Double seronegative myasthenia gravis with antiphospholipid syndrome: a case report

INTRODUCTION Myasthenia gravis is an autoimmune disease characterized by fluctuating muscle weakness. It is often associated with other autoimmune disorders, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Many aspects of autoimmune diseases are not completely understood, particularly when they occur in association, which suggests a common pathogenetic mechanism. CASE PRESENTATION We report a case of a 42-year-old Caucasian woman with antiphospholipid syndrome, in whom myasthenia gravis developed years later. She tested negative for both antibodies against the acetylcholine receptor and against muscle-specific receptor tyrosine-kinase, but had typical decremental responses at the repetitive nerve stimulation testing, so that a generalized myasthenia gravis was diagnosed. Her thromboplastin time and activated partial thromboplastin time were high, anticardiolipin and anti-β2 glycoprotein-I antibodies were slightly elevated, as a manifestation of the antiphospholipid syndrome. She had a good clinical response when treated with a combination of pyridostigmine, prednisone and azathioprine. CONCLUSIONS Many patients with myasthenia gravis test positive for a large variety of auto-antibodies, testifying of an immune dysregulation, and some display mild T-cell lymphopenia associated with hypergammaglobulinemia and B-cell hyper-reactivity. Both of these mechanisms could explain the occurrence of another autoimmune condition, such as antiphospholipid syndrome, but further studies are necessary to shed light on this matter.Clinicians should be aware that patients with an autoimmune diagnosis such as antiphospholipid syndrome who develop signs and neurological symptoms suggestive of myasthenia gravis are at risk and should prompt an emergent evaluation by a specialist.

Social Salience and the Sociolinguistic Monitor: a Case Study of ING and TH-fronting in Britain

This article examines the role of social salience, or the relative ability of a linguistic variable to evoke social meaning, in structuring listeners’ perceptions of quantitative sociolinguistic distributions. Building on the foundational work of Labov et al. (2006, 2011) on the “sociolinguistic monitor” (a proposed cognitive mechanism responsible for sociolinguistic perception), we examine whether listeners’ evaluative judgments of speech change as a function of the type of variable presented. We consider two variables in British English, ING and TH-fronting, which we argue differ in their relative social salience. Replicating the design of Labov et al.’s studies, we test 149 British listeners’ reactions to different quantitative distributions of these variables. Our experiments elicit a very different pattern of perceptual responses than those reported previously. In particular, our results suggest that a variable’s social salience determines both whether and how it is perceptually evaluated. We argue that this finding is crucial for understanding how sociolinguistic information is cognitively processed.

Short-term functional versus patient-reported outcome of the bicruciate stabilized total knee arthroplasty: prospective consecutive case series

BACKGROUND The main goals of the standard treatment for advanced symptomatic knee osteoarthritis, total knee arthroplasty (TKA), are pain reduction and restoration of knee motion.The aim of this study was to analyse the outcome of the patient-based Knee Injury and Osteoarthritis Outcome Score (KOOS), and the surgeon-based Knee Society Score (KSS) and its Knee Score (KS) and Knee Functional Score (KFS) components after (TKA) using the Journey knee prosthesis, and to assess the correlation of these scores with range of motion (ROM). METHODS In a prospective case series study between August 1st 2008 and May 31st 2011, 99 patients, all operated by a single surgeon, received Journey bicruciate stabilized total knee prostheses. The female/male ratio was 53/34, the mean patient age at surgery was 68 years (range 41-83 years), and the left/right knee ratio was 55/44. The KOOS, range of motion, and KS and KFS were obtained preoperatively and at 1-year follow-up. The pre- and postoperative levels of the outcome measures were compared using the Wilcoxon signed-rank test. Correlation between ROM and patient outcomes was analysed with the Spearman coefficient. RESULTS All KOOS subscores improved significantly. Ninety percent of patients improved by at least the minimum clinically relevant difference of 10 points in stiffness and other symptoms, 94.5% in pain, 94.5% in activities of daily living, 84.9% in sports and recreation, and 90% in knee-related quality of life. The mean passive and active ROM improved from 122.4° (range 90-145°) and 120.4° (range 80-145°) preoperatively to 129.4° (range 90-145°) and 127.1° (range 100-145°) postoperatively. The highest correlation coefficients for ROM and KOOS were observed for the activity and pain subscores. Very low or no correlation was seen for the sport subscore.There was a significant and clinically relevant improvement of KSS (preop/postop 112.2/174.5 points), and its KS (preop/postop 45.6/86.8 points) and KFS (preop/postop 66.6/87.8 points) components. CONCLUSIONS The Journey bicruciate stabilized knee prosthesis showed good 1-year postoperative results in terms of both functional and patient-based outcome. However, higher knee ROM correlates only moderately with patient-based outcome, implying that functionality afforded by the Journey bicruciate TKA is not equivalent to patient satisfaction.

