Functional, structural and molecular plasticity of mammalian skeletal muscle in response to exercise stimuli

Biological systems have acquired effective adaptive strategies to cope with physiological challenges and to maximize biochemical processes under imposed constraints. Striated muscle tissue demonstrates a remarkable malleability and can adjust its metabolic and contractile makeup in response to alterations in functional demands. Activity-dependent muscle plasticity therefore represents a unique model to investigate the regulatory machinery underlying phenotypic adaptations in a fully differentiated tissue. Adjustments in form and function of mammalian muscle have so far been characterized at a descriptive level, and several major themes have evolved. These imply that mechanical, metabolic and neuronal perturbations in recruited muscle groups relay to the specific processes being activated by the complex physiological stimulus of exercise. The important relationship between the phenotypic stimuli and consequent muscular modifications is reflected by coordinated differences at the transcript level that match structural and functional adjustments in the new training steady state. Permanent alterations of gene expression thus represent a major strategy for the integration of phenotypic stimuli into remodeling of muscle makeup. A unifying theory on the molecular mechanism that connects the single exercise stimulus to the multi-faceted adjustments made after the repeated impact of the muscular stress remains elusive. Recently, master switches have been recognized that sense and transduce the individual physical and chemical perturbations induced by physiological challenges via signaling cascades to downstream gene expression events. Molecular observations on signaling systems also extend the long-known evidence for desensitization of the muscle response to endurance exercise after the repeated impact of the stimulus that occurs with training. Integrative approaches involving the manipulation of single factors and the systematic monitoring of downstream effects at multiple levels would appear to be the ultimate method for pinpointing the mechanism of muscle remodeling. The identification of the basic relationships underlying the malleability of muscle tissue is likely to be of relevance for our understanding of compensatory processes in other tissues, species and organisms.

Fitting ACE Structural Equation Models to Case-Control Family Data

Investigators interested in whether a disease aggregates in families often collect case-control family data, which consist of disease status and covariate information for families selected via case or control probands. Here, we focus on the use of case-control family data to investigate the relative contributions to the disease of additive genetic effects (A), shared family environment (C), and unique environment (E). To this end, we describe a ACE model for binary family data and then introduce an approach to fitting the model to case-control family data. The structural equation model, which has been described previously, combines a general-family extension of the classic ACE twin model with a (possibly covariate-specific) liability-threshold model for binary outcomes. Our likelihood-based approach to fitting involves conditioning on the proband’s disease status, as well as setting prevalence equal to a pre-specified value that can be estimated from the data themselves if necessary. Simulation experiments suggest that our approach to fitting yields approximately unbiased estimates of the A, C, and E variance components, provided that certain commonly-made assumptions hold. These assumptions include: the usual assumptions for the classic ACE and liability-threshold models; assumptions about shared family environment for relative pairs; and assumptions about the case-control family sampling, including single ascertainment. When our approach is used to fit the ACE model to Austrian case-control family data on depression, the resulting estimate of heritability is very similar to those from previous analyses of twin data.

Effects of high-dose heroin versus morphine in intravenous drug users: a randomised double-blind crossover study

The purpose of this study is to evaluate the effects of high doses of injected opiates as prescribed maintenance in intravenous drugs users. This was accomplished via a randomised double-blind study with crossover at an outpatient clinic in Bern, Switzerland. The subjects were 39 patients with a long history of intravenous opioid use and persistent abuse despite treatment; they were randomly allocated to two groups. Group A was started on controlled injection of graduated doses of morphine up to a satisfying individual dose and was then switched as a double blind to heroin at a randomly determined day between week three and four. Subsequently this group was given heroin for the remaining two to three weeks of the study. Group B was started on heroin and was then switched to morphine in the same manner. Equipotent solutions of 3% morphine and 2% heroin were administered. The main outcome measures were clinical observations, structural interviews and self report of subjective experiences to assess the effects of the drugs. In 16 cases, the study had to be discontinued owing to severe morphine-induced histamine reactions. Thirteen participants in Group B presented these adverse reactions on the day of the switch-over. Full data were thus only obtainable for 17 participants. Average daily doses were 491 mg for heroin and 597 mg for morphine. The findings indicate that heroin significantly produced a lower grade of itching, flushing, urticaria and pain/nausea. A negative correlation between dose and euphoria was observed for both heroin and morphine. The authors concluded that as heroin produces fewer side effects it is the preferred high-dose maintenance prescription to morphine. The perceived euphoric effects are limited in both substances.

