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Since its first proposal, the concept of on- and off-track lesions in anterior shoulder instability has gained clinical relevance as a tool to predict the failure rate of arthroscopic Bankart repair. Current literature only reports either short-term follow-up or long-term results of small sample sizes. The aim of this study was to provide a long-term evaluation of recurrent instability following arthroscopic Bankart repair in a large cohort using the on-track vs. off-track concept as a predictor for failure.We retrospectively analyzed 271 patients who underwent primary arthroscopic Bankart repair for anterior shoulder instability between 1998 and 2007. All patients with a minimum follow-up of 78 months and a preoperative computed tomographic (CT) or magnetic resonance imaging (MRI) scan were included into the study. Preoperative CT and/or MRI scans were used to determine the glenoid track and width of Hill-Sachs lesion. Recurrence of instability was defined as presence of instability symptoms (dislocation, subluxation, and/or apprehension) or revision surgery (stabilization procedure) and was assessed as the primary outcome parameter.The glenoid track of 163 shoulders was assessed (female n = 51, male n = 112) with a mean follow-up of 124 months (99.4-145.6, standard deviation = 2.5) and a mean age of 24 years (20-34.). An off-track Hill-Sachs lesion was found in 77 cases (47%), and in 86 cases (53 %) it was on-track. The rate of recurrent instability in the off-track group was 74% (n = 57) compared with 27% (n = 23) in the on-track group (P.001). The overall rate of revision surgery due to instability was 29% (n = 48) after a mean time of 50.9 months (±42.8) following Bankart repair. The rate of revision surgery in the off-track group was 48% (n = 37) after a mean of 53.5 months (±42.0) vs. 13% (n = 11) after 42.3 months (±46.3) in the on-track group (P.001).This study shows that the on- and off-track concept helps to distinguish patients for whom an isolated arthroscopic Bankart repair yields long-term benefits. Because of the high rate of recurrent instability in the off-track group, an off-track lesion should be treated surgically in such a way that the off-track lesion is converted into an on-track lesion.

Can imaging provide sufficient risk stratification to warrant revascularization of a stable plaque with negative fractional flow reserve (FFR)? Prophylactic stenting could at best be applied selectively since the composite group of FFR-negative lesions has a death or myocardial infarction rate of approximately 1%/year or less but modern stents have a rate of 2% to 3.5%/year. Because vulnerable features exist in a minority of lesions, at least 9,000 patients must be screened in order to enroll a cohort with sufficient risk. While several ongoing randomized trials are testing the concept of plaque sealing in FFR-negative lesions, preventive stenting depends on such a small effect that sample sizes to validate or refute its benefit become prohibitive. Since FFR provides a quantitative, straightforward, and reproducible metric of plaque vulnerability and burden without the need for or expense of additional catheter devices, intracoronary imaging cannot meaningfully guide prophylactic stenting when faced with a negative FFR.

Objectives We conducted a review and meta-analysis of published data to compare revascularization to deferral strategy for coronary lesions with grey zone fractional flow reserve (FFR). Background Optimal treatment for coronary stenoses with FFR values between 0.75 and 0.80, the so-called grey zone, remains a matter of debate. Methods We included all studies evaluating revascularization versus deferral for lesions with grey zone FFR. The primary outcome was study-defined major adverse cardiac events (MACE). Secondary outcomes were the composite of death or MI and target vessel revascularization (TVR). A total of 2362 patients were included, of whom 1181 underwent revascularization (revascularization group) and 1181 received medical treatment only (deferral group). Results After a mean follow-up period of 2.4 years, no difference was found for the primary outcome of the study-defined MACE between the two groups [RR = 1.33 (0.73–2.44), p = 0.35]. In addition, there was no difference for the secondary outcomes of death or MI and TVR between the two groups [RR = 1.39 (0.56–3.47), p = 0.48 and RR = 1.49 (0.89–2.51), p = 0.13, respectively]. Conclusions In this meta-analysis revascularization of coronary stenoses with grey zone FFR showed no advantage over a deferral strategy in terms of study-defined MACE. Case by case judgment should be implemented to guide treatment in this special subset of patients.

