A 35-year-old woman was acutely hospitalized with oedema of the upper limbs, reduced force, severe movement reduction and muscle pain in both upper extremities. Her symptoms started after three days of intense exercise doing kayaking and a lot of pull-ups in crossfit. Rhabdomyolysis is a syndrome, characterized by muscle necrosis. Usually there is a marked elevation of creatine kinase (CK) concentration with symptoms as described and myoglobinuria (dark coloured urine). After hard muscular work there will often be asymptomatic, but significant elevations in CK concentration, and in rare cases life-threatening rhabdomyolysis with electrolyte imbalances and acute kidney failure.
We have investigated the mobility of two EGFP-tagged DNA repair proteins, WRN and BLM. In particular, we focused on the dynamics in two locations, the nucleoli and the nucleoplasm. We found that both WRN and BLM use a "DNA-scanning" mechanism, with rapid binding-unbinding to DNA resulting in effective diffusion. In the nucleoplasm WRN and BLM have effective diffusion coefficients of 1.62 and 1.34 ?m(2)/s, respectively. Likewise, the dynamics in the nucleoli are also best described by effective diffusion, but with diffusion coefficients a factor of ten lower than in the nucleoplasm. From this large reduction in diffusion coefficient we were able to classify WRN and BLM as DNA damage scanners. In addition to WRN and BLM we also classified other DNA damage proteins and found they all fall into one of two categories. Either they are scanners, similar to WRN and BLM, with very low diffusion coefficients, suggesting a scanning mechanism, or they are almost freely diffusing, suggesting that they interact with DNA only after initiation of a DNA damage response.
To evaluate the effect of perioperative gabapentin treatment for the prevention of persistent post-thoracotomy pain and to establish whether gabapentin has a significant therapeutic impact on acute postoperative pain.
Variability in patients' postoperative pain experience and response to treatment challenges effective pain management. Variability in pain reflects individual differences in inhibitory pain modulation and psychological sensitivity, which in turn may be clinically relevant for the disposition to acquire pain. The aim of this study was to investigate the effects of conditioned pain modulation and situational pain catastrophizing on postoperative pain and pain persistency.
Using empirical data from a social media site (Twitter) and on trading volumes of financial securities, we analyze the correlated human activity in massive social organizations. The activity, typically excited by real-world events and measured by the occurrence rate of international brand names and trading volumes, is characterized by intermittent fluctuations with bursts of high activity separated by quiescent periods. These fluctuations are broadly distributed with an inverse cubic tail and have long-range temporal correlations with a power spectrum. We describe the activity by a stochastic point process and derive the distribution of activity levels from the corresponding stochastic differential equation. The distribution and the corresponding power spectrum are fully consistent with the empirical observations.
Theoretical models that describe oscillations in biological systems are often either a limit cycle oscillator, where the deterministic nonlinear dynamics gives sustained periodic oscillations, or a noise-induced oscillator, where a fixed point is linearly stable with complex eigenvalues, and addition of noise gives oscillations around the fixed point with fluctuating amplitude. We investigate how each class of models behaves under the external periodic forcing, taking the well-studied van der Pol equation as an example. We find that when the forcing is additive, the noise-induced oscillator can show only one-to-one entrainment to the external frequency, in contrast to the limit cycle oscillator which is known to entrain to any ratio. When the external forcing is multiplicative, on the other hand, the noise-induced oscillator can show entrainment to a few ratios other than one-to-one, while the limit cycle oscillator shows entrain to any ratio. The noise blurs the entrainment in general, but clear entrainment regions for limit cycles can be identified as long as the noise is not too strong.