Lazy lips: hyperkalemia and acute tetraparesis-a case report from an urban emergency department.

A 58-year-old male patient was admitted to our emergency department at a large university hospital due to acute onset of general weakness. It was reported that the patient was bradycardic at 30/min and felt an increasing weakness of the limbs. At admission to the emergency department, the patient was not feeling any discomfort and denied dyspnoea or pain. The primary examination of the nervous system showed the cerebral nerves II-XII intact, muscle strength of the lower extremities was 4/5, and a minimal sensory loss of the left hemisphere was found. In addition, the patient complained about lazy lips. During ongoing examinations, the patient developed again symptomatic bradycardia, accompanied by complete tetraplegia. The following blood test showed severe hyperkalemia probably induced by use of aldosterone antagonists as the cause of the patient's neurologic symptoms. Hyperkalemia is a rare but treatable cause of acute paralysis that requires immediate treatment. Late diagnosis can delay appropriate treatment leading to cardiac arrhythmias and arrest.

Detecting single-target changes in multiple object tracking: The case of peripheral vision.

In sports games, it is often necessary to perceive a large number of moving objects (e.g., the ball and players). In this context, the role of peripheral vision for processing motion information in the periphery is often discussed especially when motor responses are required. In an attempt to test the basal functionality of peripheral vision in those sports-games situations, a Multiple Object Tracking (MOT) task that requires to track a certain number of targets amidst distractors, was chosen. Participants’ primary task was to recall four targets (out of 10 rectangular stimuli) after six seconds of quasi-random motion. As a second task, a button had to be pressed if a target change occurred (Exp 1: stop vs. form change to a diamond for 0.5 s; Exp 2: stop vs. slowdown for 0.5 s). While eccentricities of changes (5-10° vs. 15-20°) were manipulated, decision accuracy (recall and button press correct), motor response time as well as saccadic reaction time were calculated as dependent variables. Results show that participants indeed used peripheral vision to detect changes, because either no or very late saccades to the changed target were executed in correct trials. Moreover, a saccade was more often executed when eccentricities were small. Response accuracies were higher and response times were lower in the stop conditions of both experiments while larger eccentricities led to higher response times in all conditions. Summing up, it could be shown that monitoring targets and detecting changes can be processed by peripheral vision only and that a monitoring strategy on the basis of peripheral vision may be the optimal one as saccades may be afflicted with certain costs. Further research is planned to address the question whether this functionality is also evident in sports tasks.

Detecting single-target changes in multiple object tracking: The case of peripheral vision

In sports games, it is often necessary to perceive a large number of moving objects (e.g., the ball and players). In this context, the role of peripheral vision for processing motion information in the periphery is often discussed especially when motor responses are required. In an attempt to test the capability of using peripheral vision in those sports-games situations, a Multiple-Object-Tracking task that requires to track a certain number of targets amidst distractors, was chosen to determine the sensitivity of detecting target changes with peripheral vision only. Participants’ primary task was to recall four targets (out of 10 rectangular stimuli) after six seconds of quasi-random motion. As a second task, a button had to be pressed if a target change occurred (Exp 1: stop vs. form change to a diamond for 0.5 s; Exp 2: stop vs. slowdown for 0.5 s). Eccentricities of changes (5-10° vs. 15-20°) were manipulated, decision accuracy (recall and button press correct), motor response time and saccadic reaction time (change onset to saccade onset) were calculated and eye-movements were recorded. Results show that participants indeed used peripheral vision to detect changes, because either no or very late saccades to the changed target were executed in correct trials. Moreover, a saccade was more often executed when eccentricities were small. Response accuracies were higher and response times were lower in the stop conditions of both experiments while larger eccentricities led to higher response times in all conditions. Summing up, it could be shown that monitoring targets and detecting changes can be processed by peripheral vision only and that a monitoring strategy on the basis of peripheral vision may be the optimal one as saccades may be afflicted with certain costs. Further research is planned to address the question whether this functionality is also evident in sports tasks.

