Functional deficits induced by cortical microinfarcts

published_or_final_versio

Intra- and interreader reproducibility of PI-RADSv2: A multireader study

Background: The Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) has been in use since 2015; while interreader reproducibility has been studied, there has been a paucity of studies investigating the intrareader reproducibility of PI-RADSv2. Purpose: To evaluate both intra- and interreader reproducibility of PI-RADSv2 in the assessment of intraprostatic lesions using multiparametric magnetic resonance imaging (mpMRI). Study Type: Retrospective. Population/Subjects: In all, 102 consecutive biopsy-naïve patients who underwent prostate MRI and subsequent MR/transrectal ultrasonography (MR/TRUS)-guided biopsy. Field Strength/Sequences: Prostate mpMRI at 3T using endorectal with phased array surface coils (TW MRI, DW MRI with ADC maps and b2000 DW MRI, DCE MRI). Assessment: Previously detected and biopsied lesions were scored by four readers from four different institutions using PI-RADSv2. Readers scored lesions during two readout rounds with a 4-week washout period. Statistical Tests: Kappa (κ) statistics and specific agreement (Po) were calculated to quantify intra- and interreader reproducibility of PI-RADSv2 scoring. Lesion measurement agreement was calculated using the intraclass correlation coefficient (ICC). Results: Overall intrareader reproducibility was moderate to substantial (κ = 0.43–0.67, Po = 0.60–0.77), while overall interreader reproducibility was poor to moderate (κ = 0.24, Po = 46). Readers with more experience showed greater interreader reproducibility than readers with intermediate experience in the whole prostate (P = 0.026) and peripheral zone (P = 0.002). Sequence-specific interreader agreement for all readers was similar to the overall PI-RADSv2 score, with κ = 0.24, 0.24, and 0.23 and Po = 0.47, 0.44, and 0.54 in T2-weighted, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE), respectively. Overall intrareader and interreader ICC for lesion measurement was 0.82 and 0.71, respectively. Data Conclusion: PI-RADSv2 provides moderate intrareader reproducibility, poor interreader reproducibility, and moderate interreader lesion measurement reproducibility. These findings suggest a need for more standardized reader training in prostate MRI. Level of Evidence: 2. Technical Efficacy: Stage 2

Treatment efficacy in a soman-poisoned guinea pig model: added value of physostigmine?

Current treatment of organophosphate poisoning is insufficient, and survivors may suffer from long-lasting adverse effects, such as cognitive deficits and sleep-wake disturbances. In the present study, we aimed at developing a guinea pig model to investigate the benefits of immediate and delayed stand-alone therapy on the development of clinical signs, EEG, heart rate, respiration and AChE activity in blood and brain after soman poisoning. The model allowed the determination of the therapeutic effects at the short-term of obidoxime, atropine and physostigmine. Obidoxime exerted the highest therapeutic efficacy at administration of the lowest dose (3.1 mg/kg i.m.), whereas two higher doses (9 and 18 mg/kg) were less effective on most parameters. Addition of atropine at 0.03 and 3 mg/kg (i.m.) to the treatment did not improve the therapeutic effects of obidoxime alone. Physostigmine (0.8 mg/kg im) at 1 min after poisoning increased mortality. Two lower doses (0.1 and 0.3 mg/kg i.m.) showed improvements on all parameters but respiration. The middle dose was most effective in preventing seizure development and therefore assessed as the most efficacious dose. Combined treatment of obidoxime and physostigmine shortened the duration of seizures, if present, from up to 80 min to ~10–15 min. In practice, treatment will be employed when toxic signs appear, with the presence of high levels of AChE inhibition in both blood and brain. Administration of physostigmine at that moment showed to be redundant or even harmful. Therefore, treatment of OP poisoning with a carbamate, such as physostigmine, should be carefully re-evaluated

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Complexity of Discrete Energy Minimization Problems

Discrete energy minimization is widely-used in computer vision and machine learning for problems such as MAP inference in graphical models. The problem, in general, is notoriously intractable, and finding the global optimal solution is known to be NP-hard. However, is it possible to approximate this problem with a reasonable ratio bound on the solution quality in polynomial time? We show in this paper that the answer is no. Specifically, we show that general energy minimization, even in the 2-label pairwise case, and planar energy minimization with three or more labels are exp-APX-complete. This finding rules out the existence of any approximation algorithm with a sub-exponential approximation ratio in the input size for these two problems, including constant factor approximations. Moreover, we collect and review the computational complexity of several subclass problems and arrange them on a complexity scale consisting of three major complexity classes -- PO, APX, and exp-APX, corresponding to problems that are solvable, approximable, and inapproximable in polynomial time. Problems in the first two complexity classes can serve as alternative tractable formulations to the inapproximable ones. This paper can help vision researchers to select an appropriate model for an application or guide them in designing new algorithms.Comment: ECCV'16 accepte