Marginal Structural Models for Partial Exposure Regimes

Intensive care unit (ICU) patients are ell known to be highly susceptible for nosocomial (i.e. hospital-acquired) infections due to their poor health and many invasive therapeutic treatments. The effects of acquiring such infections in ICU on mortality are however ill understood. Our goal is to quantify these effects using data from the National Surveillance Study of Nosocomial Infections in Intensive Care Units (Belgium). This is a challenging problem because of the presence of time-dependent confounders (such as exposure to mechanical ventilation)which lie on the causal path from infection to mortality. Standard statistical analyses may be severely misleading in such settings and have shown contradicting results. While inverse probability weighting for marginal structural models can be used to accommodate time-dependent confounders, inference for the effect of ?ICU acquired infections on mortality under such models is further complicated (a) by the fact that marginal structural models infer the effect of acquiring infection on a given, fixed day ?in ICU?, which is not well defined when ICU discharge comes prior to that day; (b) by informative censoring of the survival time due to hospital discharge; and (c) by the instability of the inverse weighting estimation procedure. We accommodate these problems by developing inference under a new class of marginal structural models which describe the hazard of death for patients if, possibly contrary to fact, they stayed in the ICU for at least a given number of days s and acquired infection or not on that day. Using these models we estimate that, if patients stayed in the ICU for at least s days, the effect of acquiring infection on day s would be to multiply the subsequent hazard of death by 2.74 (95 per cent conservative CI 1.48; 5.09).

Patient satisfaction and side effects in primary care: An observational study comparing homeopathy and conventional medicine

Background This study is part of a nationwide evaluation of complementary medicine in Switzerland (Programme Evaluation of Complementary Medicine PEK) and was funded by the Swiss Federal Office of Public Health. The main objective of this study is to investigate patient satisfaction and perception of side effects in homeopathy compared with conventional care in a primary care setting. Methods We examined data from two cross-sectional studies conducted in 2002–2003. The first study was a physician questionnaire assessing structural characteristics of practices. The second study was conducted on four given days during a 12-month period in 2002/2003 using a physician and patient questionnaire at consultation and a patient questionnaire mailed to the patient one month later (including Europep questionnaire). The participating physicians were all trained and licensed in conventional medicine. An additional qualification was required for medical doctors providing homeopathy (membership in the Swiss association of homeopathic physicians SVHA). Results A total of 6778 adult patients received the questionnaire and 3126 responded (46.1%). Statistically significant differences were found with respect to health status (higher percentage of chronic and severe conditions in the homeopathic group), perception of side effects (higher percentage of reported side effects in the conventional group) and patient satisfaction (higher percentage of satisfied patients in the homeopathic group). Conclusion Overall patient satisfaction was significantly higher in homeopathic than in conventional care. Homeopathic treatments were perceived as a low-risk therapy with two to three times fewer side effects than conventional care

Training in hypoxia and its effects on skeletal muscle tissue

It is well established that local muscle tissue hypoxia is an important consequence and possibly a relevant adaptive signal of endurance exercise training in humans. It has been reasoned that it might be advantageous to increase this exercise stimulus by working in hypoxia. However, as long-term exposure to severe hypoxia has been shown to be detrimental to muscle tissue, experimental protocols were developed that expose subjects to hypoxia only for the duration of the exercise session and allow recovery in normoxia (live low-train high or hypoxic training). This overview reports data from 27 controlled studies using some implementation of hypoxic training paradigms. Hypoxia exposure varied between 2300 and 5700 m and training duration ranged from 10 days to 8 weeks. A similar number of studies was carried out on untrained and on trained subjects. Muscle structural, biochemical and molecular findings point to a specific role of hypoxia in endurance training. However, based on the available data on global estimates of performance capacity such as maximal oxygen uptake (VO2max) and maximal power output (Pmax), hypoxia as a supplement to training is not consistently found to be of advantage for performance at sea level. There is some evidence mainly from studies on untrained subjects for an advantage of hypoxic training for performance at altitude. Live low-train high may be considered when altitude acclimatization is not an option.

