Left ventricular fibrosis and CMR tissue characterization of papillary muscles in mitral valve prolapse patients.

PURPOSE: Mitral valve prolapse (MVP) is associated with left ventricle (LV) fibrosis, including the papillary muscles (PM), which is in turn linked to malignant arrhythmias. This study aims to evaluate comprehensive tissue characterization of the PM by cardiovascular magnetic resonance (CMR) imaging and its association with LV fibrosis observed by intraoperative biopsies. METHODS: MVP patients with indication for surgery due to severe mitral regurgitation (n = 19) underwent a preoperative CMR with characterization of the PM: dark-appearance on cine, T1 mapping, conventional bright blood (BB) and dark blood (DB) late gadolinium enhancement (LGE). CMR T1 mapping was performed on 21 healthy volunteers as controls. LV inferobasal myocardial biopsies were obtained in MVP patients and compared to CMR findings. RESULTS: MVP patients (54 ± 10 years old, 14 male) had a dark-appearance of the PM with higher native T1 and extracellular volume (ECV) values compared with healthy volunteers (1096 ± 78ms vs. 994 ± 54ms and 33.9 ± 5.6% vs. 25.9 ± 3.1%, respectively, p < 0.001). Seventeen MVP patients (89.5%) had fibrosis by biopsy. BB-LGE + in LV and PM was identified in 5 (26.3%) patients, while DB-LGE + was observed in LV in 9 (47.4%) and in PM in 15 (78.9%) patients. DB-LGE + in PM was the only technique that showed no difference with detection of LV fibrosis by biopsy. Posteromedial PM was more frequently affected than the anterolateral (73.7% vs. 36.8%, p = 0.039) and correlated with biopsy-proven LV fibrosis (Rho 0.529, p = 0.029). CONCLUSIONS: CMR imaging in MVP patients referred for surgery shows a dark-appearance of the PM with higher T1 and ECV values compared with healthy volunteers. The presence of a positive DB-LGE at the posteromedial PM by CMR may serve as a better predictor of biopsy-proven LV inferobasal fibrosis than conventional CMR techniques.

Left Ventricular Fibrosis and CMR Tissue Characterization of Papillary Muscles in Mitral Valve Prolapse Patients.

Purpose: Mitral valve prolapse (MVP) is associated with left ventricle (LV) fibrosis, including the papillary muscles (PM), which is in turn linked to malignant arrhythmias. This study aims to evaluate comprehensive tissue characterization of the PM by cardiovascular magnetic resonance (CMR) imaging and its association with LV fibrosis observed by intraoperative biopsies. Methods: MVP patients with indication for surgery due to severe mitral regurgitation (n=19) underwent a preoperative CMR with characterization of the PM: dark-appearance on cine, T1 mapping, conventional bright blood (BB) and dark blood (DB) late gadolinium enhancement (LGE). CMR T1 mapping was performed on 21 healthy volunteers as controls. LV inferobasal myocardial biopsies were obtained in MVP patients and compared to CMR findings. Results: MVP patients (54±10 years old, 14 male) had a dark-appearance of the PM with higher native T1 and extracellular volume (ECV) values compared with healthy volunteers (1096±78ms vs 994±54ms and 33.9±5.6% vs 25.9±3.1%, respectively, p<0.001). Seventeen MVP patients (89.5%) had fibrosis by biopsy. BB-LGE+ in LV and PM was identified in 5 (26.3%) patients, while DB-LGE+ was observed in LV in 9 (47.4%) and in PM in 15 (78.9%) patients. DB-LGE+ in PM was the only technique that showed no difference with detection of LV fibrosis by biopsy. Posteromedial PM was more frequently affected than the anterolateral (73.7% vs 36.8%, p=0.039) and correlated with biopsy-proven LV fibrosis (Rho 0.529, p=0.029). Conclusions: CMR imaging in MVP patients referred for surgery shows a dark-appearance of the PM with higher T1 and ECV values compared with healthy volunteers. The presence of a positive DB-LGE at the posteromedial PM by CMR may serve as a better predictor of biopsy-proven LV inferobasal fibrosis than conventional CMR techniques.

Histopathological insights into mitral valve prolapse-induced fibrosis.