PURPOSE: Arthroscopic anterior cruciate ligament (ACL) reconstruction is a painful procedure requiring intensive postoperative pain management. Femoral nerve block is widely used in ACL surgery. However, femoral nerve block does not cover the donor site of the hamstring tendons. Local infiltration analgesia is a simple technique that has proven effective in postoperative pain management after total knee arthroplasty. Further, local infiltration analgesia covers the donor site and is associated with few complications. It was hypothesised that local infiltration analgesia at the donor site and wounds would decrease pain and opioid consumption after ACL reconstruction with hamstring tendon graft. METHODS: Sixty patients undergoing primary ACL surgery with hamstring tendon graft were randomised to receive either local infiltration analgesia or femoral nerve block. Pain was scored on the numeric rating scale, and use of opioid, range of motion and adverse effects were assessed at the postoperative recovery unit (0 h), 3, 24 and 48 h, postoperatively. RESULTS: There were no significant differences between the groups in pain intensity or total opioid consumption at any of the follow-up points. Further, there were no differences between groups concerning side effects and range of motion. CONCLUSIONS: Local infiltration analgesia and femoral nerve block are similar in the management of postoperative pain after ACL reconstruction with hamstring tendon graft. Until randomised studies have investigated femoral nerve block combined with infiltration at the donor site, we recommend local infiltration analgesia in ACL reconstruction with hamstring tendon graft. LEVEL OF EVIDENCE: I.
Several studies have reported that interactions of mothers with preterm infants show differential characteristics compared to that of mothers with full-term infants. Interaction of preterm dyads is often reported as less harmonious. However, observations and explanations concerning the underlying mechanisms are inconsistent. In this work 30 preterm and 42 full-term mother-infant dyads were observed at one year of age. Free play interactions were videotaped and coded using a micro-analytic coding system. The video records were coded at one second resolution and studied by a novel approach using network analysis tools. The advantage of our approach is that it reveals the patterns of behavioral transitions in the interactions. We found that the most frequent behavioral transitions are the same in the two groups. However, we have identified several high and lower frequency transitions which occur significantly more often in the preterm or full-term group. Our analysis also suggests that the variability of behavioral transitions is significantly higher in the preterm group. This higher variability is mostly resulted from the diversity of transitions involving non-harmonious behaviors. We have identified a maladaptive pattern in the maternal behavior in the preterm group, involving intrusiveness and disengagement. Application of the approach reported in this paper to longitudinal data could elucidate whether these maladaptive maternal behavioral changes place the infant at risk for later emotional, cognitive and behavioral disturbance.
Chronic pain patients frequently suffer from depression. This systematic review finds that patients suffering from rheumatoid arthritis (RA) have a higher prevalence of depression than controls without RA. Depression is related to pain intensity, passive coping strategies and disability. For patients this may result in a decreased quality of life and a shorter lifespan. For society it results in increased health costs.
The Wnt signaling pathway transducing the stabilization of ?-catenin is essential for metazoan embryo development and is misregulated in many diseases such as cancers. In recent years models have been proposed for the Wnt signaling pathway during the segmentation process in developing embryos. Many of these include negative feedback loops where Axin2 plays a key role. However, Axin2 null mice show no segmentation phenotype. We therefore propose a new model where the negative feedback involves Dkk1 rather than Axin2. We show that this model can exhibit the same type of oscillations as the previous models with Axin2 and as observed in experiments. We show that a spatial Wnt gradient can consistently convert this temporal periodicity into the spatial periodicity of somites, provided the oscillations in new cells arising in the presomitic mesoderm are synchronized with the oscillations of older cells. We further investigate the hypothesis that a change in the Wnt level in the tail bud during the later stages of somitogenesis can lengthen the time period of the oscillations and hence the size and separation of the later somites.