To improve oral reading fluency rate and promote its generalization to unpracticed texts, this study investigated a Varied Practice approach that involved passages with a high proportion of overlapping words (M = 85% unique word overlap). Fourth graders were randomly assigned either to the Varied Practice treatment (n = 405), where they read three different passages one time each, or the Repeated Reading comparison (n = 422), in which they read the same passage three times each. Both groups read with a partner for about 20 min, 3–4 times per week, over an average 12 weeks (30 total sessions). Results indicated that students in Varied Practice demonstrated significantly better fluency outcomes than students in Repeated Reading, but both groups demonstrated growth near the 90th percentile. Results of a quantile regression revealed that low-to-middle achievers benefited from Varied Practice the most. Overall, the findings suggest fluency approaches rooted in statistical learning hold promise as an alternative to approaches focused on practicing words in redundant contexts.

Purpose A multiphasic cine sequence performed during magnetic resonance enterography (MRE) has been shown to increase diagnostic accuracy of MRE demonstrating limited movement in inflamed intestine in patients with Crohn’s disease (CD). Our aim was to confirm in our study population that intestinal inflammation was associated with decreased motility and determine if factors suggestive of complicated disease such as the presence of a stricture or fistula were associated with decreased motility on the MRE cine sequence. Methods This was a retrospective study of 59 patients (mean age 40.8 ± 16.1) with Crohn’s disease who had a small bowel lesion on MRE. Two gastrointestinal radiologists independently scored MRE findings using a qualitative, subjective scoring system. Univariate and multivariable ordered logistic regression models were used to evaluate the associations between cine sequence score, radiologic image findings, and clinical data. Results On univariate analysis, radiologic findings reflecting active inflammation, the presence of a stricture, and penetrating disease were associated with decreased motility. On multivariable analysis, hyper-enhancement, the presence of a comb sign, and global evidence of active inflammation remained associated with decreased motility. Of the factors suggesting complicated disease, the presence of stricture (Odds Ratio 0.40, 95% Confidence Interval 0.17-0.95, p-value 0.038) was associated with decreased motility. Conclusions As previously shown, well-established radiologic findings of bowel inflammation were associated with decreased small bowel motility. In this study, we have added that the radiologic finding of a fixed stricture is also associated with decreased motility.

Objectives The goal of this study was to investigate sex differences in adenosine-free coronary pressure indexes. Background Several adenosine-free coronary pressure wire indexes have been proposed to assess the functional significance of coronary artery lesions; however, there is a theoretical concern that sex differences may affect diagnostic performance because of differences in resting flow and distal myocardial mass. Methods In this CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?) substudy, contrast fractional flow reserve (cFFR), obtained during contrast-induced submaximal hyperemia, the instantaneous wave-free ratio (iFR), and distal/proximal coronary pressure ratio (Pd/Pa) were compared with fractional flow reserve (FFR) in 547 men and 216 women. Using FFR ≤0.8 as a reference, the diagnostic performance of each index was compared. Results Men and women had similar diameter stenosis (p = 0.78), but women were less likely to have FFR ≤0.80 than men (42.5% vs. 51.5%, p = 0.04). Sensitivity was similar among cFFR, iFR, and Pd/Pa when comparing women and men, respectively (cFFR, 77.5% vs. 75.3%; p = 0.69; iFR, 84.9% vs. 79.4%; p = 0.30; Pd/Pa, 78.8% vs. 77.3%; p = 0.78). cFFR was more specific than iFR or Pd/Pa regardless of sex (cFFR, 94.3% vs. 95.8%; p = 0.56; iFR, 75.6% vs. 80.1%; p = 0.38; Pd/Pa, 80.6% vs. 78.7%; p = 0.69). By receiver-operating characteristic curve analysis, cFFR provided better diagnostic accuracy than resting indexes irrespective of sex (p ≤ 0.0001). Conclusions Despite the theoretical concern, the diagnostic sensitivity and specificity of cFFR, iFR, and Pd/Pa did not differ between the sexes. Irrespective of sex, cFFR provides the best diagnostic performance.

