Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models.

Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases.

Relative identifiability of anisotropic properties from magnetic resonance elastography.

Although magnetic resonance elastography (MRE) has been used to estimate isotropic stiffness in the heart, myocardium is known to have anisotropic properties. This study investigated the determinability of global transversely isotropic material parameters using MRE and finite-element modeling (FEM). A FEM-based material parameter identification method, using a displacement-matching objective function, was evaluated in a gel phantom and simulations of a left ventricular (LV) geometry with a histology-derived fiber field. Material parameter estimation was performed in the presence of Gaussian noise. Parameter sweeps were analyzed and characteristics of the Hessian matrix at the optimal solution were used to evaluate the determinability of each constitutive parameter. Four out of five material stiffness parameters (Young's modulii E1 and E3 , shear modulus G13 and damping coefficient s), which describe a transversely isotropic linear elastic material, were well determined from the MRE displacement field using an iterative FEM inversion method. However, the remaining parameter, Poisson's ratio, was less identifiable. In conclusion, Young's modulii, shear modulii and damping can theoretically be well determined from MRE data, but Poisson's ratio is not as well determined and could be set to a reasonable value for biological tissue (close to 0.5).

Innovative Application of Cerebral rSO2 Monitoring During Shunt Tap in Pediatric Ventricular Malfunctioning Shunts.

OBJECTIVE: This study aimed to determine the reliability and potential application of cerebral regional tissue oxygenation (rSO2) monitoring in malfunctioning ventricular shunts during tap. METHODS: This is a prospective case series using convenience sample in subjects with confirmed malfunctioning shunt who had left and right cerebral rSO2 monitoring every 5 seconds before, during, and 1 hour after shunt tap. RESULTS: Ninety-four subjects had cerebral rSO2 monitoring. Sixty-three subjects had proximal malfunctions, and 31 subjects had distal shunt malfunctions. The intrasubject's cerebral rSO2 trend and variability at pretap, during, and posttap times were highly correlated. Overall, the average rSO2 is lower in pretap as compared with posttap. Left cerebral rSO2 had lower means and larger SD as compared with right cerebral rSO2. Left pretap and posttap cerebral rSO2 variability was significantly associated with the location of shunt malfunction regardless of pretap, during, or posttap periods (P < 0.001), whereas right rSO2 variability was not predictive for malfunction location. Left cerebral rSO2 variability showed utility for identifying the location of malfunction with area under the receiver operating characteristic curve equal to 0.8. CONCLUSIONS: Reliable cerebral rSO2 readings before, during, and after shunt tap were demonstrated. Left cerebral rSO2 changes from before to after shunt tap were more predictive for shunt malfunction location than right cerebral rSO2 changes. Observing cerebral rSO2 changes in relationship to shunt tap represents a potential surrogate in measuring cerebral pressures and blood flow changes after cerebral spinal fluid drainage. Significantly greater cerebral rSO2 changes occur for distal malfunction versus proximal malfunction after shunt tap, indicating its potential as an adjunct tool for detecting shunt malfunction type.

Chronological progression of body dissatisfaction and drive for thinness in females 12 to 17 years of age.

The purpose of this secondary study of cross-sectional data was to examine patterns of scores on the Eating Disorders Inventory in a healthy sample of female adolescents thought to have a high potential for risk. Data were obtained as part of a consultation to identify risk of developing eating disorders. The screening and subsequent group level analysis was carried out with 44 female dancers 12 to 17 years of age enrolled in grades 7 to 12 in a Magnet school. This secondary analysis examined three components of the Eating Disorder Inventory (EDI-3): body dissatisfaction, drive for thinness, and bulimia for the purpose of comparing group findings across ages and grades. Some level of body dissatisfaction was widespread in the population, body dissatisfaction increased beginning notably at age 14 and increased sharply at age 15, with further increases until age 16. The correlation between body dissatisfaction and drive for thinness was shown to be statistically significant (r = 0.83, p < 0.001). Awareness that body dissatisfaction and drive for thinness increase at ages 15 and 16 means disordered eating may begin at this time. If body dissatisfaction and drive for thinness begins early in life and markedly increases at ages 14 and 15, eating disorder prevention must begin in childhood and continue into adolescence.