The regulatory system of the transcription factor NF-?B plays a great role in many cell functions, including inflammatory response. Interestingly, the NF-?B system is known to up-regulate production of its own triggering signal-namely, inflammatory cytokines such as TNF, IL-1, and IL-6. In this paper we investigate a previously presented model of the NF-?B, which includes both spatial effects and the positive feedback from cytokines. The model exhibits the properties of an excitable medium and has the ability to propagate waves of high cytokine concentration. These waves represent an optimal way of sending an inflammatory signal through the tissue as they create a chemotactic signal able to recruit neutrophils to the site of infection. The simple model displays three qualitatively different states; low stimuli leads to no or very little response. Intermediate stimuli leads to reoccurring waves of high cytokine concentration. Finally, high stimuli leads to a sustained high cytokine concentration, a scenario which is toxic for the tissue cells and corresponds to chronic inflammation. Due to the few variables of the simple model, we are able to perform a phase-space analysis leading to a detailed understanding of the functional form of the model and its limitations. The spatial effects of the model contribute to the robustness of the cytokine wave formation and propagation.
We investigate the dynamics of an ecological system made up of one predator feeding on two different prey species. In a large range of parameter space, the system displays oscillating solutions. We show that, in the regime in which the two preys coexist, the better fit prey consistently peaks first. Further, we classify the possible oscillations of the network by a symbolic dynamics method. Our findings show that the symbolic orbits of an ecological system contain information about which of two preys is the better fit, and when one is bound to extinction.
Waves propagating in "excitable media" is a reliable way to transmit signals in space. A fascinating example where living cells comprise such a medium is Dictyostelium D. which propagates waves of chemoattractant to attract distant cells. While neutrophils chemotax in a similar fashion as Dictyostelium D., it is unclear if chemoattractant waves exist in mammalian tissues and what mechanisms could propagate them.
Loss of joint cartilage may be an early feature of chronic inflammatory joint diseases like juvenile idiopathic arthritis (JIA). Conventional radiography usually detects only late changes such as joint space narrowing and bone erosion rather than early inflammatory changes. Joint cartilage is easily visualized with high-frequency ultrasonography (US), but age- and gender-related normal standard reference values should be established before US measurement of cartilage thickness becomes standard procedure in the clinic.
The p53 signalling pathway has hundreds of inputs and outputs. It can trigger cellular senescence, cell-cycle arrest and apoptosis in response to diverse stress conditions, including DNA damage, hypoxia and nutrient deprivation. Signals from all these inputs are channeled through a single node, the transcription factor p53. Yet, the pathway is flexible enough to produce different downstream gene expression patterns in response to different stresses.
Oscillations are commonly observed in cellular behavior and span a wide range of timescales, from seconds in calcium signaling to 24 hours in circadian rhythms. In between lie oscillations with time periods of 1-5 hours seen in NF-?B, p53 and Wnt signaling, which play key roles in the immune system, cell growth/death and embryo development, respectively. In the first part of this article, we provide a brief overview of simple deterministic models of oscillations. In particular, we explain the mechanism of saturated degradation that has been used to model oscillations in the NF-?B, p53 and Wnt systems. The second part deals with the potential physiological role of oscillations. We use the simple models described earlier to explore whether oscillatory signals can encode more information than steady-state signals. We then discuss a few simple genetic circuits that could decode information stored in the average, amplitude or frequency of oscillations. The presence of frequency-detector circuit downstream of NF-?B or p53 would be a strong clue that oscillations are important for the physiological response of these signaling systems.
Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow in an intermittent fashion, with periods of growth followed by long pauses. The observed exponential distributions of stop and growth times support a Markovian model, in which fibrils shift between the two states with specific rates. Even if the individual rates vary considerably, we observe that the probability of being in the growing (stopping) state is very close to 1/4 (3/4) in all experiments.
Pathogens and parasites are ubiquitous in the living world, being limited only by availability of suitable hosts. The ability to transmit a particular disease depends on competing infections as well as on the status of host immunity. Multiple diseases compete for the same resource and their fate is coupled to each other. Such couplings have many facets, for example cross-immunization between related influenza strains, mutual inhibition by killing the host, or possible even a mutual catalytic effect if host immunity is impaired. We here introduce a minimal model for an unlimited number of unrelated pathogens whose interaction is simplified to simple mutual exclusion. The model incorporates an ongoing development of host immunity to past diseases, while leaving the system open for emergence of new diseases. The model exhibits a rich dynamical behavior with interacting infection waves, leaving broad trails of immunization in the host population. This obtained immunization pattern depends only on the system size and on the mutation rate that initiates new diseases.