No entropy enigmas for N=4 dyons

We explain why multi-centered black hole configurations where at least one of the centers is a large black hole do not contribute to the indexed degeneracies in theories with N=4 supersymmetry. This is a consequence of the fact that such configurations, although supersymmetric, belong to long supermultiplets. As a result, there is no entropy enigma in N=4 theories, unlike in N=2 theories.Comment: 14 page

Electrical behaviour, characteristics and properties of anodic aluminium oxide films coloured by nickel electrodeposition

Porous anodic films on 1050 aluminium substrate were coloured by AC electrodeposition of nickel. Several experiments were performed at different deposition voltages and nickel concentrations in the electrolyte in order to correlate the applied electrical power to the electrical behaviour, as well as the characteristics and properties of the coatings. The content of nickel inside the coatings reached 1.67 g/m2, depending on the experimental conditions. According to the applied AC voltage in comparison with the threshold voltage Ut, the coating either acted only as a capacitor when U\Ut and, when U[Ut, the behaviour during the anodic and cathodic parts of the power sine wave was different. In particular, due to the semi-conducting characteristics of the barrier layer, additional oxidation of the aluminium substrate occurred during the anodic part of the electrical signal, whilst metal deposition (and solvent reduction) occurred during the cathodic part; these mechanisms correspond to the blocked and pass directions of the barrier layer/electrolyte junction, respectively

Association between labour market trends and trends in young people's mental health in ten European countries 1983-2005

<p>Abstract</p> <p>Background</p> <p>Mental health problems have become more common among young people over the last twenty years, especially in certain countries. The reasons for this have remained unclear. The hypothesis tested in this study is that national trends in young people's mental health are associated with national trends in young people's labour market.</p> <p>Methods</p> <p>National secular changes in the proportion of young people with mental health problems and national secular labour market changes were studied from 1983 to 2005 in Austria, Belgium, Denmark, Finland, Hungary, Norway, Spain, Sweden, Switzerland and the United Kingdom.</p> <p>Results</p> <p>The correlation between the national secular changes in the proportion of young people not in the labour force and the national secular changes in proportion of young people with mental health symptoms was 0.77 for boys and 0.92 for girls.</p> <p>Conclusion</p> <p>Labour market trends may have contributed to the deteriorating trend in mental health among young people. A true relationship, should other studies confirm it, would be an important aspect to take into account when forming labour market policies or policies concerning the delivery of higher education.</p

Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells

Major contributors to atherosclerosis are oxidative damage and endoplasmic reticulum (ER) stress-induced apoptosis; both of which can be diminished by the anti-oxidative protein paraoxonase-2 (PON2). ER stress is also relevant to cancer and associated with anti-cancer treatment resistance. Hence, we addressed, for the first time, whether PON2 contributes to tumorigenesis and apoptotic escape. Intriguingly, we found that several human tumors upregulated PON2 and such overexpression provided resistance to different chemotherapeutics (imatinib, doxorubicine, staurosporine, or actinomycin) in cell culture models. This was reversed after PON2 knock-down. Remarkably, just deficiency of PON2 caused apoptosis of selective tumor cells per se, demonstrating a previously unanticipated oncogenic function. We found a dual mechanistic role. During ER stress, high PON2 levels lowered redox-triggered induction of pro-apoptotic CHOP particularly via the JNK pathway, which prevented mitochondrial cell death signaling. Apart from CHOP, PON2 also diminished intrinsic apoptosis as it prevented mitochondrial superoxide formation, cardiolipin peroxidation, cytochrome c release, and caspase activation. Ligand-stimulated apoptosis by TRAIL or TNFα remained unchanged. Finally, PON2 knock-down caused vast reactive oxygen species formation and stimulated JNK-triggered CHOP expression, but inhibition of JNK signaling did not prevent cell death, demonstrating the pleiotropic, dominating anti-oxidative effect of PON2. Therefore, targeting redox balance is powerful to induce selective tumor cell death and proposes PON2 as new putative anti-tumor candidate