Logarithmic Upturn in Low-Temperature Electronic Transport as a Signature of d-Wave Order in Cuprate Superconductors.

In cuprate superconductors, high magnetic fields have been used extensively to suppress superconductivity and expose the underlying normal state. Early measurements revealed insulatinglike behavior in underdoped material versus temperature T, in which resistivity increases on cooling with a puzzling log(1/T) form. We instead use microwave measurements of flux-flow resistivity in YBa_{2}Cu_{3}O_{6+y} and Tl_{2}Ba_{2}CuO_{6+δ} to study charge transport deep inside the superconducting phase, in the low-temperature and low-field regime. Here, the transition from metallic low-temperature resistivity (dρ/dT>0) to a log(1/T) upturn persists throughout the superconducting doping range, including a regime at high carrier dopings in which the field-revealed normal-state resistivity is Fermi-liquid-like. The log(1/T) form is thus likely a signature of d-wave superconducting order, and the field-revealed normal state's log(1/T) resistivity may indicate the free-flux-flow regime of a phase-disordered d-wave superconductor.

Alterations of hair cortisol and dehydroepiandrosterone in mother-infant-dyads with maternal childhood maltreatment.

BACKGROUND: Child maltreatment (CM) has severe effects on psychological and physical health. The hypothalamic-pituitary-adrenal (HPA) axis, the major stress system of the body, is dysregulated after CM. The analysis of cortisol and dehydroepiandrosterone (DHEA) in scalp hair presents a new and promising methodological approach to assess chronic HPA axis activity. This study investigated the effects of CM on HPA axis activity in the last trimester of pregnancy by measuring the two important signaling molecules, cortisol and DHEA in hair, shortly after parturition. In addition, we explored potential effects of maternal CM on her offspring's endocrine milieu during pregnancy by measuring cortisol and DHEA in newborns' hair. METHODS: CM was assessed with the Childhood Trauma Questionnaire (CTQ). Cortisol and DHEA were measured in hair samples of 94 mothers and 30 newborns, collected within six days after delivery. Associations of maternal CM on her own and her newborn's cortisol as well as DHEA concentrations in hair were analyzed with heteroscedastic regression models. RESULTS: Higher CM was associated with significantly higher DHEA levels, but not cortisol concentrations in maternal hair. Moreover, maternal CM was positively, but only as a non-significant trend, associated with higher DHEA levels in the newborns' hair. CONCLUSIONS: Results suggest that the steroid milieu of the mother, at least on the level of DHEA, is altered after CM, possibly leading to non-genomic transgenerational effects on the developing fetus in utero. Indeed, we observed on an explorative level first hints that the endocrine milieu for the developing child might be altered in CM mothers. These results need extension and replication in future studies. The measurement of hair steroids in mothers and their newborns is promising, but more research is needed to better understand the effects of a maternal history of CM on the developing fetus.

Thermomechanical method for cement extraction in revision arthroplasty.

BACKGROUND: In joint revision surgery, bone cement extraction remains a major challenge which even today has not seen a satisfactory solution yet. We studied in an experimental setting the impact of heat sources on the mechanical properties and microstructure of bone cement and determined the glass transition temperature (T G) of bone cement. As a result, it would be possible to establish a thermomechanical method which makes use of the structural and material-specific property changes inherent in bone cement at elevated temperatures. METHODS: Prepared samples of polymerized bone cement were thermoanalyzed with a Netzsch STA 409 C thermal analyzer. Samples weighing approx. 55 mg were heated to 390 °C at a rate of 5 K/min. Both simultaneous differential thermal analysis and thermogravimetry were employed. The thermomechanically induced changes in the microstructure of the material were analyzed with a computed tomography scanner specifically developed for materials testing (3D-µXCT). RESULTS: The bone cement changed from a firm elastic state over entropy-plastic (air atmosphere 60-155 °C) to a plastic viscosity state (air atmosphere >155 °C). Between 290 and 390 °C, the molten mass disintegrated (decomposition temperature). CONCLUSION: Our study was able to determine the glass transition temperature (T G) of bone cement which was about 60 and 65 °C under air and nitrogen, respectively. Heating the dry bone cement up to at least 65 °C would be more than halve the strength needed to detach it. Bone cement extraction would then be easy and swift.