We propose a model for the segmentation clock in vertebrate somitogenesis, based on the Wnt signaling pathway. The core of the model is a negative feedback loop centered around the Axin2 protein. Axin2 is activated by beta-catenin, which in turn is degraded by a complex of GSK3beta and Axin2. The model produces oscillatory states of the involved constituents with typical time periods of a few hours (ultradian oscillations). The oscillations are robust to changes in parameter values and are often spiky, where low concentration values of beta-catenin are interrupted by sharp peaks. Necessary for the oscillations is the saturated degradation of Axin2. Somite formation in chick and mouse embryos is controlled by a spatial Wnt gradient which we introduce in the model through a time-dependent decrease in Wnt3a ligand level. We find that the oscillations disappear as the ligand concentration decreases, in agreement with observations on embryos.
We study pair dispersion in a three-dimensional incompressible high Reynolds number turbulent flow generated by Fourier transforming the dynamics of the Gledzer-Ohkitani-Yamada (GOY) shell model into real space. We show that GOY shell model can successfully reproduce both the Batchelor and the Richardson-Obukhov regimes of turbulent relative dispersion. We also study how the crossover time scales with the initial separations of a particle pair and compare it to the prediction by Batchelor.
Surgical correction of pectus excavatum (PE) is primarily performed to achieve cosmetic and psychological benefits for the patient. Minimally invasive repair of PE is often associated with severe postoperative pain. This study estimates the effect of the severity of PE on the postoperative consumption of opioid analgesics following this procedure to optimise pain management.
There is an increasing interest among pediatric rheumatologist for using ultrasonography (US) in the daily clinical examination of children with juvenile idiopathic arthritis (JIA). Loss of joint cartilage may be an early feature of destructive disease in JIA. However, US still needs validation before it can be used as a diagnostic bedside tool in a pediatric setting. This study aims to assess the inter- and intraobserver reliability of US measurements of cartilage thickness in the joints of healthy children.
We construct a hexagonal lattice of repressing genes, such that each node represses three of the neighbors, and use it as a model for genetic regulation in spatially extended systems. Using symmetry arguments and stability analysis we argue that the repressor lattice can be in a nonfrustrated oscillating state with only three distinct phases. If the system size is not commensurate with three, oscillating solutions of several different phases are possible. As the strength of the interactions between the nodes increases, the system undergoes many transitions, breaking several symmetries. Eventually dynamical frustrated states appear, where the temporal evolution is chaotic, even though there are no built-in frustrations. Applications of the repressor lattice to real biological systems are discussed.
In Parkinsons disease (PD), there is evidence that alpha-synuclein (alphaSN) aggregation is coupled to dysfunctional or overburdened protein quality control systems, in particular the ubiquitin-proteasome system. Here, we develop a simple dynamical model for the on-going conflict between alphaSN aggregation and the maintenance of a functional proteasome in the healthy cell, based on the premise that proteasomal activity can be titrated out by mature alphaSN fibrils and their protofilament precursors. In the presence of excess proteasomes the cell easily maintains homeostasis. However, when the ratio between the available proteasome and the alphaSN protofilaments is reduced below a threshold level, we predict a collapse of homeostasis and onset of oscillations in the proteasome concentration. Depleted proteasome opens for accumulation of oligomers. Our analysis suggests that the onset of PD is associated with a proteasome population that becomes occupied in periodic degradation of aggregates. This behavior is found to be the general state of a proteasome/chaperone system under pressure, and suggests new interpretations of other diseases where protein aggregation could stress elements of the protein quality control system.