Computed tomography and magnetic resonance enterography have become routine small bowel imaging tests to evaluate patients with established or suspected Crohn's disease, but the interpretation and use of these imaging modalities can vary widely. A shared understanding of imaging findings, nomenclature, and utilization will improve the utility of these imaging techniques to guide treatment options, as well as assess for treatment response and complications. Representatives from the Society of Abdominal Radiology Crohn's Disease-Focused Panel, the Society of Pediatric Radiology, the American Gastroenterological Association, and other experts, systematically evaluated evidence for imaging findings associated with small bowel Crohn's disease enteric inflammation and established recommendations for the evaluation, interpretation, and use of computed tomography and magnetic resonance enterography in small bowel Crohn's disease. This work makes recommendations for imaging findings that indicate small bowel Crohn's disease, how inflammatory small bowel Crohn's disease and its complications should be described, elucidates potential extra-enteric findings that may be seen at imaging, and recommends that cross-sectional enterography should be performed at diagnosis of Crohn's disease and considered for small bowel Crohn's disease monitoring paradigms. A useful morphologic construct describing how imaging findings evolve with disease progression and response is described, and standard impressions for radiologic reports that convey meaningful information to gastroenterologists and surgeons are presented.

The requirements of the ultra thin pixel detectors for the Mu3e experiment at PSI can be achieved by the HVCMOS technology, which allows the design of fast monolithic detectors. The latest nearly full size prototype, MuPix8, has a size of about 1 × 2 cm 2 . The pixel readout circuitry was fully redesigned in comparison to the previous MuPix versions. MuPix8’s readout electronics implement a new concept with two comparators and two different operation modes. One mode uses two threshold voltages for time walk correction, the other is a ramp-ADC. First tests show a detection efficiency of 99.6% for 4 GeV electrons.

Background: Pressure measurement for the duration of the wave-free period (WFP) is considered essential for resting-state physiological assessment of coronary stenosis severity using the in...

The enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA2 as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH2 units) were studied. The four PL-diclofenac conjugates were synthesized and characterized by LC/MS and NMR. PLA2-mediated activation of the prodrugs was analyzed in-vitro, and the remaining intact complex and free drug liberation were assessed after incubation with PLA2. The rate and degree of PLA2-mediated activation were highly dependent on the linker length; 2- and 4-carbon linker conjugates were activated to lower extent than the 6-carbon conjugate, and longer linker again decreased the affinity towards PLA2. The 6-carbon linker conjugate was found to be the optimal and released ~95% of the free drug after incubation with PLA2, whereas only ~20% were delivered by the 2-carbon linker prodrug. The 6-carbon linker conjugate was shown to be stable in intestinal perfusate, fresh plasma, and pH4.0 and 6.8 buffers, but not at pH1.0. In conclusion, the results of this work confirm the feasibility of our general aim to exploit PLA2 as a prodrug-activating enzyme of PL-drug conjugates. This may provide a novel oral drug targeting approach in IBD therapy.

Calcium and redox signals are presently established as essential regulators of many cellular processes. Nevertheless, we are still far from fully understanding the physiological and pathological importance of these universal second messengers. It is becoming increasingly apparent that many cellular functions are not regulated by global changes in the abundance of Ca(2+) ions and/or reactive oxygen and nitrogen species (ROS and RNS), but by the formation of transient local micro-domains or by signaling limited to a particular cellular compartment. Therefore, it is essential to identify and quantify Ca(2+) and redox signals in single cells with a high spatial and temporal resolution. The best tools for this purpose are the genetically encoded fluorescent indicators (GEFI). These protein sensors can be targeted into different cellular compartments, feature different colors, can be used to establish transgenic animal models, and are relatively inert to the cellular environment. Based on the chemical properties of Ca(2+) and ROS/RNS, currently more sensors exist for the detection of Ca(2+)- than for redox signals. Here, we shortly describe the most popular genetically encoded fluorescent Ca(2+) and redox indicators, discuss advantages and disadvantages based on our experience, show examples of different applications, and thus provide a brief guide that will help scientists choose the right combination of Ca(2+) and redox sensors to answer specific scientific questions.

The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.