The physiological consequences of crib-biting in horses in response to an ACTH challenge test

Stereotypies are repetitive and relatively invariant patterns of behavior, which are observed in a wide range of species in captivity. Stereotypic behavior occurs when environmental demands produce a physiological response that, if sustained for an extended period, exceeds the natural physiological regulatory capacity of the organism, particularly in situations that include unpredictability and uncontrollability. One hypothesis is that stereotypic behavior functions to cope with stressful environments, but the existing evidence is contradictory. To address the coping hypothesis of stereotypies, we triggered physiological reactions in 22 horses affected by stereotypic behavior (crib-biters) and 21 non-crib-biters (controls), using an ACTH challenge test. Following administration of an ACTH injection, we measured saliva cortisol every 30min and heart rate (HR) continuously for a period of 3h. We did not find any differences in HR or HR variability between the two groups, but crib-biters (Group CB) had significantly higher cortisol responses than controls (Group C; mean±SD: CB, 5.84±2.62ng/ml, C, 4.76±3.04ng/ml). Moreover, crib-biters that did not perform the stereotypic behavior during the 3-hour test period (Group B) had significantly higher cortisol levels than controls, which was not the case of crib-biters showing stereotypic behavior (Group A) (B, 6.44±2.38ng/ml A, 5.58±2.69ng/ml). Our results suggest that crib-biting is a coping strategy that helps stereotypic individuals to reduce cortisol levels caused by stressful situations. We conclude that preventing stereotypic horses from crib-biting could be an inappropriate strategy to control this abnormal behavior, as it prevents individuals from coping with situations that they perceive as stressful.

A patterned abrasion caused by the impact of a cartridge case may simulate an atypical muzzle imprint mark.

In contact shots, the muzzle imprint is an informative finding associated with the entrance wound. It typically mirrors the constructional components being in line with the muzzle or just behind. Under special conditions, other patterned skin marks located near a gunshot entrance wound may give the impression to be part of the muzzle imprint. A potential mechanism causing a patterned pressure abrasion in close proximity to the bullet entrance site is demonstrated on the basis of a suicidal shot to the temple. The skin lesion in question appeared as a ring-shaped excoriation with a diameter corresponding to that of the cartridge case. Two hypotheses concerning the causative mechanism were investigated by test shots: - After being ejected, the cartridge case ricocheted inside a confined space (car cabin in the particular case) and secondarily hit the skin near the gunshot entrance wound. - The ejection of the cartridge case failed so that the case became stuck in the ejection port and its mouth contacted the skin when the body collapsed after being hit.

Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method

Herein, we report the discovery of the first potent and selective inhibitor of TRPV6, a calcium channel overexpressed in breast and prostate cancer, and its use to test the effect of blocking TRPV6-mediated Ca2+-influx on cell growth. The inhibitor was discovered through a computational method, xLOS, a 3D-shape and pharmacophore similarity algorithm, a type of ligand-based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule, two successive rounds of LBVS followed by optimization by chemical synthesis led to a selective molecule with 0.3 μM inhibition of TRPV6. The ability of xLOS to identify different scaffolds early in LBVS was essential to success. The xLOS method may be generally useful to develop tool compounds for poorly characterized targets.

Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients.

BACKGROUND A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0-40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events. METHODS We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated. RESULTS The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8). CONCLUSION In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score. TRIAL REGISTRATION Clinicaltrials.gov identifier NCT00761787.

SOMS: SurrOgate MultiStart algorithm for use with nonlinear programming for global optimization

SOMS is a general surrogate-based multistart algorithm, which is used in combination with any local optimizer to find global optima for computationally expensive functions with multiple local minima. SOMS differs from previous multistart methods in that a surrogate approximation is used by the multistart algorithm to help reduce the number of function evaluations necessary to identify the most promising points from which to start each nonlinear programming local search. SOMS’s numerical results are compared with four well-known methods, namely, Multi-Level Single Linkage (MLSL), MATLAB’s MultiStart, MATLAB’s GlobalSearch, and GLOBAL. In addition, we propose a class of wavy test functions that mimic the wavy nature of objective functions arising in many black-box simulations. Extensive comparisons of algorithms on the wavy testfunctions and on earlier standard global-optimization test functions are done for a total of 19 different test problems. The numerical results indicate that SOMS performs favorably in comparison to alternative methods and does especially well on wavy functions when the number of function evaluations allowed is limited.