Structural response and dynamics of fluid-structure-control interaction in wind turbine blades

Reducing the uncertainties related to blade dynamics by the improvement of the quality of numerical simulations of the fluid structure interaction process is a key for a breakthrough in wind-turbine technology. A fundamental step in that direction is the implementation of aeroelastic models capable of capturing the complex features of innovative prototype blades, so they can be tested at realistic full-scale conditions with a reasonable computational cost. We make use of a code based on a combination of two advanced numerical models implemented in a parallel HPC supercomputer platform: First, a model of the structural response of heterogeneous composite blades, based on a variation of the dimensional reduction technique proposed by Hodges and Yu. This technique has the capacity of reducing the geometrical complexity of the blade section into a stiffness matrix for an equivalent beam. The reduced 1-D strain energy is equivalent to the actual 3-D strain energy in an asymptotic sense, allowing accurate modeling of the blade structure as a 1-D finite-element problem. This substantially reduces the computational effort required to model the structural dynamics at each time step. Second, a novel aerodynamic model based on an advanced implementation of the BEM(Blade ElementMomentum) Theory; where all velocities and forces are re-projected through orthogonal matrices into the instantaneous deformed configuration to fully include the effects of large displacements and rotation of the airfoil sections into the computation of aerodynamic forces. This allows the aerodynamic model to take into account the effects of the complex flexo-torsional deformation that can be captured by the more sophisticated structural model mentioned above. In this thesis we have successfully developed a powerful computational tool for the aeroelastic analysis of wind-turbine blades. Due to the particular features mentioned above in terms of a full representation of the combined modes of deformation of the blade as a complex structural part and their effects on the aerodynamic loads, it constitutes a substantial advancement ahead the state-of-the-art aeroelastic models currently available, like the FAST-Aerodyn suite. In this thesis, we also include the results of several experiments on the NREL-5MW blade, which is widely accepted today as a benchmark blade, together with some modifications intended to explore the capacities of the new code in terms of capturing features on blade-dynamic behavior, which are normally overlooked by the existing aeroelastic models.

Augmenting the piezoelectric in portland cement paste for structural health monitoring applications

This report details the outcomes of a study designed to investigate the piezoelectric properties of Portland cement paste for its possible applications in structural health monitoring. Specifically, this study provides insights into the effects on piezoelectric properties of hardened cement paste from the application of an electric field during the curing process. As part of the reporting of this study, the state of the art in structural health monitoring is reviewed. In this study it is demonstrated that application of an electric field using a spatially-coarse array of electrodes to cure cement paste was not effective in increasing the magnitude of the piezoelectric coupling, but did increase repeatability of the piezoelectric response of the hardened material.

TUNING, AVO, AND FLAT-SPOT EFFECTS IN A SEISMIC ANALYSIS OF NORTH SEA BLOCK F3

Reflection seismic data from the F3 block in the Dutch North Sea exhibits many large-amplitude reflections at shallow horizons, typically categorized as “brightspots ” (Schroot and Schuttenhelm, 2003), mainly because of their bright appearance. In most cases, these bright reflections show a significant “flatness” contrasting with local structural trends. While flatspots are often easily identified in thick reservoirs, we have often occasionally observed apparent flatspot tuning effects at fluid contacts near reservoir edges and in thin reservoir beds, while only poorly understanding them. We conclude that many of the shallow large-amplitude reflections in block F3 are dominated by flatspots, and we investigate the thin-bed tuning effects that such flatspots cause as they interact with the reflection from the reservoir’s upper boundary. There are two possible effects to be considered: (1) the “wedge-model” tuning effects of the flatspot and overlying brightspots, dimspots, or polarity-reversals; and (2) the stacking effects that result from possible inclusion of post-critical flatspot reflections in these shallow sands. We modeled the effects of these two phenomena for the particular stratigraphic sequence in block F3. Our results suggest that stacking of post-critical flatspot reflections can cause similar large-amplitude but flat reflections, in some cases even causing an interface expected to produce a ‘dimspot’ to appear as a ‘brightspot’. Analysis of NMO stretch and muting shows the likely exclusion of critical offset data in stacked output. If post-critical reflections are included in stacking, unusual results will be observed. In the North Sea case, we conclude the tuning effect was the primary reason causing for the brightness and flatness of these reflections. However, it is still important to note that care should be taken while applying muting on reflections with wide range of incidence angles and the inclusion of critical offset data may cause some spurious features in the stacked section.