As major contributors to research, higher education institutions have to tackle scientific questions that arise in connection with the transition of societies around the world towards more sustainable development. But universities are also significant societal actors – they shape their local, regional and national environments and are therefore important drivers for a sustainable future. A new way of cooperation and networking between higher education and regional actors is required in order to take up society-driven challenges for a cooperative solution-finding process. This paper aims at reflecting and analysing the diverse roles of higher education institutions in networking with regional actors. Three cases of networking and capacity building between higher education and regional actors, which were developed in the framework of the European Union project 3-LENSUS (Lifelong Learning Network for Sustainable Development), will be assessed in this paper: the COPERNICUS Alliance, the Database on Learning for Sustainable Development and the Seminar Series for Sustainable Development. The examples are methodologically reflected on the basis of the Graz Model for Integrative Development, as this model not only reflects the actions but in particular the processes behind the cases. As major contributors to research, higher education institutions have to tackle scientific questions that arise in connection with the transition of societies around the world towards more sustainable development. But universities are also significant societal actors – they shape their local, regional and national environments and are therefore important drivers for a sustainable future. A new way of cooperation and networking between higher education and regional actors is required in order to take up society-driven challenges for a cooperative solution-finding process. This paper aims at reflecting and analysing the diverse roles of higher education institutions in networking with regional actors. Three cases of networking and capacity building between higher education and regional actors, which were developed in the framework of the European Union project 3-LENSUS (Lifelong Learning Network for Sustainable Development), will be assessed in this paper: the COPERNICUS Alliance, the Database on Learning for Sustainable Development and the Seminar Series for Sustainable Development. The examples are methodologically reflected on the basis of the Graz Model for Integrative Development, as this model not only reflects the actions but in particular the processes behind the cases.

Background In general, treatment efficacy in depressed patients is evaluated mainly based on the core symptoms of depression. However, patients might consider different outcomes. This study used choice-based conjoint analysis (CBC) to evaluate patient preferences for depression treatment outcomes. Methods Adult subjects from Germany, currently or previously on antidepressant treatment, were presented with 18 pairs of hypothetical treatment outcome scenarios, differing in eight attributes (2–3 factor levels each): depressed mood, loss of interest and enjoyment, loss of energy/fatigue, sleep disturbance, feelings of guilt, depression-related pain, treatment duration, side effects after 2 weeks. Attributes and factor levels were defined by literature review, expert consultations, and in-depth subject interviews. Data were analyzed using multinomial logit modeling; individual part-worth utilities were estimated using hierarchical Bayes routines. Results Two hundred twenty-seven subjects (89.4% currently treated with antidepressants, 30.0% with depression-related pain) completed the survey. They valued the relative importance of outcomes as follows: loss of energy/fatigue 18.5%, side effects after 2 weeks 14.2%, loss of interest and enjoyment 13.5%, depression-related pain 12.0%, sleep disturbance 12.0%, feelings of guilt 11.5%, treatment duration 9.9%, depressed mood 8.5%. Limitations Participants were not required to meet ICD-10 or DSM-IV criteria for depression and had heterogeneous disease severity. Conclusions CBC analysis was able to reveal patient preferences for outcomes of depression treatment. Subjects valued the ability to cope with activities of everyday living highest. They considered being free of depression-related pain and side effects more important than being free of depressed mood. These findings should be considered when making treatment decisions.

An impaired central cholinergic system is at least partly involved in Alzheimer's disease (AD) pathogenesis, with cholinergic markers such as acetylcholinesterase (AChE) activity and protein levels decreasing as cognitive decline progresses. AD patients receive AChE inhibitor drugs to enhance cholinergic responses in the brain. The present study characterises the cholinergic system of mice heterozygous for AChE (HZ) as a suitable in vivo model for permanently reduced AChE activity. In comparison to homozygous, wild type (WT) mice, HZ mice show a 40% reduction of AChE activity in the brain, while their hippocampal ACh levels are increased by 56% as measured by microdialysis; choline acetyltransferase levels remain unaltered, and choline uptake increases 2-fold. We demonstrate that HZ mice are significantly more sensitive to local AChE inhibition (BW284c51), but remain insensitive to butyrylcholinesterase (BuChE) inhibition (bambuterol). HZ mice are also more sensitive to the peripheral application of the selective AChE inhibitor donepezil or the mixed inhibitor physostigmine; extracellular ACh levels rise significantly after administration of both drugs; also glucose levels are moderately increased indicating potentially non-cholinergic effects of donepezil. Behavioural tests show comparable cognitive function in both mouse strains. Our results are discussed in relation to the use of AChE/BuChE inhibitors in AD patients.

