A new model construction by making a detour via intuitionistic theories II: Interpretability lower bound of Feferman's explicit mathematics T0

We partially solve a long-standing problem in the proof theory of explicit mathematics or the proof theory in general. Namely, we give a lower bound of Feferman’s system T0 of explicit mathematics (but only when formulated on classical logic) with a concrete interpretat ion of the subsystem Σ12-AC+ (BI) of second order arithmetic inside T0. Whereas a lower bound proof in the sense of proof-theoretic reducibility or of ordinalanalysis was already given in 80s, the lower bound in the sense of interpretability we give here is new. We apply the new interpretation method developed by the author and Zumbrunnen (2015), which can be seen as the third kind of model construction method for classical theories, after Cohen’s forcing and Krivine’s classical realizability. It gives us an interpretation between classical theories, by composing interpretations between intuitionistic theories.

Developments in mechanical thrombectomy devices for the treatment of acute ischemic stroke

Several recent prospective randomized controlled trials of endovascular stroke therapy using latest generation thrombectomy devices, so called stent-retrievers, have shown significantly improved clinical outcome compared to the standard treatment with intra-venous thrombolysis using r-tPA alone. Despite some differences in inclusion criteria between these studies, all required non-invasive vessel imaging to proof occlusion of a major brain supplying vessel. Furthermore, in most studies additional imaging techniques were used to exclude patients with already established large cerebral infarction or unfavorable collateral or penumbral status. Patients with small infarct volume, severe neurological deficits and in whom thrombectomy can be initiated within the first 6 hours after symptom onset seem to benefit the most. Therefore, mechanical thrombectomy using stent-retrievers in addition to intra-venous thrombolysis is recommended for the treatment of acute ischemic stroke with proven major vessel occlusion in the anterior circulation.

Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases

Meprin and , zinc metalloproteinases, play significant roles in inflammation, including inflammatory bowel disease (IBD), possibly by activating cytokines, like interleukin 1 , interleukin 18, or tumor growth factor . Although a number of potential activators for meprins are known, no endogenous inhibitors have been identified. In this work, we analyzed the inhibitory potential of human plasma and identified bovine fetuin-A as an endogenous meprin inhibitor with a K(i) (inhibition constant) of 4.2 × 10(-5) M for meprin and a K(i) of 1.1 × 10(-6) M meprin . This correlated with data obtained for a fetuin-A homologue from carp (nephrosin inhibitor) that revealed a potent meprin and inhibition (residual activities of 27 and 22%, respectively) at a carp fetuin concentration of 1.5 × 10(-6) M. Human fetuin-A is a negative acute phase protein involved in inflammatory diseases, thus being a potential physiological regulator of meprin activity. We report kinetic studies of fetuin-A with the proteolytic enzymes astacin, LAST, LAST_MAM, trypsin, and chymotrypsin, indeed demonstrating that fetuin-A is a broad-range protease inhibitor. Fetuin-A inhibition of meprin activity was 40 times weaker than that of meprin activity. Therefore, we tested cystatin C, a protein structurally closely related to fetuin-A. Indeed, cystatin C was an inhibitor for human meprin (K(i) = 8.5 × 10(-6) M) but, interestingly, not for meprin . Thus, the identification of fetuin-A and cystatin C as endogenous proteolytic regulators of meprin activity broadens our understanding of the proteolytic network in plasma.

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis.

Evidence for chemokine-mediated coalescence of preformed flotillin hetero-oligomers in human T-cells

We have shown previously that endogenous flotillin-1 and -2, closely related proteins implicated in scaffolding of membrane microdomains, are rapidly recruited to the uropods of chemoattractant-stimulated human neutrophils and T-cells and are involved in cell polarization. Coexpressed flotillin-1 and -2, but not singly expressed proteins, are also targeted to the uropod of T-cells and neutrophils. Biochemical studies suggest formation of flotillin homo- and hetero-oligomers in other cell types, but so far knowledge is lacking on in situ flotillin organization in leukocytes. We have now analyzed flotillin organization in human T-cells using fluorescence resonance energy transfer (FRET). Coexpressed C-terminally tagged flotillin-1-mCherry and flotillin-2-enhanced green fluorescent protein (EGFP) show significant FRET when analyzed in intact human T-cells in the absence and presence of chemokine. In contrast, little FRET was observed between coexpressed flotillin-1-mCherry and flotillin-1-EGFP before or after chemokine addition, indicating predominant formation of heterodimers and/or -oligomers. Interestingly coexpression of untagged flotillin-2 strongly enhanced FRET between differently tagged flotillin-1 molecules in resting and chemokine-stimulated cells, indicating that close contacts of flotillin-1 molecules only occur in flotillin-2-containing hetero-oligomers. Comparable results were obtained for tagged flotillin-2. We further show that disruption of the actin network, depletion of intracellular calcium, and inhibition of phospholipase C all result in suppression of chemokine-induced polarization and flotillin cap formation, but do not abolish FRET between tagged flotillin-1 and -2. Our results support predominant formation of flotillin-1 and -2 hetero-oligomers in resting and chemokine-stimulated human T-cells which may importantly contribute to structuring of the uropod.