Marked improvement in the success rate of medical management of early pregnancy failure following the implementation of a novel institutional protocol and treatment guidelines: a follow-up study.

PURPOSE: To analyze the success rate, time to passage of tissue and subjective patient experience of a newly implemented protocol for medical management of early pregnancy failure (EPF) over a 2-year period. METHODS: A retrospective chart review of all patients with early pregnancy failure primarily opting for medical management was performed. 200 mg mifepristone were administered orally, followed by a single vaginal dose of 800 mcg misoprostol after 36-48 h. We followed-up with our patients using a written questionnaire. RESULTS: 167 women were included in the present study. We observed an overall success rate of 92 %, defined as no need for surgical management after medication administration. We could not identify predictive values for success in a multivariate regression analysis. Most patients (84 %) passed tissue within 6 h after misoprostol administration. The protocol was well tolerated with a low incidence of side effects. Pain was managed well with sufficient analgesics. Responders to the questionnaire felt adequately informed prior to treatment and rated their overall experience as positive. CONCLUSION: The adaption of the institutional medical protocol resulted in a marked improvement of success rate when compared to the previously used protocol (92 vs. 61 %). We credit this increase to the adjusted medication schema as well as to targeted physician education on the expected course and interpretation of outcome measures. Our results underscore that the medical management of EPF is a safe and effective alternative to surgical evacuation in the clinical setting.

Rates of serious infections, opportunistic infections, inflammatory bowel disease, and malignancies in subjects receiving etanercept vs. controls from clinical trials in ankylosing spondylitis: a pooled analysis.

OBJECTIVES: Therapies involving anti-tumour necrosis factor are associated with increased risk of serious infections, opportunistic infections, and some types of malignancies in subjects with rheumatic diseases. However, limited data have been collected for subjects with ankylosing spondylitis (AS). The aim of this retrospective analysis of all sponsor-conducted trials was to examine the rates of serious infections, inflammatory bowel disease (IBD), malignancies, and non-malignant skin cancers during treatment in subjects with AS. METHOD: Data from five randomized controlled trials (one sulfasalazine-controlled, four placebo-controlled) and four open-label studies evaluating etanercept were pooled for analyses. All randomized subjects who received at least one dose of treatment were included in the study. RESULTS: Analyses included 1323 subjects (> 1500 subject-years of treatment). Rate ratios of serious infections and IBD events for etanercept vs. placebo/sulfasalazine during the double-blind studies were 2.19 [95% confidence interval (CI) 0.22-107.79] and 1.09 (95% CI 0.06-64.56), respectively. There were no reports of opportunistic infections. Using the Surveillance, Epidemiology and End Results database, the standardized incidence ratio for malignancies was 1.47 (95% CI 0.54-3.21). CONCLUSIONS: These data suggest that etanercept is well tolerated in subjects with AS. Despite the large number of patients, the 95% CI data all cross 1.0, limiting possible conclusions. No new safety signals were observed.

Well-differentiated neuroendocrine neoplasia: relapse-free survival and predictors of recurrence after curative intended resections.

BACKGROUND: Resection with curative intention is the cornerstone of treatment in patients with neuroendocrine tumors. A proportion of patients will relapse after R0 resection, but the factors predictive of recurrence are not well understood. METHODS: A database established 1998 at the University Hospital Marburg was queried for all patients with documented R0 resection. Recurrence-free survival and overall survival were estimated using the Kaplan-Meier method. Uni- and multivariate analyses were performed. RESULTS: 180 patients with a median age of 52 years entered the analysis. We observed 77 recurrences after a median time of 2.9 years. 24% of the recurrences occurred later than 5 years after operation. Median recurrence-free survival of the whole cohort was 101 months. In univariate analysis grade by Ki-67, stage, high lymph node ratio and microangioinvasion were significant predictors of recurrence. On multivariate analysis these parameters were confirmed as independent prognostic parameters with stage and microangioinvasion being the most important predictors. CONCLUSIONS: After R0 resection of neuroendocrine tumors, postoperative surveillance should be extended to at least 10 years. Patients with distant metastases and microangioinvasion are at high risk of recurrence. Clinical trials of adjuvant treatment protocols are indicated in these patients.