We formulate general rules for a coarse graining of the dynamics, which we term "symbolic dynamics," of feedback networks with monotonic interactions, such as most biological modules. Networks which are more complex than simple cyclic structures can exhibit multiple different symbolic dynamics. Nevertheless, we show several examples where the symbolic dynamics is dominated by a single pattern that is very robust to changes in parameters and is consistent with the dynamics being dictated by a single feedback loop. Our analysis provides a method for extracting these dominant loops from short time series, even if they only show transient trajectories.
Knowledge of the importance of diet on gastrointestinal function and symptoms is generally poorly. In recent years, The New Nordic Food Culture is suggested to have favourable effects. Unfortunally there are huge waiting lists at the most popular restaurants, so we investigated the more traditional "Nordic kitchen". There are no previous studies concerning intake of fried bacon and parsley sauce (FBPS) in healthy middle-aged footballers.
In many developing tissues, neighboring cells enter different developmental pathways, resulting in a fine-grained pattern of different cell states. The most common mechanism that generates such patterns is lateral inhibition, for example through Delta-Notch coupling. In this work, we simulate growth of tissues consisting of a hexagonal arrangement of cells laterally inhibiting their neighbors. We find that tissue growth by cell division and cell migration tends to produce ordered patterns, whereas lateral growth leads to disordered, patchy patterns. Ordered patterns are very robust to mutations (gene silencing or activation) in single cells. In contrast, mutation in a cell of a disordered tissue can produce a larger and more widespread perturbation of the pattern. In tissues where ordered and disordered patches coexist, the perturbations spread mostly at boundaries between patches. If cell division occurs on time scales faster than the degradation time, disordered patches will appear. Our work suggests that careful experimental characterization of the disorder in tissues could pinpoint where and how the tissue is susceptible to large-scale damage even from single cell mutations.
Complex networks are important tools for analyzing the information flow in many aspects of nature and human society. Using data from the microblogging service Twitter, we study networks of correlations in the occurrence of words from three different categories, international brands, nouns and US major cities. We create networks where the strength of links is determined by a similarity measure based on the rate of co-occurrences of words. In comparison with the null model, where words are assumed to be uncorrelated, the heavy-tailed distribution of pair correlations is shown to be a consequence of groups of words representing similar entities.
As a model for cell-to-cell communication in biological tissues, we construct repressor lattices by repeating a regulatory three-node motif on a hexagonal structure. Local interactions can be unidirectional, where a node either represses or activates a neighbor that does not communicate backwards. Alternatively, they can be bidirectional where two neighboring nodes communicate with each other. In the unidirectional case, we perform stability analyses for the transitions from stationary to oscillating states in lattices with different regulatory units. In the bidirectional case, we investigate transitions from oscillating states to ordered patterns generated by local switches. Finally, we show how such stable patterns in two-dimensional lattices can be generalized to three-dimensional systems.
The aim of this study was to develop a human experimental bone pain model. Fourteen healthy men were included in two study sessions. Pressure pain threshold (PPT) was estimated using probes of different sizes. Computer-controlled and hand-held algometry were applied to the skin area covering right and left medial tibia before and after local anaesthesia (LA) of the skin and reproducibility was evaluated. Pain experience (McGill questionnaire) was compared between healthy volunteers and 12 patients with vertebral fractures. Computer-controlled algometer: No differences in PPT between study sessions for 6 and 8-mm probes (p = 0.43 and 0.32) were seen. There was a difference in PPT before and after LA for the 6-mm probe (p = 0.008), but not for the 8-mm probe (p = 0.26). Hand-held algometer: A difference in PPT between study sessions was observed for 4- and 8-mm probes (p = 0.03 and 0.007), but not for 2, 6 and 10-mm probes (p = 0.19, 0.05 and 0.25). No differences in PPT were seen before and after LA for 2, 4, 8 and 10-mm probes (p = 0.35, 0.15, 0.08 and 0.53), but LA significantly influenced PPT with the 6-mm probe (p = 0.01). Similar words were chosen in the McGill pain questionnaire by healthy volunteers and patients, qualitatively describing the deep pain sensation. The pain evoked by hand-held algometer and the 2-mm probe was not influenced by LA, and PPT was reproducible between sessions and is recommended for studies of experimentally evoked bone-associated pain.