Mitral valve prolapse (MVP) is a cardiac valve disease that not only affects the mitral valve (MV), provoking mitral regurgitation, but also leads to maladaptive structural changes in the heart. Such structural changes include the formation of left ventricular (LV) regionalized fibrosis, especially affecting the papillary muscles and inferobasal LV wall. The occurrence of regional fibrosis in MVP patients is hypothesized to be a consequence of increased mechanical stress on the papillary muscles and surrounding myocardium during systole and altered mitral annular motion. These mechanisms appear to induce fibrosis in valve-linked regions, independent of volume-overload remodeling effects of mitral regurgitation. In clinical practice, quantification of myocardial fibrosis is performed with cardiovascular magnetic resonance (CMR) imaging, even though CMR has sensitivity limitations in detecting myocardial fibrosis, especially in detecting interstitial fibrosis. Regional LV fibrosis is clinically relevant because even in the absence of mitral regurgitation, it has been associated with ventricular arrhythmias and sudden cardiac death in MVP patients. Myocardial fibrosis may also be associated with LV dysfunction following MV surgery. The current article provides an overview of current histopathological studies investigating LV fibrosis and remodeling in MVP patients. In addition, we elucidate the ability of histopathological studies to quantify fibrotic remodeling in MVP and gain deeper understanding of the pathophysiological processes. Furthermore, molecular changes such as alterations in collagen expression in MVP patients are reviewed.

Clarifying How Degree Entropies and Degree-Degree Correlations Relate to Network Robustness.

It is often claimed that the entropy of a network's degree distribution is a proxy for its robustness. Here, we clarify the link between degree distribution entropy and giant component robustness to node removal by showing that the former merely sets a lower bound to the latter for randomly configured networks when no other network characteristics are specified. Furthermore, we show that, for networks of fixed expected degree that follow degree distributions of the same form, the degree distribution entropy is not indicative of robustness. By contrast, we show that the remaining degree entropy and robustness have a positive monotonic relationship and give an analytic expression for the remaining degree entropy of the log-normal distribution. We also show that degree-degree correlations are not by themselves indicative of a network's robustness for real networks. We propose an adjustment to how mutual information is measured which better encapsulates structural properties related to robustness.

Gains v. losses, or context dependence generated by confusion?

Tversky and Kahneman introduced the term framing for the finding that people give different answers to the same question depending on the way it is posed. One form of framing involves presenting the same outcome as either a gain or a loss. An experiment on starlings by Marsh and Kacelnik suggests that this form of framing occurs in non-humans. We argue that the experimental result demonstrates framing in the general sense of context dependence but does not provide compelling evidence of framing in terms of gains and losses. A version of scalar utility theory which is extended to include the possibility of memory errors accounts for the data and suggests future lines of research.

Emergence and dynamics of self-producing information niches as a step towards pre-evolutionary organization.

As a step towards understanding pre-evolutionary organization in non-genetic systems, we develop a model to investigate the emergence and dynamics of proto-autopoietic networks in an interacting population of simple information processing entities (automata). Our simulations indicate that dynamically stable strongly connected networks of mutually producing communication channels emerge under specific environmental conditions. We refer to these distinct organizational steady states as information niches In each case, we measure the information content by the Shannon entropy, and determine the fitness landscape, robustness and transition pathways for information niches subjected to intermittent environmental perturbations under non-evolutionary conditions. By determining the information required to generate each niche, we show that niche transitions are only allowed if accompanied by an equal or increased level of information production that arises internally or via environmental perturbations that serve as an exogenous source of population diversification. Overall, our simulations show how proto-autopoietic networks of basic information processors form and compete, and under what conditions they persist over time or go extinct. These findings may be relevant to understanding how inanimate systems such as chemically communicating protocells can initiate the transition to living matter prior to the onset of contemporary evolutionary and genetic mechanisms.

Scalar utility theory and proportional processing: What does it actually imply?

Scalar Utility Theory (SUT) is a model used to predict animal and human choice behaviour in the context of reward amount, delay to reward, and variability in these quantities (risk preferences). This article reviews and extends SUT, deriving novel predictions. We show that, contrary to what has been implied in the literature, (1) SUT can predict both risk averse and risk prone behaviour for both reward amounts and delays to reward depending on experimental parameters, (2) SUT implies violations of several concepts of rational behaviour (e.g. it violates strong stochastic transitivity and its equivalents, and leads to probability matching) and (3) SUT can predict, but does not always predict, a linear relationship between risk sensitivity in choices and coefficient of variation in the decision-making experiment. SUT derives from Scalar Expectancy Theory which models uncertainty in behavioural timing using a normal distribution. We show that the above conclusions also hold for other distributions, such as the inverse Gaussian distribution derived from drift-diffusion models. A straightforward way to test the key assumptions of SUT is suggested and possible extensions, future prospects and mechanistic underpinnings are discussed.