Occupational orthopedic problems and its relation to personal radiation protection in interventional radiology.

PURPOSE: Several studies report occupational orthopedic problems among interventional cardiologists. These health problems are usually multifactorial. However, the personal protective equipment used should play a major role. An online survey was conducted to determine the frequency of such health problems among interventional radiologists and to correlate them with the use of personal radiation protective clothing. MATERIAL AND METHODS: An anonymous online survey that comprised of 17 questions was sent via e-mail to 1427 members of the German Society for Interventional Radiology (DeGIR) in Germany, Austria and Switzerland. The questions were focused on interventional workload, the use of personal radiation protection apparel and orthopedic problems. Given the different scale levels, the associations between the variables were analyzed using different statistical methods. A significance level of p < 0.05 was chosen. RESULTS: There were 221 survey responders (15.5% response rate). About half of responders (47.7%) suffered from more than five episodes of orthopedic problems during their interventional career. Lumbar spine was involved in 81.7% of these cases, cervical spine in 32.8%, shoulder in 28.5% and knee in 24.7%. Because of orthopedic problems, 16.1% of the responders had to reduce and 2.7% had to stop their interventional practice. The number of affected body regions correlates with the fit of the radiation protection means (p < 0.05, r = 0.135) and the reduction of activity as an interventional radiologist (p < 0.05, r = -0.148). CONCLUSION: Overall, the survey reveals widespread orthopedic problems at several body regions among interventional radiologists, associated with the fit of radiation protection systems, among other factors. A connection between the orthopaedic complaints and the radiation protection system used could not be established.

Joint replacement increases radiation exposure to the staff in angiography: A phantom study.

INTRODUCTION: The present study investigates the influence of joint prostheses on the amount of scattered radiation in a simulated angiography set-up. MATERIALS AND METHODS: A clinical angiography system (Artis Zee, Siemens Healthineers, Germany) with a water phantom as a scattering object was used. The scattered radiation of the water phantom was repeatedly measured without prosthesis, with a knee prosthesis and a hip prosthesis made from titanium, aluminum, vanadium, ceramics and polyethylene. For radiation measurement an ionization chamber (ambient dose equivalent rate from 0.1 µSv/h - 100 Sv/h, UMo, Berthold Technologies, Germany) was used. It was positioned on the right side of the phantom simulating an interventional procedure via the right femoral artery. The ionization chamber was positioned at 5 different heights (30, 100, 130, 150 and 165 cm), simulating different body parts of the interventionist. In addition, the amount of scattered radiation in relation to the tube angulation was investigated. RESULTS: Averaged over all angulations at a height of 165 cm, the radiation dose was 2.7 times higher (1935 µSv/h, p < 0.01) when a hip prosthesis was present in comparison to no prosthesis (713 µSv/h). The radiation dose was 3.9 times higher with the integration of a knee prosthesis (2778 µSv/h, p < 0.01) compared to that without prosthesis. The average radiation dose over all angulations and all heights was 1491 µSv/h without prosthesis, 4538 µSv/h with a hip prothesis and 5023 µSv/h with a knee prosthesis respectively. CONCLUSION: This experimental study shows a significant increase in the radiation dose when a joint prosthesis is present in the examination field. Special attention and sufficient radiation protection is therefore necessary for investigations with implanted prostheses.

Interactive map communication: pilot study of the visual perceptions and preferences of public health practitioners.

OBJECTIVES: To conduct a pilot study into the comprehension and visualisation preferences of geographic information by public health practitioners (PHPs), particularly in the context of interactive, Internet-based atlases. STUDY DESIGN: Structured human-computer interaction interviews. METHODS: Seven academia-based PHPs were interviewed as information service users based on a structured questionnaire to assess their understanding of geographic representations of morbidity data, and identify their visualisation preferences in a geographic information systems environment. RESULTS: Awareness of area-based deprivation indices and the Index of Multiple Deprivation 2007 health and disability domain was near-universal. However, novice users of disease maps had difficulties in interpreting data classifications, in understanding supplementary information in the form of box plots and histograms, and in making use of links between interactive tabular and cartographic information. Choices for colour plans when viewing maps showed little agreement between users, although pre-viewing comments showed preferences for red-blue diverging schema. CONCLUSIONS: PHPs new to geographic information would benefit from enhanced interpretive support documentation to meet their needs when using Internet-based, interactive public health atlases, which are rarely provided at such sites. Technical, software-related support alone is insufficient. Increased interaction between PHPs and mapmakers would be beneficial to maximise the potential of the current growth in interactive, electronic atlases, and improve geographic information support for public health decision-making and informing the wider public.