Quantification of network perfusion in ASL cerebral blood flow data with seed based and ICA approaches

Independent component analysis (ICA) or seed based approaches (SBA) in functional magnetic resonance imaging blood oxygenation level dependent (BOLD) data became widely applied tools to identify functionally connected, large scale brain networks. Differences between task conditions as well as specific alterations of the networks in patients as compared to healthy controls were reported. However, BOLD lacks the possibility of quantifying absolute network metabolic activity, which is of particular interest in the case of pathological alterations. In contrast, arterial spin labeling (ASL) techniques allow quantifying absolute cerebral blood flow (CBF) in rest and in task-related conditions. In this study, we explored the ability of identifying networks in ASL data using ICA and to quantify network activity in terms of absolute CBF values. Moreover, we compared the results to SBA and performed a test-retest analysis. Twelve healthy young subjects performed a fingertapping block-design experiment. During the task pseudo-continuous ASL was measured. After CBF quantification the individual datasets were concatenated and subjected to the ICA algorithm. ICA proved capable to identify the somato-motor and the default mode network. Moreover, absolute network CBF within the separate networks during either condition could be quantified. We could demonstrate that using ICA and SBA functional connectivity analysis is feasible and robust in ASL-CBF data. CBF functional connectivity is a novel approach that opens a new strategy to evaluate differences of network activity in terms of absolute network CBF and thus allows quantifying inter-individual differences in the resting state and task-related activations and deactivations.

Speech perception benefits of internet versus conventional telephony for hearing-impaired individuals

Telephone communication is a challenge for many hearing-impaired individuals. One important technical reason for this difficulty is the restricted frequency range (0.3-3.4 kHz) of conventional landline telephones. Internet telephony (voice over Internet protocol [VoIP]) is transmitted with a larger frequency range (0.1-8 kHz) and therefore includes more frequencies relevant to speech perception. According to a recently published, laboratory-based study, the theoretical advantage of ideal VoIP conditions over conventional telephone quality has translated into improved speech perception by hearing-impaired individuals. However, the speech perception benefits of nonideal VoIP network conditions, which may occur in daily life, have not been explored. VoIP use cannot be recommended to hearing-impaired individuals before its potential under more realistic conditions has been examined.

Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression

Angiopoietin-2 (Ang2) is among the relevant growth factors induced by hypoxia and plays an important role in the initiation of retinal neovascularizations. Ang2 is also involved in incipient diabetic retinopathy, as it may cause pericyte loss. To investigate the impact of Ang2 on developmental and hypoxia-induced angiogenesis, we used a transgenic mouse line overexpressing human Ang2 in the mouse retina. Transgenic mice displayed a reduced coverage of capillaries with pericytes (-14%; p < 0.01) and a 46% increase of vascular density of the capillary network at postnatal day 10 compared to wild type mice. In the model of oxygen-induced retinopathy (OIR), Ang2 overexpression resulted in enhanced preretinal (+103%) and intraretinal neovascularization (+29%). Newly formed intraretinal vessels in OIR were also pericyte-deficient (-26%; p < 0.01). The total expression of Ang2 in transgenic mice was seven-fold, compared with wild type controls. Ang2 modulated expression of genes encoding VEGF (+65%) and Ang1 (+79%) in transgenic animals. These data suggest that Ang2 is involved in pericyte recruitment, and modulates intraretinal, and preretinal vessel formation in the eye under physiological and pathological conditions.

Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis

Eph receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins, regulate axon guidance and bundling in the developing brain, control cell migration and adhesion, and help patterning the embryo. Here we report that two ephrinB ligands and three EphB receptors are expressed in and regulate the formation of the vascular network. Mice lacking ephrinB2 and a proportion of double mutants deficient in EphB2 and EphB3 receptor signaling die in utero before embryonic day 11.5 (E11.5) because of defects in the remodeling of the embryonic vascular system. Our phenotypic analysis suggests complex interactions and multiple functions of Eph receptors and ephrins in the embryonic vasculature. Interaction between ephrinB2 on arteries and its EphB receptors on veins suggests a role in defining boundaries between arterial and venous domains. Expression of ephrinB1 by arterial and venous endothelial cells and EphB3 by veins and some arteries indicates that endothelial cell-to-cell interactions between ephrins and Eph receptors are not restricted to the border between arteries and veins. Furthermore, expression of ephrinB2 and EphB2 in mesenchyme adjacent to vessels and vascular defects in ephB2/ephB3 double mutants indicate a requirement for ephrin-Eph signaling between endothelial cells and surrounding mesenchymal cells. Finally, ephrinB ligands induce capillary sprouting in vitro with a similar efficiency as angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF), demonstrating a stimulatory role of ephrins in the remodeling of the developing vascular system.

Enumerating constrained elementary flux vectors of metabolic networks

The concept of elementary vector is generalised to the case where the steady-state space of the metabolic network is not a flux cone but is a general polyhedron due to further inhomogeneous constraints on the flows through some of the reactions. On one hand, this allows to selectively enumerate elementary modes which satisfy certain optimality criteria and this can yield a large computational gain compared with full enumeration. On the other hand, in contrast to the single optimum found by executing a linear program, this enables a comprehensive description of the set of alternate optima often encountered in flux balance analysis. The concepts are illustrated on a metabolic network model of human cardiac mitochondria.

An EEG approach to the neurodevelopmental hypothesis of schizophrenia studying schizophrenics, normal controls and adolescents

Based on an integrative brain model which focuses on memory-driven and EEG state-dependent information processing for the organisation of behaviour, we used the developmental changes of the awake EEG to further investigate the hypothesis that neurodevelopmental abnormalities (deviations in organisation and reorganisation of cortico-cortical connectivity during development) are involved in the pathogenesis of schizophrenia. First-episode, neuroleptic-naive schizophrenics and their matched controls and three age groups of normal adolescents were studied (total: 70 subjects). 19-channel EEG delta-theta, alpha and beta spectral band centroid frequencies during resting (baseline) and after verbal stimuli were used as measure of the level of attained complexity and momentary excitability of the neuronal network (working memory). Schizophrenics compared with all control groups showed lower delta-theta activity centroids and higher alpha and beta activity centroids. Reactivity centroids (centroid after stimulus minus centroid during resting) were used as measure of update of working memory. Schizophrenics showed partial similarities in delta-theta and beta reactivity centroids with the 11-year olds and in alpha reactivity centroids with the 13-year olds. Within the framework of our model, the results suggest multifactorially elicited imbalances in the level of excitability of neuronal networks in schizophrenia, resulting in network activation at dissociated complexity levels, partially regressed and partially prematurely developed. It is hypothesised that activation of age- and/or state-inadequate representations for coping with realities becomes manifest as productive schizophrenic symptoms. Thus, the results support some aspects of the neurodevelopmental hypothesis.

Modulating the granularity of category formation by global cortical states

The unsupervised categorization of sensory stimuli is typically attributed to feedforward processing in a hierarchy of cortical areas. This purely sensory-driven view of cortical processing, however, ignores any internal modulation, e.g., by top-down attentional signals or neuromodulator release. To isolate the role of internal signaling on category formation, we consider an unbroken continuum of stimuli without intrinsic category boundaries. We show that a competitive network, shaped by recurrent inhibition and endowed with Hebbian and homeostatic synaptic plasticity, can enforce stimulus categorization. The degree of competition is internally controlled by the neuronal gain and the strength of inhibition. Strong competition leads to the formation of many attracting network states, each being evoked by a distinct subset of stimuli and representing a category. Weak competition allows more neurons to be co-active, resulting in fewer but larger categories. We conclude that the granularity of cortical category formation, i.e., the number and size of emerging categories, is not simply determined by the richness of the stimulus environment, but rather by some global internal signal modulating the network dynamics. The model also explains the salient non-additivity of visual object representation observed in the monkey inferotemporal (IT) cortex. Furthermore, it offers an explanation of a previously observed, demand-dependent modulation of IT activity on a stimulus categorization task and of categorization-related cognitive deficits in schizophrenic patients.