Mutual information reveals multiple structural relaxation mechanisms in a model glass former.

Among the key challenges to our understanding of solidification in the glass transition is that it is accompanied by little apparent change in structure. Recently, geometric motifs have been identified in glassy liquids, but a causal link between these motifs and solidification remains elusive. One 'smoking gun' for such a link would be identical scaling of structural and dynamic lengthscales on approaching the glass transition, but this is highly controversial. Here we introduce an information theoretic approach to determine correlations in displacement for particle relaxation encoded in the initial configuration of a glass-forming liquid. We uncover two populations of particles, one inclined to relax quickly, the other slowly. Each population is correlated with local density and geometric motifs. Our analysis further reveals a dynamic lengthscale similar to that associated with structural properties, which may resolve the discrepancy between structural and dynamic lengthscales.

Is quantum probability rational?

We concentrate on two aspects of the article by Pothos & Busemeyer (P&B): the relationship between classical and quantum probability and quantum probability as a basis for rational decisions. We argue that the mathematical relationship between classical and quantum probability is not quite what the authors claim. Furthermore, it might be premature to regard quantum probability as the best practical rational scheme for decision making.

Using mutual information to measure order in model glass formers.

Whether or not there is growing static order accompanying the dynamical heterogeneity and increasing relaxation times seen in glassy systems is a matter of dispute. An obstacle to resolving this issue is that the order is expected to be amorphous and so not amenable to simple order parameters. We use mutual information to provide a general measurement of order that is sensitive to multiparticle correlations. We apply this to two glass-forming systems (two-dimensional binary mixtures of hard disks with different size ratios to give varying amounts of hexatic order) and show that there is little growth of amorphous order in the system without crystalline order. In both cases we measure the dynamical length with a four-point correlation function and find that it increases significantly faster than the static lengths in the system as density is increased. We further show that we can recover the known scaling of the dynamic correlation length in a kinetically constrained model, the two-vacancy-assisted-hopping triangular lattice gas.

Quantum mechanics can reduce the complexity of classical models.

Mathematical models are an essential component of quantitative science. They generate predictions about the future, based on information available in the present. In the spirit of simpler is better; should two models make identical predictions, the one that requires less input is preferred. Yet, for almost all stochastic processes, even the provably optimal classical models waste information. The amount of input information they demand exceeds the amount of predictive information they output. Here we show how to systematically construct quantum models that break this classical bound, and that the system of minimal entropy that simulates such processes must necessarily feature quantum dynamics. This indicates that many observed phenomena could be significantly simpler than classically possible should quantum effects be involved.

A new method for inferring hidden markov models from noisy time sequences.

We present a new method for inferring hidden Markov models from noisy time sequences without the necessity of assuming a model architecture, thus allowing for the detection of degenerate states. This is based on the statistical prediction techniques developed by Crutchfield et al. and generates so called causal state models, equivalent in structure to hidden Markov models. The new method is applicable to any continuous data which clusters around discrete values and exhibits multiple transitions between these values such as tethered particle motion data or Fluorescence Resonance Energy Transfer (FRET) spectra. The algorithms developed have been shown to perform well on simulated data, demonstrating the ability to recover the model used to generate the data under high noise, sparse data conditions and the ability to infer the existence of degenerate states. They have also been applied to new experimental FRET data of Holliday Junction dynamics, extracting the expected two state model and providing values for the transition rates in good agreement with previous results and with results obtained using existing maximum likelihood based methods. The method differs markedly from previous Markov-model reconstructions in being able to uncover truly hidden states.

Increasing complexity with quantum physics.

We argue that complex systems science and the rules of quantum physics are intricately related. We discuss a range of quantum phenomena, such as cryptography, computation and quantum phases, and the rules responsible for their complexity. We identify correlations as a central concept connecting quantum information and complex systems science. We present two examples for the power of correlations: using quantum resources to simulate the correlations of a stochastic process and to implement a classically impossible computational task.

Nature computes: information processing in quantum dynamical systems.

Nature intrinsically computes. It has been suggested that the entire universe is a computer, in particular, a quantum computer. To corroborate this idea we require tools to quantify the information processing. Here we review a theoretical framework for quantifying information processing in a quantum dynamical system. So-called intrinsic quantum computation combines tools from dynamical systems theory, information theory, quantum mechanics, and computation theory. We will review how far the framework has been developed and what some of the main open questions are. On the basis of this framework we discuss upper and lower bounds for intrinsic information storage in a quantum dynamical system.