Analysis of uveitis rates across all etanercept ankylosing spondylitis clinical trials.

OBJECTIVE: To assess uveitis (including iritis and iridocyclitis) incidence from clinical trials of etanercept in patients with ankylosing spondylitis (AS). METHODS: Clinical trials of etanercept in AS (four placebo-controlled; one active-controlled; three open-label) were examined for reports of uveitis. Between-group differences with confidence intervals (CIs) in the uveitis rates were calculated for the double-blind, active-controlled and long-term studies. RESULTS: In placebo-controlled trials, the uveitis rate per 100 subject years (95% CI) for etanercept (8.6 (4.5 to 14.2)) was lower than that for placebo (19.3 (11.0 to 29.8), p = 0.03). In the active comparator trial, rates for etanercept and sulfasalazine were similar (10.7 (5.5 to 17.6) and 14.7 (6.4 to 26.5), respectively; p = 0.49). The long-term rate for etanercept, estimated from both placebo-controlled and open-label extension studies was 12.0 (10.0 to 14.1). CONCLUSIONS: In subjects with AS, rates of uveitis events with etanercept were lower than with placebo in placebo-controlled trials and similar to sulfasalazine in an active comparator trial.

Patient-reported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated with remission: the COMET trial.

OBJECTIVES: To compare the effects of etanercept (ETN) 50 mg once weekly plus methotrexate (MTX) versus MTX alone on patient-reported outcomes (PROs) and the relationship between remission and PRO improvement. METHODS: In this double-blind, randomised clinical trial (COMET), PROs included: the Health Assessment Questionnaire (HAQ), EuroQoL health status, fatigue and pain visual analogue scales, Hospital Anxiety and Depression Scale, and Medical Outcomes Short-Form-36. Mean changes from baseline were analysed by analysis of covariance using the last observation carried forward method. Results from week 52 are presented. RESULTS: Most PROs demonstrated significantly greater improvements with ETN+MTX than MTX alone, including physical functioning, pain, fatigue and overall health status. A significantly greater improvement in HAQ score was observed in the ETN+MTX than the MTX group (-1.02 vs -0.72; p<0.001) and a greater proportion reached the minimal clinically important difference of 0.22 (88% vs 78%; p<0.006). The relationship between PRO score and clinical status indicated that improvement was greatest among patients achieving remission. CONCLUSIONS: Early treatment with ETN+MTX leads to significantly greater improvements in multiple dimensions of PROs than MTX alone. The close relationship between disease activity and PRO improvement suggests that early treatment, with remission as a goal, should maximise the chance of restoring normal functioning and HRQoL.

Sustained efficacy and safety, including patient-reported outcomes, with etanercept treatment over 5 years in patients with ankylosing spondylitis.

OBJECTIVES: To assess long-term safety and clinical efficacy of etanercept 25 mg subcutaneously twice weekly up to 5 years in subjects with ankylosing spondylitis (AS). METHODS: An open-label (OL), multicentre, phase 4, 156-week extension study of subjects with AS who had completed a 12-week randomised, placebo-controlled study (N=84; n=45 etanercept, n=39 placebo) followed by a 96-week OL study (n=81; n=42 etanercept/etanercept; n=39 placebo/etanercept); 59 subjects who completed the 96-week OL extension enrolled in the current OL trial and continued etanercept 25 mg BIW for an additional 156 weeks (total duration: 264 weeks, original etanercept group; 252 weeks, original placebo group). Safety was based on spontaneous reports of adverse events (AEs). Last observation carried forward was used for imputation of missing values. RESULTS: Thirty-seven of 59 subjects (63%) completed 5 years of etanercept treatment. Serious non infectious AEs and serious infections occurred at a rate of 0.17 and 0.03 events per subject years, respectively; inflammatory bowel disease and uveitis (including iritis and iridiocyclitis) occurred at 0.01 and 0.14, respectively. No cases of tuberculosis or opportunistic infections were reported. Assessment in Ankylosing Spondylitis (ASAS) responses and improvements in Bath Ankylosing Spondylitis Functional Index and spinal mobility were sustained from week 108 through week 264. CONCLUSIONS: Etanercept was well tolerated with no new safety signals detected in subjects with AS over 5 years. Clinical efficacy and improvements in function and mobility seen during the double-blind and first OL study were sustained. These results support etanercept therapy for the long-term management of this chronic disease.