STRUCTURAL CONTROL OF A SMALL-SCALE TEST-BED SHAKER STRUCTURE USING A SPONGE-TYPE MAGNETO-RHEOLOGICAL FLUID DAMPER

Semi-active damping devices have been shown to be effective in mitigating unwanted vibrations in civil structures. These devices impart force indirectly through real-time alterations to structural properties. Simulating the complex behavior of these devices for laboratory-scale experiments is a major challenge. Commercial devices for seismic applications typically operate in the 2-10 kN range; this force is too high for small-scale testing applications where requirements typically range from 0-10 N. Several challenges must be overcome to produce damping forces at this level. In this study, a small-scale magneto-rheological (MR) damper utilizing a fluid absorbent metal foam matrix is developed and tested to accomplish this goal. This matrix allows magneto-rheological (MR) fluid to be extracted upon magnetic excitation in order to produce MR-fluid shear stresses and viscosity effects between an electromagnetic piston, the foam, and the damper housing. Dampers for uniaxial seismic excitation are traditionally positioned in the horizontal orientation allowing MR-fluid to gather in the lower part of the damper housing when partially filled. Thus, the absorbent matrix is placed in the bottom of the housing relieving the need to fill the entire device with MR-fluid, a practice that requires seals that add significant unwanted friction to the desired low-force device. The damper, once constructed, can be used in feedback control applications to reduce seismic vibrations and to test structural control algorithms and wireless command devices. To validate this device, a parametric study was performed utilizing force and acceleration measurements to characterize damper performance and controllability for this actuator. A discussion of the results is presented to demonstrate the attainment of the damper design objectives.

MODEL UPDATING AND STRUCTURAL HEALTH MONITORING OF HORIZONTAL AXIS WIND TURBINES VIA ADVANCED SPINNING FINITE ELEMENTS AND STOCHASTIC SUBSPACE IDENTIFICATION METHODS

Wind energy has been one of the most growing sectors of the nation’s renewable energy portfolio for the past decade, and the same tendency is being projected for the upcoming years given the aggressive governmental policies for the reduction of fossil fuel dependency. Great technological expectation and outstanding commercial penetration has shown the so called Horizontal Axis Wind Turbines (HAWT) technologies. Given its great acceptance, size evolution of wind turbines over time has increased exponentially. However, safety and economical concerns have emerged as a result of the newly design tendencies for massive scale wind turbine structures presenting high slenderness ratios and complex shapes, typically located in remote areas (e.g. offshore wind farms). In this regard, safety operation requires not only having first-hand information regarding actual structural dynamic conditions under aerodynamic action, but also a deep understanding of the environmental factors in which these multibody rotating structures operate. Given the cyclo-stochastic patterns of the wind loading exerting pressure on a HAWT, a probabilistic framework is appropriate to characterize the risk of failure in terms of resistance and serviceability conditions, at any given time. Furthermore, sources of uncertainty such as material imperfections, buffeting and flutter, aeroelastic damping, gyroscopic effects, turbulence, among others, have pleaded for the use of a more sophisticated mathematical framework that could properly handle all these sources of indetermination. The attainable modeling complexity that arises as a result of these characterizations demands a data-driven experimental validation methodology to calibrate and corroborate the model. For this aim, System Identification (SI) techniques offer a spectrum of well-established numerical methods appropriated for stationary, deterministic, and data-driven numerical schemes, capable of predicting actual dynamic states (eigenrealizations) of traditional time-invariant dynamic systems. As a consequence, it is proposed a modified data-driven SI metric based on the so called Subspace Realization Theory, now adapted for stochastic non-stationary and timevarying systems, as is the case of HAWT’s complex aerodynamics. Simultaneously, this investigation explores the characterization of the turbine loading and response envelopes for critical failure modes of the structural components the wind turbine is made of. In the long run, both aerodynamic framework (theoretical model) and system identification (experimental model) will be merged in a numerical engine formulated as a search algorithm for model updating, also known as Adaptive Simulated Annealing (ASA) process. This iterative engine is based on a set of function minimizations computed by a metric called Modal Assurance Criterion (MAC). In summary, the Thesis is composed of four major parts: (1) development of an analytical aerodynamic framework that predicts interacted wind-structure stochastic loads on wind turbine components; (2) development of a novel tapered-swept-corved Spinning Finite Element (SFE) that includes dampedgyroscopic effects and axial-flexural-torsional coupling; (3) a novel data-driven structural health monitoring (SHM) algorithm via stochastic subspace identification methods; and (4) a numerical search (optimization) engine based on ASA and MAC capable of updating the SFE aerodynamic model.

Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes

Inhibition of ErbB2 (HER2) with monoclonal antibodies, an effective therapy in some forms of breast cancer, is associated with cardiotoxicity, the pathophysiology of which is poorly understood. Recent data suggest, that dual inhibition of ErbB1 (EGFR) and ErbB2 signaling is more efficient in cancer therapy, however, cardiac safety of this therapeutic approach is unknown. We therefore tested an ErbB1-(CGP059326) and an ErbB1/ErbB2-(PKI166) tyrosine kinase inhibitor in an in-vitro system of adult rat ventricular cardiomyocytes and assessed their effects on 1. cell viability, 2. myofibrillar structure, 3. contractile function, and 4. MAPK- and Akt-signaling alone or in combination with Doxorubicin. Neither CGP nor PKI induced cardiomyocyte necrosis or apoptosis. PKI but not CGP caused myofibrillar structural damage that was additive to that induced by Doxorubicin at clinically relevant doses. These changes were associated with an inhibition of excitation-contraction coupling. PKI but not CGP decreased p-Erk1/2, suggesting a role for this MAP-kinase signaling pathway in the maintenance of myofibrils. These data indicate that the ErbB2 signaling pathway is critical for the maintenance of myofibrillar structure and function. Clinical studies using ErbB2-targeted inhibitors for the treatment of cancer should be designed to include careful monitoring for cardiac dysfunction.

Chondrocyte mechanotransduction: effects of compression on deformation of intracellular organelles and relevance to cellular biosynthesis

OBJECTIVE: The effects of mechanical deformation of intact cartilage tissue on chondrocyte biosynthesis in situ have been well documented, but the mechanotransduction pathways that regulate such phenomena have not been elucidated completely. The goal of this study was to examine the effects of tissue deformation on the morphology of a range of intracellular organelles which play a major role in cell biosynthesis and metabolism. DESIGN: Using chemical fixation, high pressure freezing, and electron microscopy, we imaged chondrocytes within mechanically compressed cartilage explants at high magnification and quantitatively and qualitatively assessed changes in organelle volume and shape caused by graded levels of loading. RESULTS: Compression of the tissue caused a concomitant reduction in the volume of the extracellular matrix (ECM), chondrocyte, nucleus, rough endoplasmic reticulum, and mitochondria. Interestingly, however, the Golgi apparatus was able to resist loss of intraorganelle water and retain a portion of its volume relative to the remainder of the cell. These combined results suggest that a balance between intracellular mechanical and osmotic gradients govern the changes in shape and volume of the organelles as the tissue is compressed. CONCLUSIONS: Our results lead to the interpretive hypothesis that organelle volume changes appear to be driven mainly by osmotic interactions while shape changes are mediated by structural factors, such as cytoskeletal interactions that may be linked to extracellular matrix deformations. The observed volume and shape changes of the chondrocyte organelles and the differential behavior between organelles during tissue compression provide evidence for an important mechanotransduction pathway linking translational and post-translational events (e.g., elongation and sulfation of glycosaminoglycans (GAGs) in the Golgi) to cell deformation.

Differential effects of anti-hypertensive treatment on the retinal microcirculation: an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) sub- study

Changes in the retinal microcirculation are associated with hypertension and predict cardiovascular mortality. There are few data describing the impact of antihypertensive therapy on retinal vascular changes. This substudy of the Anglo-Scandinavian Cardiac Outcomes Trial compared the effects of an amlodipine-based regimen (373 patients) with an atenolol-based regimen (347 patients) on retinal microvascular measurements made from fundus photographs. The retinal photographs were taken at a stage in the trial when treatments were stable and blood pressure was well controlled. Amlodipine-based treatment was associated with a smaller arteriolar length:diameter ratio than atenolol-based treatment (13.32 [10.75 to 16.04] versus 14.12 [11.27 to 17.81], median [interquartile range]; P<0.01). The association remained significant after adjustment for age, sex, cholesterol, systolic and diastolic blood pressures, body mass index, smoking, and statin treatment. This effect appeared to be largely attributable to shorter retinal arteriolar segment lengths in the amlodipine-treated group and is best explained by the vasodilator effects of amlodipine causing the visible emergence of branching side vessels. Photographic assessment of the retinal vascular network may be a useful approach to evaluating microvascular structural responses in clinical trials of antihypertensive therapy.