Uptake of bone-seekers is solely associated with mineralisation! A study with 99mTc-MDP, 153Sm-EDTMP and 18F-fluoride on osteoblasts.

PURPOSE: Although polyphosphonates (PPs) were introduced as bone imaging agents in nuclear medicine in the early 1970s, the mechanisms involved in their uptake still remain unclear. Suggested mechanisms range from mineral adsorption with disputed binding to the organic phase, over incorporation into the mineralisation process to a combination of both mechanisms. Thus, our investigations aimed to: (1) evaluate adsorption parameters of (99m)Tc-MDP, (153)Sm-EDTMP and (18)F-fluoride on mineralising osteoblast cultures, (2) correlate the radiotracer binding measured in the cell cultures with binding values from our previously presented mineral model and (3) compare binding with cell number. METHODS: Primary osteoblasts were obtained by sequential digestion of foetal mice calvariae. The cells were incubated with 0.3 mumol of radiolabelled PPs or 25 MBq (18)F-fluoride for 120 min. Gamma signals from labelled samples were detected with a Millennium Hawkeye SPECT camera or with a dedicated Advance full-ring PET scanner and the binding percentages were calculated. RESULTS: From days 8 to 15 of culture, the percent binding of all evaluated tracers increased significantly, whereas the protein concentration showed insignificant changes. Additional comparisons of the binding values with our recently published pre-vivo model revealed remarkable agreement, suggesting solely bone-forming minerals to be responsible for radiotracer binding. CONCLUSION: This study provides evidence that binding of the evaluated radiotracers is not associated with osteoblast numbers but only with the concentration of bone-forming minerals. The presented correlations substantiate our recently presented pre-vivo model for the evaluation of bone-seekers: mechanisms associated with the uptake of bone-seekers are irreversible and mineral-associated processes.

Binding studies of [(18)F]-fluoride and polyphosphonates radiolabelled with [(111)In], [(99m)Tc], [(153)Sm], and [(188)Re] on bone compartments: a new model for the pre vivo evaluation of bone seekers?

INTRODUCTION: Although the first polyphosphonates were already introduced in the early 1970s, mechanisms involved in uptake still remain speculative. The present work aimed to establish a new method to rate the influence of various factors on the uptake and to evaluate new bone-seekers on these bone compartments. METHODS: Radioactive-labelled diphosphonates and [(18)F]-fluoride were added to a vial containing hydroxyapatite (HA), collagen, or amorphous calcium phosphate (ACP) in 3 ml of Hanks' Balanced Salt Solution (HBSS). After incubation, these suspensions were filtered, the radioactivity was measured in the gamma-counter, and the percentage of irreversibly bound radioactivity was calculated. RESULTS: Kinetic experiments revealed uptake increase over time for [(99m)Tc]-MDP and [(18)F]-fluoride on various amounts of matrix. After 120 min, static studies on HA yielded: [(99m)Tc]-EDTMP < [(188)Re]-/Re-EDTMP < [(99m)Tc]-/11 microl Re-EDTMP < [(99m)Tc]-/In-EDTMP < [(99m)Tc]-/15 microl Re-EDTMP < nca [(188)Re]-EDTMP < [(111)In]-/Re-EDTMP < [(111)In]-EDTMP < [(111)In]-/In-EDTMP < [(99m)Tc]-DPD < [(99m)Tc]-/80 microl Re-EDTMP < [(99m)Tc]-EDTMP "boiled" < [(99m)Tc]-/150 microl Re-EDTMP < [(153)Sm]-EDTMP < [(99m)Tc]-/11 microl Re-EDTMP "boiled" < [(18)F]-ions < [(99m)Tc]-MDP. Collagen showed very low uptake. Reincubation experiments suggest that bone tracers are irreversibly bound. CONCLUSION: The presented method is rapid and feasible to examine the adsorption of radioactive-labelled substances on bone components. Correlations between our findings and published in vivo data support the application as a simple model.

Isotopic renal function studies in severe hypothyroidism and after thyroid hormone replacement therapy.