[Timing and concepts of surgical treatment of upper gastrointestinal haemorrhage]. / Die chirurgische Therapie der oberen gastrointestinalen Blutung - Konzepte und zeitliche Planung.

BACKGROUND: Upper gastrointestinal bleeding is a frequently occurring clinical scenario with a potentially serious prognosis. In spite of excellent endoscopic results, the mortality rate after an insufficient endoscopic treatment is exception-ally high (12.5-36 %). It is crucial to recognise factors in which endoscopy reaches its limitations. Until now, no uniform guidelines and concepts concerning diagnosis and treatment as well as timing of surgical interventions, in particular, have been defined. The main goal of this study is to lower the morbidity and mortality rates after upper gastrointestinal bleeding, with potential risk stratification according to the literature and our own data. PATIENTS / MATERIAL AND METHODS: In a retrospectively designed study 220 patients were evaluated with upper gastrointestinal haemorrhage, who were hospitalised as emergencies from 1999 to 2002. Only those patients were accepted in the study who were examined within 48 hours endoscopically by oesophagogastroduodenoscopy. In order to exclude bleeding complications of a preceding endoscopic therapy, those patients were excluded who had been investigated by endoscopy in the past than 8 days. RESULTS: After endoscopic evaluation of the bleed-ing activity of 33 Forrest I a / I b bleedings 5 patients and of 52 Forrest II a / II b / II c bleedings 6 patients had to undergo surgery. The haemoglobin content of conventionally treated patients was on average 10.3 mg / dL as compared to 8.4 mg / dL for the operated patients. The conventionally treated patients received an average of 3 red cell concentrates whereas the operated patients had 11 blood transfusions. The source of haemorrhage in the operated patients was located in bulbus duodeni (n = 7), cardia and fundus (n = 2) and the corpus (n = 2). CONCLUSION: The evaluation of our own patient data including the experiences of other authors shows that a risk stratification is possible and meaningful. The indication for surgery thereby -depends on different factors: the comorbidity of the patient, the haemodynamic in- / stability, the number of necessary blood transfusions and the localisation of the bleeding source.

Ivory vs. osseous ivory substitutes-Non-invasive diffractometric discrimination.

A new discrimination method for the bioapatite materials bone, antler and ivory was developed using X-ray diffractometry and comprises non-invasive measurements in order to take valuable objects into account. Our approach deals with the analysis of peak intensity ratios resulting from several measurements on each object. For instance, the intensity ratio of the apatite reflections 002 and 310 has been described in the literature as representing the degree of apatite crystal orientation and varies depending on the sample orientation. The decisive factor for the material identification is the value dispersion of intensity ratios resulting from the total of all measurements on one object. This pattern of data points, visualised via kernel density estimation (KDE), is characteristic for ivory, bone and antler, respectively, and enables the discrimination of these materials. The observation is justifiable since apatite crystal orientation adapts to the collagen fibre arrangement which shows major differences between different sorts of bioapatite materials. The patterns of data points were received via analysis of 88 objects made of bone (n = 30), antler (n = 27) and ivory (n = 31). In order to verify several identifications X-ray computer tomography was supplemented. The presented method usefully supplements already existing approaches concerning microscopic, elementary and biochemical analyses.

Protective Efficacy of Different Ocular Radiation Protection Devices: A Phantom Study.

