Persistent clinical efficacy and safety of anti-tumour necrosis factor \textgreeka therapy with infliximab in patients with ankylosing spondylitis over 5 years: evidence for different types of response

Background: There is insufficient evidence for the long-term efficacy and safety of anti-tumour necrosis factor therapy in patients with ankylosing spondylitis (AS). This is the first report on the treatment with infliximab over 5 years.Methods: As part of a multicentre randomised trial, 69 patients with active AS at baseline (BL) have been continuously treated with infliximab (5 mg/kg i.v. every 6 weeks)---except for a short discontinuation after 3 years (FU1). The primary outcome of this extension was remission according to the ASsessment in Ankylosing Spondylitis (ASAS) criteria at the end of year 5 of the study (FU2).Results: Of the 43 patients who completed year 3, 42 agreed to continue, 38 of which (90.5%) finished year 5 (55% of 69 initially). Partial clinical remission was achieved in 13 of 38 patients (34.2%) at FU1 and FU2. At FU2, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 2.5±1.9 (BL:6.4, FU1:2.5). BASDAI values <4 were seen in 79% of patients at both, FU1 and FU2. ASAS 20% and 40% responses were seen in 32 (84%) and 24 (63%) patients at FU2, respectively. Most patients classified as non-responders at FU2 were part-time responders, as all but one patient achieved an ASAS 20% response at least once within the last 2 years. Three types of responders were identified. No major side effects occurred during years 4 and 5 of infliximab therapy.Conclusions: Infliximab is safe and efficacious in AS patients over 5 years. The majority of the patients remained on treatment and had rather persistent levels of low disease activity. Different response types could be identified

The pre-hydrolysis state of p21ras in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins

AbstractBackground: In numerous biological events the hydrolysis of guanine triphosphate (GTP) is a trigger to switch from the active to the inactive protein form. In spite of the availability of several high-resolution crystal structures, the details of the mechanism of nucleotide hydrolysis by GTPases are still unclear. This is partly because the structures of the proteins in their active states had to be determined in the presence of non-hydrolyzable GTP analogues (e.g. GppNHp). Knowledge of the structure of the true Michaelis complex might provide additional insights into the intrinsic protein hydrolysis mechanism of GTP and related nucleotides.Results: The structure of the complex formed between p21ras and GTP has been determined by X-ray diffraction at 1.6 Å using a combination of photolysis of an inactive GTP precursor (caged GTP) and rapid freezing (100K). The structure of this complex differs from that of p21ras–GppNHp (determined at 277K) with respect to the degree of order and conformation of the catalytic loop (loop 4 of the switch II region) and the positioning of water molecules around the γ-phosphate group. The changes in the arrangement of water molecules were induced by the cryo-temperature technique.Conclusions: The results shed light on the function of Gln61 in the intrinsic GTP hydrolysis reaction. Furthermore, the possibility of a proton shuffling mechanism between two attacking water molecules and an oxygen of the γ-phosphate group can be proposed for the basal GTPase mechanism, but arguments are presented that render this protonation mechanism unlikely for the GTPase activating protein (GAP)-activated GTPase

Quaternary structure of the European spiny lobster (Palinurus elephas) 1 x 6-mer hemocyanin from cryoEM and amino acid sequence data

Arthropod hemocyanins are large respiratory proteins that are composed of up to 48 subunits (8 x 6-mer) in the 75 kDa range. A 3D reconstruction of the 1 x 6-mer hemocyanin from the European spiny lobster Palinuris elephas has been performed from 9970 single particles using cryoelectron microscopy. An 8 Angstrom resolution of the hemocyanin 3D reconstruction has been obtained from about 600 final class averages. Visualisation of structural elements such as a-helices has been achieved. An amino acid sequence alignment shows the high sequence identity (>80%.) of the hemocyanin subunits from the European spiny lobster P. elephas and the American spiny lobster Panulirus interruptus. Comparison of the P. elephas hemocyanin electron microscopy (EM) density map with the known P. interruptus X-ray structure shows a close structural correlation, demonstrating the reliability of both methods for reconstructing proteins, By molecular modelling, we have found the putative locations for the amino acid sequence (597-605) and the C-terminal end (654-657), which are absent in the available P. interruptus X-ray data. (C) 2002 Elsevier Science Ltd. All rights reserve