AIM: To investigate the possible changes in the renal tubular function in severe short-term hypothyroidism using (99m)Tc-MAG(3) renography. METHODS: 27 consecutive thyroidectomized patients (7 males and 20 females) aged 19-79 (mean 53) years were included in the present study. (99m)Tc-MAG(3) renography was performed in all patients before and after thyroid hormone replacement therapy. In addition, (51)Cr-EDTA clearance and serum creatinine concentrations were determined. RESULTS: The serum creatinine concentrations were significantly increased in hypothyroidism as compared with the concentrations after thyroxine substitution (1.30 +/- 0.44 vs. 1.04 +/- 0.32 mg/dl, p < 0.05). According to the (51)Cr-EDTA clearance, the glomerular filtration rate was significantly lower in hypothyroidism than after treatment (61 +/- 18 vs. 75 +/- 23 ml/min). In contrast, we did not find any significant change in the renographic parameters for (99m)Tc-MAG(3) before and after treatment (total excreted activity 20 min after administration 51 +/- 12 vs. 54 +/- 14%; T(max) left:right 4.2 +/- 1.77 : 3.91 +/- 1.06 min vs. 4.1 +/- 1.66 : 4.4 +/- 1.96 min). CONCLUSIONS: We did not find any influence of thyroid hormones on the outcome of (99m )Tc-MAG(3) renography. As (99m)Tc-MAG(3) reflects the tubular function, it seems that the renal hemodynamic changes in severe hypothyroidism mainly affect the glomerular function. In general, the glomerular filtration rate reduction seems to be reversible after hormone substitution therapy; however, care has to be taken in patients with renal insufficiency.

Technetium-99m-tetrofosmin scintigraphy in patients with metastatic soft tissue sarcoma.

The lipophilic cationic compound Tc-99m-tetrofosmin has been demonstrated to be a valuable tool for the detection of a variety of tumours. Tc-99m-tetrofosmin uptake by sarcomas in vitro as well as in primary tumours has been reported. Data on the visualisation of metastatic soft tissue sarcomas using this tracer are missing so far. Ten consecutive patients with histopathologically verified metastatic soft tissue sarcoma were included in the present study. Five patients had previously received cytotoxic treatment, the other five patients were chemonaive. All patients underwent whole body planar examination after administration of 500-550 MBq Tc-99m-tetrofosmin, and in case of lung metastases on CT scan, SPECT images were carried out. Non-physiological accumulation of the tracer was considered as a positive result. Scintigraphic results were compared to conventional imaging by means of MRI/CT scanning. Visualisation of distant metastases was achieved in five patients all of whom were chemonaive, while in the chemotherapeutically pretreated patient group (n=5) false negative results were seen. Progressive disease was confirmed by follow-up in all patients. Pulmonary metastases were visualised only in SPECT acquisition and not on planar images. In one patient with diffuse bone marrow infiltration (inflammatory myofibroblastic sarcoma) Tc-99m-tetrofosmin scintigraphy was positive, while CT showed a negative result. According to our results, detection of metastatic soft tissue sarcomas by Tc-99m-tetrofosmin scintigraphy was strongly dependent on the history of previous treatment of the patient. A positive finding before initiation of chemotherapy was not indicative for subsequent therapeutic response. In the staging of chemonaive patients with metastatic soft tissue sarcoma Tc-99m-tetrofosmin may provide some additional information.

Tc-99m-labeled human polyclonal immunoglobulin G (HIG) scintigraphy in Sjögren's syndrome.

OBJECTIVE: To evaluate the usefulness of Tc-99m-HIG scintigraphy in patients with Sjögren's syndrome. METHODS: Twelve consecutive patients with verified secondary Sjögren's syndrome were included in this prospective study. The control group consisted of seven patients with Lupus erythematosus; none of them showed clinical signs of Sjögren's syndrome. Planar and SPECT images of the head were performed six hours after i.v. administration of Tc-99m HIG. RESULTS: Eleven out of twelve patients with secondary Sjögren's syndrome showed a positive result, while one was false negative. Tracer accumulation in patients with positive scintigraphy varied. All patients of the control group were negative. CONCLUSION: Our data in a limited number of patients suggest that Tc-99m HIG scintigraphy could be a modality with high sensitivity and specificity for the diagnosis of Sjögren's syndrome and can provide objective information on the severity of the disease.

Toward the spectrum of free polyethylene: linear alkanes studied by carbon 1s photoelectron spectroscopy and theory.

Trends in carbon 1s ionization energies for the linear alkanes have been investigated using third-generation synchrotron radiation. The study comprises CH(4), C(2)H(6), C(3)H(8), C(4)H(10), C(5)H(12), C(6)H(14), and C(8)H(18). Both inter- and intramolecular shifts in ionization energy have been determined from gas-phase spectra and ab initio calculations. The shifts are decomposed into initial-state and final-state contributions and are shown to relate to the fundamental chemical properties of group electronegativity and polarizability. By extrapolation, we predict C1s spectra of larger n-alkanes, converging toward isolated strands of polyethylene.