PURPOSE: The aim of this study was to investigate the efficacy of different designs and types of ocular radiation protection devices depending on simulated varied body heights in a phantom-simulated thoracic intervention. MATERIALS AND METHODS: A clinical angiography system with a standardized fluoroscopy protocol with an anthropomorphic chest phantom as a scattering object and optically stimulated luminescence dosimeters for measuring radiation dose were used. The dosimeters were placed at the position of eyes of an anthropomorphic head phantom simulating the examiner. The head phantom was placed on a height-adjustable stand simulating the height of the examiner from 160 to 200 cm with 10 cm increments. The dose values were then measured with no radiation protection, a weightless-like radiation protection garment, radiation protection glasses and visors. RESULTS: The average dose reduction using radiation protection devices varied between 57.7 and 83.4% (p < 0.05) in comparison with no radiation protection. Some radiation protection glasses and visors showed a significant dose reduction for the eye lenses when the height of the examiner increased. The right eye was partially less protected, especially if the distances between the simulated examiner's head and the scatter object were small. CONCLUSION: All the investigated protection devices showed a significant reduction in radiation exposure to the simulated examiner. For some devices, the radiation dose increased with decreasing distance to the scattering object, especially for the right eye lens.

Scatter radiation reduction with a radiation-absorbing pad in interventional radiology examinations.

PURPOSE: Radiation-absorbing pads are an additional possibility to reduce scattered radiation at its source. The goal of this study is to investigate the efficacy of a new reusable radiation-absorbing pad at its origin in an experimental setup. MATERIAL AND METHODS: All measurements were carried out using a clinical angiography system with a standardized fluoroscopy protocol, different C-arm angulations and an anthropomorphic torso phantom as a scattering body. An ionization chamber was used to measure the radiation exposure at five different heights of a simulated operator during a simulated transfemoral angiography intervention. Measurements were carried out with and without radiation-absorbing pads with lead equivalents of 0.25 and 0.5 mm placed onto the scattering body. For all measurements a mobile acrylic shield and an under-table lead curtain was used. RESULTS: At all operator heights from 100 to 165 cm a significant radiation dose reduction of up to 80.6 % (p < 0.01) using the radiation-absorbing pad was measured, when compared to no radiation-absorbing pad. At the height of 165 cm the radiation-absorbing pad with a lead equivalence of 0.5 mm showed a significant radiation dose reduction (51.4 %, p < 0.01) in comparison to a lead equivalence of 0.25 mm. CONCLUSION: The addition of a radiation-absorbing pad to the standard protection means results in a significant dose reduction for the operator, particularly for upper body parts.

Spatial differences in active caspase-8 defines its role in T-cell activation versus cell death.

Caspase-8, a cysteine-protease, initiates apoptosis when activated by death receptors. Caspase-8 is also essential for initiating T lymphocyte proliferation following T-cell antigen receptor (TCR) signaling. Given these disparate functions of caspase-8, we sought to determine whether this represented only a difference in the magnitude of caspase-8 activation, or different intracellular locations of active caspase-8. We demonstrate by high-resolution multicolor confocal laser scanning microscopy an aggregation of active caspase-8 within membrane lipid rafts in T cells stimulated with anti-CD3. This suggests that following TCR stimulation active caspase-8 physically interacts with lipid raft proteins, possibly to form a signaling platform. In contrast, Fas stimulation of T cells resulted in a much more profound activation of caspase-8 that was exclusively cytosolic. These confocal microscopic findings were confirmed using discontinuous sucrose gradient ultracentrifugation to isolate lipid raft versus cytosolic components. This sequestration model of caspase-8 activation was further supported by the observation that a classic caspase-8 substrate, BID, was not cleaved in CD3-stimulated T cells, but was cleaved after Fas engagement. Our data support a model that the location of active caspase-8 may profoundly influence its functional capacity as a regulator of either cell cycling or cell death.

Inhibition of radiographic progression with combination etanercept and methotrexate in patients with moderately active rheumatoid arthritis previously treated with monotherapy.