SOP: Parallel surrogate global optimization with Pareto center selection for computationally expensive single objective problems

This paper presents a parallel surrogate-based global optimization method for computationally expensive objective functions that is more effective for larger numbers of processors. To reach this goal, we integrated concepts from multi-objective optimization and tabu search into, single objective, surrogate optimization. Our proposed derivative-free algorithm, called SOP, uses non-dominated sorting of points for which the expensive function has been previously evaluated. The two objectives are the expensive function value of the point and the minimum distance of the point to previously evaluated points. Based on the results of non-dominated sorting, P points from the sorted fronts are selected as centers from which many candidate points are generated by random perturbations. Based on surrogate approximation, the best candidate point is subsequently selected for expensive evaluation for each of the P centers, with simultaneous computation on P processors. Centers that previously did not generate good solutions are tabu with a given tenure. We show almost sure convergence of this algorithm under some conditions. The performance of SOP is compared with two RBF based methods. The test results show that SOP is an efficient method that can reduce time required to find a good near optimal solution. In a number of cases the efficiency of SOP is so good that SOP with 8 processors found an accurate answer in less wall-clock time than the other algorithms did with 32 processors.

Detecting single-target changes in multiple object tracking: The case of peripheral vision

In the current study it is investigated whether peripheral vision can be used to monitor multi-ple moving objects and to detect single-target changes. For this purpose, in Experiment 1, a modified MOT setup with a large projection and a constant-position centroid phase had to be checked first. Classical findings regarding the use of a virtual centroid to track multiple ob-jects and the dependency of tracking accuracy on target speed could be successfully replicat-ed. Thereafter, the main experimental variations regarding the manipulation of to-be-detected target changes could be introduced in Experiment 2. In addition to a button press used for the detection task, gaze behavior was assessed using an integrated eye-tracking system. The anal-ysis of saccadic reaction times in relation to the motor response shows that peripheral vision is naturally used to detect motion and form changes in MOT because the saccade to the target occurred after target-change offset. Furthermore, for changes of comparable task difficulties, motion changes are detected better by peripheral vision than form changes. Findings indicate that capabilities of the visual system (e.g., visual acuity) affect change detection rates and that covert-attention processes may be affected by vision-related aspects like spatial uncertainty. Moreover, it is argued that a centroid-MOT strategy might reduce the amount of saccade-related costs and that eye-tracking seems to be generally valuable to test predictions derived from theories on MOT. Finally, implications for testing covert attention in applied settings are proposed.

Network Dynamics in Natural Resource Governance: A Case Study of Swiss Landscape Management

Structural characteristics of social networks have been recognized as important factors of effective natural resource governance. However, network analyses of natural resource governance most often remain static, even though governance is an inherently dynamic process. In this article, we investigate the evolution of a social network of organizational actors involved in the governance of natural resources in a regional nature park project in Switzerland. We ask how the maturation of a governance network affects bonding social capital and centralization in the network. Applying separable temporal exponential random graph modeling (STERGM), we test two hypotheses based on the risk hypothesis by Berardo and Scholz (2010) in a longitudinal setting. Results show that network dynamics clearly follow the expected trend toward generating bonding social capital but do not imply a shift toward less hierarchical and more decentralized structures over time. We investigate how these structural processes may contribute to network effectiveness over time.

Plant species decline due to abandonment of meadows cannot easily be reversed by mowing. A case study from the southern Alps

Abstract. We resumed mowing in two plots of ca. 100 m2 in an abandoned meadow dominated by Brachypodium pinnatum on the slope of Monte Generoso (Switzerland). We monitored species composition and hay yield using point quadrats and biomass samples. Species frequencies changed little during 10 yr (1988–1997) while hay yields showed large fluctuations according to mean relative humidity in April-June. We performed a seed-addition experiment to test whether the establishment of meadow species is limited by lack of diaspores or favourable microsites for germination and recruitment from the seed bank. We sowed ca. 12 000 seeds of 12 species originating from a nearby meadow individually in plots of a 4 × 6 unbalanced Latin square with four treatments, burning, mowing, mowing and removal of a layer of decayed organic matter, and a control. We monitored the fate of seedling individuals for 24 months. Seedlings of all species were established and survived for 12 months, 10 species survived during at least 24 months, some reached a reproductive stage. Species responded to different qualities of microsites provided by the different treatments thus required different regeneration niches. Spontaneous long-distance immigration was insignificant. We conclude that the former species composition of abandoned meadows cannot easily be restored by mowing alone because many plant species of meadows do not have persistent seed banks and immigration over distances of more than 25 m and successful establishment is very unlikely.