Until today, the mainstay of phenylketonuria (PKU) treatment is a phenylalanine (Phe)-restricted diet. Strict dietary treatment decreases flexibility and autonomy and still has a major impact on patients and their families. Compliance is often poor, particularly in adolescence. The aim of this study was to investigate the effect of the intake of fruits and vegetables containing Phe less than 100 mg/100g ('simplified diet'), as recommended by WHO for all individuals, instead of classical totally restricted diet on the course and treatment control of the disease in a well-characterized PKU cohort (n=80). All individual blood Phe measurements of each patient (1992-2009) were statistically analyzed before and after diet switch. Epidemiological data, age at diagnosis, PAH mutations, BH(4) responsiveness, as well as Phe control measurements and detailed diet information were tabulated in a local database. 62.5% had BH4 loading test and 40% had PAH analysis; 50/80 switched from classical to simplified diet, including 26 classical PKU, 13 moderate PKU, 7 mild PKU and 4 mild hyperphenylalaninemia (HPA). Median Phe levels on a simplified diet did not differ significantly to the median Phe levels on classical diet in all disease groups. Our results indicate that a simplified diet has no negative effect on blood Phe control in patients with hyperphenylalaninemia, independent of severity of the phenotype or the age at diet switch, over the period of 3 years. Thus, a simpler approach to dietary treatment of PKU available to all HPA patients is more likely to be accepted and adhered by patients and might also increase quality of life.

Many health claims have been made about the medicinal benefits of drinking green tea, including neuroprotection. This study mainly focuses on Epigallocatechin 3-gallate (EGCG), a potent antioxidant, which is abundantly found in green tea. Cadmium [Cd(2+)] is a toxic pollutant that leads to neurotoxicity in both animals and humans. Although the entrance of Cd(2+) in the adult central nervous system is limited, developmental neurotoxicity has been evidenced as result of the blood-brain barrier (BBB) immaturity. Moreover, high Cd(2+) levels are known to impair BBB function. Furthermore, the molecular mechanisms related to its neurotoxic properties remain unknown. This study evaluates the potential protective effect of the major green tea polyphenol, EGCG, against Cd(2+)-induced mitotoxicity under in vitro conditions, using mitochondrial-enriched fractions from rat brain. Co-incubation of EGCG with Cd(2+) prevented the Cd(2+)-induced mitochondrial dysfunction (capacity to reduce MTT to formazan). In addition, EGCG completely prevented mitochondrial lipid peroxidation induced by Cd(2+) but did not affect non protein thiols levels. Spectroscopic studies have shown EGCG able to form a chemical complex with Cd(2+), in an equimolar ratio. In this study we demonstrate EGCG effectiveness in protecting against Cd(2+)-induced mitochondrial dysfunction and lipid peroxidation probably due to its antioxidant and chelating effects.

A fast method that can be used to classify unknown jet fuel types or detect possible property changes in jet fuel physical properties is of paramount interest to national defense and the airline industries. While fast gas chromatography (GC) has been used with conventional mass spectrometry (MS) to study jet fuels, fast GC was combined with fast scanning MS and used to classify jet fuels into lot numbers or origin for the first time by using fuzzy rule-building expert system (FuRES) classifiers. In the process of building classifiers, the data were pretreated with and without wavelet transformation and evaluated with respect to performance. Principal component transformation was used to compress the two-way data images prior to classification. Jet fuel samples were successfully classified with 99.8 ± 0.5% accuracy for both with and without wavelet compression. Ten bootstrapped Latin partitions were used to validate the generalized prediction accuracy. Optimized partial least squares (o-PLS) regression results were used as positively biased references for comparing the FuRES prediction results. The prediction results for the jet fuel samples obtained with these two methods were compared statistically. The projected difference resolution (PDR) method was also used to evaluate the fast GC and fast MS data. Two batches of aliquots of ten new samples were prepared and run independently 4 days apart to evaluate the robustness of the method. The only change in classification parameters was the use of polynomial retention time alignment to correct for drift that occurred during the 4-day span of the two collections. FuRES achieved perfect classifications for four models of uncompressed three-way data. This fast GC/fast MS method furnishes characteristics of high speed, accuracy, and robustness. This mode of measurement may be useful as a monitoring tool to track changes in the chemical composition of fuels that may also lead to property changes.

Thermodilution through continuous infusion of saline is a novel technique to selectively quantify absolute coronary flow. Together with distal coronary pressure, this technique allows for assessment of microvascular resistance (MVR). Of note, intracoronary infusion of room-temperature saline is