OBJECTIVE: To determine the effect of changing from etanercept or methotrexate monotherapy to etanercept plus methotrexate combination therapy on radiographic progression in rheumatoid arthritis (RA) patients. METHODS: Patients enrolled in this 1-year open-label study previously completed a 3-year blinded study in which they received methotrexate or etanercept monotherapy or the combination of both. All patients received the combination of etanercept 25 mg subcutaneously twice weekly plus oral methotrexate up to 20 mg/week. The primary radiographic endpoint was a change in modified total Sharp score (TSS), as assessed by blinded readers. RESULTS: At baseline, patients previously receiving methotrexate monotherapy (etanercept-added, n = 52) or etanercept monotherapy (methotrexate-added, n = 68) had moderate disease activity levels (mean disease activity score (DAS) of 2.6 and 2.5, respectively), whereas patients previously receiving combination therapy (n = 90) had a low disease activity level (mean DAS of 2.0). The addition of etanercept to methotrexate monotherapy resulted in a significant reduction in radiographic progression (p<0.05). Mean TSS changes in the previous year versus the current year were +1.79 versus +0.25 for the etanercept-added group (p<0.05); +0.51 versus -0.18 for the methotrexate-added group (NS) and +0.42 versus +0.24 for the combination group (NS). CONCLUSION: In these RA patients with on average moderate disease activity despite previous methotrexate monotherapy, combination treatment with etanercept and methotrexate inhibited radiographic progression and improved radiographic outcomes. These data, in conjunction with the previously published clinical data, support the use of combination therapy in RA patients with moderate disease activity.

Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.

The selectins are calcium-dependent C-type lectins that bind certain sialylated, fucosylated, sulfated glycoprotein ligands. L-selectin also recognizes endothelial proteoglycans in a calcium-dependent manner, via heparan sulfate (HS) glycosaminoglycan chains enriched in unsubstituted glucosamine units. We now show that these HS chains can also bind P-selectin, but not E-selectin. However, while L-selectin binding requires micromolar levels of free calcium, P-selectin recognition is largely divalent cation-independent. Despite this, HS chains bound to P-selectin are eluted by ethylenediamine tetraacetic acid (EDTA), but only at high concentrations. Porcine intestinal mucosal (mast cell-derived) heparin (PIM-heparin) shows similar properties, with no binding to E-selectin, calcium-dependent binding of a subfraction to L-selectin and to P-selectin, and calcium-independent binding of a larger fraction to P-selectin, the latter being disrupted by high EDTA concentrations. Analysis of defined heparin fragment pools shows a size dependence for interaction, with tetradecasaccharides showing easily detectable binding to L- and P-selectin affinity columns. L-selectin binding fragments include more heavily sulfated and epimerized regions and, as with the endothelial HS chains, they are enriched in free amino groups. The P-selectin binding component includes this fraction as well as some less highly modified regions. Thus, endothelium-derived HS chains and mast cell-derived heparins could play a role in modulating the biology of selectins in vivo. Notably, P- and L-selectin binding to sialyl-Lewisx and to HL-60 cells (which are known to carry the native ligand PSGL-1) is inhibited by unfractionated pharmaceutical heparin preparations at concentrations 12-50-fold lower than those recommended for effective anticoagulation in vivo. In contrast, two low molecular weight heparins currently considered as clinical replacements for unfractionated heparin are much poorer inhibitors. Thus, patients undergoing heparin therapy for other reasons may be experiencing clinically significant inhibition of L- and P-selectin function, and the current switchover to low-molecular weight heparins may come at some loss of this effect. Low-dose unfractionated heparin should be investigated as a treatment option for acute and chronic diseases in which P- and L-selectin play pathological roles.

DNA aptamers block L-selectin function in vivo. Inhibition of human lymphocyte trafficking in SCID mice.

Selectins participate in the initial events leading to leukocyte extravasation from the blood into tissues. Thus the selectins have generated much interest as targets for antiinflammatory agents. Therapeutic molecules based on the monomeric carbohydrate ligand sialyl Lewis X (SLe(X)) have low affinities and are not specific for a given selectin. Using SELEX (Systematic Evolution of Ligands by EXponential Enrichment) technology, we have generated aptamers specific for L-selectin that require divalent cations for binding and have low nanomolar affinity. In vitro, the deoxyoligonucleotides inhibit L-selectin binding to immobilized SLe(X) in static assays and inhibit L-selectin-mediated rolling of human lymphocytes and neutrophils on cytokine-activated endothelial cells in flow-based assays. These aptamers also block L-selectin-dependent lymphocyte trafficking in vivo, indicating their potential utility as therapeutics.