We analyze a class of network motifs in which a short, two-node positive feedback motif is inserted in a three-node negative feedback loop. We demonstrate that such networks can undergo a bifurcation to a state where a stable fixed point and a stable limit cycle coexist. At the bifurcation point the period of the oscillations diverges. Further, intrinsic noise can make the system switch between oscillatory state and the stationary state spontaneously. We find that this switching also occurs in previous models of circadian clocks that use this combination of positive and negative feedbacks. Our results suggest that real-life circadian systems may need specific regulation to prevent or minimize such switching events.
Inflammatory responses in eucaryotic cells are often associated with oscillations in the nuclear-cytoplasmic translocation of the transcription factor NF-kB. In most laboratory realizations, the oscillations are triggered by a cytokine stimulus. We use a mathematical model to show that an oscillatory external stimulus can synchronize the NF-kB oscillations into states where the ratios of the internal to external frequency are close to rational numbers. We predict a response diagram of the TNF-driven NF-kB system which exhibits bands of synchronization known as "Arnold tongues". We suggest that when the amplitude of the external stimulus exceeds a certain threshold, chaotic dynamics of the nuclear NF-kB concentration may occur. This behavior seems independent of the shape of the external oscillation and the non-linearities transducing this signal.
We study competition between two biological species advected by a compressible velocity field. Individuals are treated as discrete Lagrangian particles that reproduce or die in a density-dependent fashion. In the absence of a velocity field and fitness advantage, number fluctuations lead to a coarsening dynamics typical of the stochastic Fisher equation. We investigate three examples of compressible advecting fields: a shell model of turbulence, a sinusoidal velocity field and a linear velocity sink. In all cases, advection leads to a striking drop in the fixation time, as well as a large reduction in the global carrying capacity. We find localization on convergence zones, and very rapid extinction compared to well-mixed populations. For a linear velocity sink, one finds a bimodal distribution of fixation times. The long-lived states in this case are demixed configurations with a single interface, whose location depends on the fitness advantage.
Most studies of persistent post-surgical pain following thoracic surgery have focused on classic posterolateral thoracotomy in mixed surgical populations without systematic assessment of disease recurrence and other potential sources of pain. The purpose of this study was to examine patterns in the prevalence of persistent post-surgical pain following lung cancer surgery and to quantitatively assess the characteristics of persistent post-surgical pain and associated sensory changes.
The 219-residue protein p25? stimulates the fibrillation of ?-synuclein (?SN) in vitro and colocalizes with it in several ?-synucleinopathies. Although p25? does not fibrillate by itself under native conditions in vitro, ?SN-free p25? aggregates have also been observed in vivo in, for example, multiple system atrophy. To investigate which environmental conditions might trigger this aggregation, we investigated the effect of polyanionic biomolecules on p25? aggregation. Heparin, polyglutamate, arachidonic acid micelles, and RNA all induce p25? aggregation. More detailed studies using heparin as template for aggregation reveal that a minimum of 10-14 heparin monosaccharide units per heparin polymer are required. Bona fide fibrils are only formed at intermediate heparin concentrations, possibly because an excess of heparin binding sites blocks the inter-p25? contacts required for amyloid formation. Other polyanions also show an optimum for amyloid formation. Aggregation involves only modest structural changes according to both spectroscopic and proteolytic experiments. The aggregates do not seed aggregation of heparin-free p25?, suggesting that heparin is required in stoichiometric amounts to form organized structures. We are able to reproduce these observations in a model involving two levels of binding of p25? to heparin. We conclude that the modest structural changes that p25? undergoes can promote weak intermolecular contacts and that polyanions such as heparin play a central role in stabilizing these aggregates but in multiple ways, leading to different types of aggregates. This highlights the role of non-protein components in promoting protein aggregation in vivo.
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