of cerebral venous and sinus thrombosis. MATERIAL AND METHODS: Patients with suspected or known cerebral venous thrombosis were examined prospectively by TOF MRV, CE MRV and MP-RAGE sequences. In 11 consecutive patients (all women; mean age, 42.5 years; age range, 25-70 years) with venous thrombosis, scores according to overall image quality, and presence or absence (score P) and differentiation (score D) of venous thrombosis were evaluated. RESULTS: By all measurements, overall image quality ranged from good to excellent. In 20 of 52 venous structures (38.5%), score P was the same on TOF MRV, CE MRV and MP-RAGE sequences. Venous thrombosis was definitely or almost definitely present or absent with TOF MRV in 20 of 52 (38.5%), with CE MRV in 97 of 99 (97.9%) and with MP-RAGE sequences in 86 of 99 (86.9%) venous structures. In all venous structures with uncertain diagnosis on TOF MRV, thrombosis was definitely or almost definitely present or absent on CE MRV and MP-RAGE sequences. Differentiation of thrombosis was better on CE MRV (score D: 3.33) than on MP-RAGE sequences (score D: 2.78), followed by TOF MRV (score D: 1.32). CONCLUSION: CE MRV was superior to TOF MRV and MP-RAGE sequences in visualizing cerebral venous and sinus thrombosis.

[Space-occupying parietal dural lesion]. / Duraständige Raumforderung parietal. Diagnose: Durale Manifestation eines Morbus Hodgkin.

An elderly female patient presented in our clinic with low grade hemiparesis. The history revealed that the patient had suffered from Hodgkin's disease and B non-Hodgkin's lymphoma, which were treated with radiotherapy and chemotherapy. The hemiparesis was now a symptom which required cranial magnetic resonance tomography.

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death.

The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

Whole-body MRI and MRA for evaluation of the prevalence of atherosclerosis in a cohort of subjectively healthy individuals.

OBJECTIVES: To assess the prevalence of cardiovascular findings in asymptomatic individuals by means of 1.5-T whole-body magnetic resonance imaging and angiography. METHODS: A cohort of 138 individuals (118 men, 20 women) with a mean age of 54 years (SD ± 7.55) was referred to whole-body MRI at 1.5-T, including contrast-enhanced whole-body MR angiography (MRA) and cardiac MRI. A total of 2,065/2,070 vessel segments (99.8%) and cardiac function were evaluated. RESULTS: Approximately one-fourth of the participating individuals had vascular abnormalities. In 17 subjects (12.3% of all subjects) significant luminal narrowing was observed in at least one vascular segment. Luminal narrowing (mild to severe) was observed in 1 (0.7% of all subjects respectively) of the renal arteries, 7 (5.0%) of the carotid arteries, and 3 (2.2%) of the pelvic and upper leg arteries, and in 17 segments (12.3%) of arteries in the lower leg. In cardiac function and perfusion imaging, wall motion disorders were observed in six patients (4.3%), with additional delayed enhancement and isolated delayed enhancement present in two cases. Functional parameters differed from reference values in 55 cases. CONCLUSIONS: Even in an asymptomatic cohort of middle-aged predominantly male individuals, atherosclerotic disease is not uncommon and is detectable by whole-body MRI. MAIN MESSAGES: • In middle-aged predominantly male individuals, atherosclerotic disease is not uncommon. • Even in an asymptomatic collective, approximately one fourth had vascular abnormalities. • Using whole-body MR angiography (MRA), 99.8% of 2,070 vessel segments could be evaluated.

FasL expression and reverse signalling.

FasL plays a central role in the induction of apoptosis within the immune system. It mediates activation-induced cell death (AICD) of T lymphocytes and contributes to the cytotoxic effector function of T and NK cells. Moreover, FasL is discussed as direct effector molecule for the establishment of immune privilege and tumour survival. Besides its death-promoting activity, FasL has been implicated in reverse signalling and might thus also play a role in T cell development and selection and the modulation of T cell activation. Considering these diverse functions, the overall FasL expression has to be tightly controlled to avoid unwanted damage. Based on an activation-associated transcriptional control, several post-transcriptional processes ensure a safe storage, a rapid mobilisation, a target-directed activity and a subsequent inactivation. Over the past years, the identification and characterisation of FasL-interacting proteins provided novel insight into the mechanisms of FasL transport, processing and reverse signalling, which might be exemplary also for the other members of the TNF family.

3T high-spatial-resolution contrast-enhanced MR angiography of the intracranial venous system with parallel imaging.

The diagnostic image quality of contrast-enhanced (CE) 3D MR venography (MRV) was prospectively compared with that of 2D time-of-flight (TOF) MRV and contrast-enhanced 3D magnetization-prepared rapid acquisition of gradient echo (MPRAGE) sequences for the visualization of the intracranial venous system at 3T in 22 patients. CE MRV provides high-quality images and was shown to be superior to TOF MRV and MPRAGE sequences in visualizing the normal intracranial venous system.

Carotid artery stents: in vitro comparison of different stent designs and sizes using CT angiography and contrast-enhanced MR angiography at 1.5T and 3T.

BACKGROUND AND PURPOSE: CT angiography (CTA) and MR angiography (MRA) are increasingly used methods for evaluation of stented vessel segments. Our aim was to compare CTA, contrast-enhanced MRA (CE-MRA) at 1.5T, and CE-MRA at 3T for the visualization of carotid artery stents and to define the best noninvasive imaging technique as an alternative to conventional angiography for each stent. MATERIALS AND METHODS: CTA and CE-MRA appearances of 18 carotid artery stents of different designs and sizes (4.0 to 10.0 mm) were investigated in vitro. For each stent, artificial lumen narrowing (ALN) was calculated. RESULTS: With CE-MRA at 3T and at 1.5T, ALN in most nitinol stents was lower than that in the groups of stainless steel and cobalt alloy stents. In most nitinol stents and in both cobalt alloy stents, ALN was lower on CE-MRA at 3T than at 1.5T. In all stainless steel stents, ALN was lower on CTA than on CE-MRA. With CTA and CE-MRA, in most stents ALN decreased with increasing stent diameter. CONCLUSIONS: CTA and CE-MRA evaluation of vessel patency after stent placement is possible but is considerably impaired by ALN. Investigators should be informed about the method of choice for every stent. Stent manufacturers should be aware of potential artifacts caused by their stents during noninvasive diagnostic methods such as CTA and CE-MRA.