Rationale and design of The Delphi Trial – I(RCT)(2): international randomized clinical trial of rheumatoid craniocervical treatment, an intervention-prognostic trial comparing 'early' surgery with conservative treatment [ISRCTN65076841]

BACKGROUND: Rheumatoid arthritis is a chronic inflammatory disease, which affects 1% of the population. Hands and feet are most commonly involved followed by the cervical spine. The spinal column consists of vertebrae stabilized by an intricate network of ligaments. Especially in the upper cervical spine, rheumatoid arthritis can cause degeneration of these ligaments, causing laxity, instability and subluxation of the vertebral bodies. Subsequent compression of the spinal cord and medulla oblongata can cause severe neurological deficits and even sudden death. Once neurological deficits occur, progression is inevitable although the rapidity of progression is highly variable. The first signs and symptoms are pain at the back of the head caused by compression of the major occipital nerve, followed by loss of strength of arms and legs. The severity of the subluxation can be observed with radiological investigations (MRI, CT) with a high sensitivity. The authors have sent a Delphi Questionnaire about the current treatment strategies of craniocervical involvement by rheumatoid arthritis to an international forum of expert rheumatologists and surgeons. The timing of surgery in patients with radiographic instability without evidence of neurological deficit is an area of considerable controversy. If signs and symptoms of myelopathy are present there is little chance of recovery to normal levels after surgery. DESIGN: In this international multicenter randomized clinical trial, early surgical atlantoaxial fixation in patients with rheumatoid arthritis and radiological abnormalities without neurological deficits will be compared with prolonged conservative treatment. The main research question is whether early surgery can prevent radiological and neurological progression. A cost-effectivity analysis will be performed. 250 patients are needed to answer the research question. DISCUSSION: Early surgery could prevent serious neurological deficits, but may have peri-operative morbidity and loss of rotation of the head and neck. The objective of this study is to identify the best timing of surgery for patients at risk for the development of neurological signs and symptoms

Photonic quantum information processing: a review

Photonic quantum technologies represent a promising platform for several applications, ranging from long-distance communications to the simulation of complex phenomena. Indeed, the advantages offered by single photons do make them the candidate of choice for carrying quantum information in a broad variety of areas with a versatile approach. Furthermore, recent technological advances are now enabling first concrete applications of photonic quantum information processing. The goal of this manuscript is to provide the reader with a comprehensive review of the state of the art in this active field, with a due balance between theoretical, experimental and technological results. When more convenient, we will present significant achievements in tables or in schematic figures, in order to convey a global perspective of the several horizons that fall under the name of photonic quantum information.Comment: 36 pages, 6 figures, 634 references. Updated version with minor changes and extended bibliograph

CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers

The membrane attack complex (MAC) is one of the immune system’s first responders. Complement proteins assemble on target membranes to form pores that lyse pathogens and impact tissue homeostasis of self-cells. How MAC disrupts the membrane barrier remains unclear. Here we use electron cryo-microscopy and flicker spectroscopy to show that MAC interacts with lipid bilayers in two distinct ways. Whereas C6 and C7 associate with the outer leaflet and reduce the energy for membrane bending, C8 and C9 traverse the bilayer increasing membrane rigidity. CryoEM reconstructions reveal plasticity of the MAC pore and demonstrate how C5b6 acts as a platform, directing assembly of a giant β-barrel whose structure is supported by a glycan scaffold. Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions

Should I stay or should I go? Trafficking of sub-lytic MAC in the retinal pigment epithelium.

Assembly of sub-lytic C5b-9 membrane attack complexes (MAC) on the plasma membrane of retinal pigment epithelial cells contributes to the pathogenesis of age-related macular degeneration. C5b-9 pores induce calcium influx, which activates signaling pathways that compromise cell function. Mechanisms that limit sub-lytic MAC activity include: cell surface complement regulatory proteins CD46, CD55, and CD59 that inhibit specific steps of MAC formation; elimination of assembled MAC by exocytosis of membrane vesicles or by endocytosis and subsequent lysosomal degradation; and rapid resealing of pores by the exocytosis of lysosomes. Aging in the post-mitotic retinal pigment epithelium is characterized by the accumulation of cellular debris called lipofuscin, which has also been associated with retinal diseases such as age-related macular degeneration. Lipofuscin has been shown to activate complement components both in vitro and in vivo, suggesting that it could contribute complement-mediated dysfunction in the retinal pigment epithelium. Here, we discuss emerging evidence that vesicular trafficking in the retinal pigment epithelium is critical for efficient removal of MAC from the cell surface and for limiting inflammation in the outer retina