The first composite score predicting Digital Ulcers in systemic sclerosis patients using Clinical data, Imaging and Patient history-CIP-DUS

Background: Digital ulcers (DU) present a challenging complication in systemic sclerosis (SSc). The aim of this study was to combine clinical characteristics and imaging methods to a composite score for the prediction of DU in SSc patients. Methods: Seventy-nine SSc patients received clinical examination, their patient history was taken and nailfold capillaroscopy (NC), colour Doppler ultrasonography (CDUS) and fluorescence optical imaging (FOI) of the hands were performed at baseline. Newly developed DU over a period of approximately 12 months were registered. We used criteria with area under the curve (AUC) of at least 0.6 in regard to the development of these new DU to create the score (CIP-DUS, clinical features, imaging, patient history-digital ulcer score). Results: Twenty-nine percent of all SSc patients developed new DU during follow-up (48.1% diffuse, 18.4% limited SSc). Based on the cross-validated (cv) AUC, a weight (cvAUC > 0.6 and ≤ 0.65: 1; cvAUC > 0.65 and ≤ 0.7: 2; cvAUC > 0.7: 3) was assigned to each selected parameter. The performance of the final CIP-DUS was assessed with and without the CDUS/FOI component. For the scleroderma patterns in NC, three points were appointed to late, two to active and one point to early capillaroscopy pattern according to Cutolo et al. The CIP-DUS including the CDUS and FOI parameters resulted in a good diagnostic performance (AUC after cross-validation: 0.83, 95%CI 0.74 to 0.92) and was well calibrated (chi-square = 12.3, p = 0.58). The cut-off associated with the maximum of sensitivity and specificity was estimated at ≥ 10 points resulting in a sensitivity of 100% and specificity of 74% for new DU during follow-up. Excluding CDUS and FOI parameters leads to a non-statistically significant lower performance (AUC after cross-validation: 0.81, 95%CI 0.72 to 0.91). However, including CDUS and FOI resulted in a better classification of patients in respect to the outcome new DU in follow-up due to significantly better reclassification performance (NRI = 62.1, p = 0.001) and discrimination improvement (IDI = 9.7, p = 0.01). Conclusion: A new score was introduced with the aim to predict digital ulcers. If applied correctly and with the new imaging techniques proposed, all patients at risk of digital ulcers throughout 12 months could be identified

Password-based group key exchange in a constant number of rounds

Abstract. With the development of grids, distributed applications are spread across multiple computing resources and require efficient security mechanisms among the processes. Although protocols for authenticated group Diffie-Hellman key exchange protocols seem to be the natural mechanisms for supporting these applications, current solutions are either limited by the use of public key infrastructures or by their scalability, requiring a number of rounds linear in the number of group members. To overcome these shortcomings, we propose in this paper the first provably-secure password-based constant-round group key exchange protocol. It is based on the protocol of Burmester and Desmedt and is provably-secure in the random-oracle and ideal-cipher models, under the Decisional Diffie-Hellman assumption. The new protocol is very efficient and fully scalable since it only requires four rounds of communication and four multi-exponentiations per user. Moreover, the new protocol avoids intricate authentication infrastructures by relying on passwords for authentication.

A Human Situation Awareness Support System to Avoid Technological Disasters

In many complex technological systems, accidents have primarily been attributed to human error. In the majority of these accidents the human operators were striving against significant challenges. They have to face data overload, the challenge of working with a complex system and the stressful task of understanding what is going on in the situation. Therefore, to design and implement complex technological systems where the information flow is quite high, and poor decisions may lead to serious consequences, Situation Awareness (SA) should be appropriately considered. A level 1 SA is highly supported in these systems through the various heterogeneous sensors and signal-processing methods but, for levels 2 and 3 there is still a need for concepts and methods. This work develops a system called the Human Situation Awareness Support System (HSASS) that supports the safety operators in an ever increasing amount of available risky status and alert information. The proposed system includes a new dynamic situation assessment method based on risk, which has the ability to support the operators understanding of the current state of the system, predict the near future, and suggest appropriate actions. The proposed system does not control the course of action and allows the human to act at his/her discretion in specific contexts