Late postoperative opacification of hydrogel intraocular lenses: analysis of 13 explanted lenses

PURPOSE: We report the clinical, morphological, and ultrastructural findings of 13 consecutively explanted opacified Hydroview(R) (hydrogel) intraocular lenses (IOLs). Our purpose was to provide a comprehensive account on the possible factors involved in late postoperative opacification of these IOLs. PATIENTS AND METHODS: Thirteen consecutive opacified hydrogel IOLs (Hydroview H 60 M, Bausch ; Lomb) were explanted due to the significant visual impairment they caused. The IOLs underwent macroscopical examination, transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and electrophoresis for protein detection. Three unused control Hydroview IOLs served for comparison. RESULTS: Macroscopical examination showed a diffuse or localized grey-whitish opacification within the IOL optic. TEM confirmed the presence of lesions inside the optic in all the explanted IOLs and revealed 3 patterns of deep deposits: a) diffuse, thick, granular, electron-dense ones; b) small, thin, lattice-like ones, with prominent electron-lucent areas; and c) elongated electron-dense formations surrounded by electron-lucent halos. SEM showed surface deposits on four IOLs. EDS revealed oxygen and carbon in all IOLs and documented calcium, phosphorus, silicon and/or iron in the deposits. Two of the patients with iron in their IOLs had eye surgery prior to their phacoemulsification. Iron correlated well with the second TEM pattern of deep lesions, whereas calcium with the third TEM pattern. No protein bands were detected on electrophoresis. Control lenses did not show any ultrastructural or chemical abnormality. CONCLUSIONS: The present study supports the presence of chemical alterations inside the polymer of the optic in late postoperative opacification of Hydroview IOLs. This opacification does not follow a unique pathway but may present under different ultrastructular patterns depending on the responsible factors. Mechanical stress during surgery may initiate a sequence of events where ions such as calcium, phosphorus, silicon, and/or iron, participate in a biochemical cascade that leads to gradual alteration of the polymer network. Intraocular inflammation due to previous operation may be a factor inducing opacification through increase of iron-binding capacity in the aqueous humour. Calcification accounts only partially for the opacification noted in this type of IOL.

Neurophysiology and neuroanatomy of reflexive and volitional saccades as revealed by lesion studies with neurological patients and transcranial magnetic stimulation (TMS)

This review discusses the neurophysiology and neuroanatomy of the cortical control of reflexive and volitional saccades in humans. The main focus is on classical lesion studies and studies using the interference method of transcranial magnetic stimulation (TMS). To understand the behavioural function of a region, it is essential to assess oculomotor deficits after a focal lesion using a variety of oculomotor paradigms, and to study the oculomotor consequences of the lesion in the chronic phase. Saccades are controlled by different cortical regions, which could be partially specialised in the triggering of a specific type of saccade. The division of saccades into reflexive visually guided saccades and intentional or volitional saccades corresponds to distinct regions of the neuronal network, which are involved in the control of such saccades. TMS allows to specifically interfere with the functioning of a region within an intact oculomotor network. TMS provides advantages in terms of temporal resolution, allowing to interfere with brain functioning in the order of milliseconds, thereby allowing to define the time course of saccade planning and execution. In the first part of the paper, we present an overview of the cortical structures important for saccade control, and discuss the pro's and con's of the different methodological approaches to study the cortical oculomotor network. In the second part, the functional network involved in reflexive and volitional saccades is presented. Finally, studies concerning recovery mechanisms after a lesion of the oculomotor cortex are discussed.

Percutaneous PFO closure with Amplatzer PFO occluder: predictors of residual shunts at 6 months follow-up

OBJECTIVE: The objective of this study was to assess predictors of residual shunts after percutaneous patent foramen ovale (PFO) closure with Amplatzer PFO occluder (AGA Medical Corporation, Golden Valley, MN, USA). METHODS: All percutaneous PFO closures, using Amplatzer PFO occluder performed at a tertiary center between May 2002 and August 2006, were reviewed. Follow-up, including saline contrast transesophageal echocardiography, was performed in all patients 6 months after the intervention. PATIENTS: A total of 135 procedures were performed. Mean age of the patients was 51 years. The indication for PFO closure was an ischemic cerebrovascular event in 92%, paradoxical systemic embolism in 4%, and a diving accident in 4%. Recurrent events prior to PFO closure were noted in 34%. A concomitant atrial septal aneurysm was present in 61%. RESULTS: At 6 months follow-up, a residual shunt was detected in 26 patients (19%). Residual shunts were more common in patients with an atrial septal aneurysm (27 vs. 8%, P= .01) and in patients treated with a 35-mm compared with a 25-mm device (39 vs. 15%, P= .01). A concomitant atrial septal aneurysm remained independently associated with residual shunts when controlled for body mass index, gender, age, atrial dimensions, and presence of a Chiari network (odds ratio 4.1, 95% confidence intervals 1.1-15.0). CONCLUSION: The presence of atrial septal aneurysms in patients undergoing percutaneous PFO closure with an Amplatzer PFO occluder significantly increases the rate of residual shunts at 6 months follow-up, even if 35-mm devices are used.