C. elegans males optimize mate-preference decisions via sex-specific responses to multimodal sensory cues.

For sexually reproducing animals, selecting optimal mates is important for maximizing reproductive fitness. In the nematode C. elegans, populations reproduce largely by hermaphrodite self-fertilization, but the cross-fertilization of hermaphrodites by males also occurs. Males' ability to recognize hermaphrodites involves several sensory cues, but an integrated view of the ways males use these cues in their native context to assess characteristics of potential mates has been elusive. Here, we examine the mate-preference behavior of C. elegans males evoked by natively produced cues. We find that males use a combination of volatile sex pheromones (VSPs), ascaroside sex pheromones, surface-associated cues, and other signals to assess multiple features of potential mates. Specific aspects of mate preference are communicated by distinct signals: developmental stage and sex are signaled by ascaroside pheromones and surface cues, whereas the presence of a self-sperm-depleted hermaphrodite is likely signaled by VSPs. Furthermore, males prefer to interact with virgin over mated, and well-fed over food-deprived, hermaphrodites; these preferences are likely adaptive and are also mediated by ascarosides and other cues. Sex-typical mate-preference behavior depends on the sexual state of the nervous system, such that pan-neuronal genetic masculinization in hermaphrodites generates male-typical social behavior. We also identify an unexpected role for the sex-shared ASH sensory neurons in male attraction to ascaroside sex pheromones. Our findings lead to an integrated view in which the distinct physical properties of various mate-preference cues guide a flexible, stepwise behavioral program by which males assess multiple features of potential mates to optimize mate preference.

Cerebral regional oxygen saturation monitoring in pediatric malfunctioning shunt patients.

BACKGROUND: Shunt malfunction produces increased intracranial pressure causing decreased cerebral regional perfusion and tissue O(2)sat. Cerebral regional oxygen saturation (rSO(2)) by near-infrared spectroscopy represents tissue perfusion and oxygen saturation. Cerebral rSO(2) is used to detect cerebral ischemia in pediatric clinical settings. OBJECTIVE: The objective of the study was to determine the reliability of cerebral rSO(2) in pediatric malfunctioning shunt. METHODS: A prospective observational study of pediatric patients presented to the pediatric emergency department was conducted. Confirmed malfunctioning shunt subjects had cerebral rSO(2) monitoring. RESULTS: A total of 131 malfunctioning shunt subjects had cerebral rSO(2) monitoring. Patient's central trend and intrasubject variability of cerebral rSO(2) readings for left and right probe and malfunction sites (n = 131) are as follows: Intrasubject left and right rSO(2) Pearson correlation was -0.46 to 0.98 (mean ± SD, 0.35 ± 0.34; median, 0.34; interquartile range, 0.06-0.61). The correlation coefficients of 99 subjects between left and right rSO(2) was significantly different (P < .001), suggesting that intrasubjects' left and right rSO(2) are highly correlated. Sample mean difference between left and right rSO(2) were -1.7% (95% confidence interval [CI], -1.8 to -1.6; P < .001) supporting overall left lower than right. Intraclass correlation for left rSO(2) was 87.4% (95% CI, 87.2%-87.6%), and that for right rSO(2) was 83.8% (95% CI, 83.8%-84%), showing intersubject differences accounting for the variation, and relative to intersubject variation, intrasubjects readings are consistent. Intrasubjects, left and right rSO(2) highly correlate and are asymmetrical. Left and right rSO(2) are consistent in intrasubject with large rSO(2) variations in trend and variability across subjects. CONCLUSION: This study demonstrates reliable cerebral rSO(2) readings in subjects with malfunctioning shunts, with asymmetrical cerebral rSO(2) hemispheric dynamics within subjects.

The Wnt/beta-catenin asymmetry pathway patterns the atonal ortholog lin-32 to diversify cell fate in a Caenorhabditis elegans sensory lineage.

Each sensory ray of the Caenorhabditis elegans male tail comprises three distinct neuroglial cell types. These three cells descend from a single progenitor, the ray precursor cell, through several rounds of asymmetric division called the ray sublineage. Ray development requires the conserved atonal-family bHLH gene lin-32, which specifies the ray neuroblast and promotes the differentiation of its progeny. However, the mechanisms that allocate specific cell fates among these progeny are unknown. Here we show that the distribution of LIN-32 during the ray sublineage is markedly asymmetric, localizing to anterior daughter cells in two successive cell divisions. The anterior-posterior patterning of LIN-32 expression and of differentiated ray neuroglial fates is brought about by the Wnt/ß-catenin asymmetry pathway, including the Wnt ligand LIN-44, its receptor LIN-17, and downstream components LIT-1 (NLK), SYS-1 (ß-catenin), and POP-1 (TCF). LIN-32 asymmetry itself has an important role in patterning ray cell fates, because the failure to silence lin-32 expression in posterior cells disrupts development of this branch of the ray sublineage. Together, our results illustrate a mechanism whereby the regulated function of a proneural-class gene in a single neural lineage can both specify a neural precursor and actively pattern the fates of its progeny. Moreover, they reveal a central role for the Wnt/ß-catenin asymmetry pathway in patterning neural and glial fates in a simple sensory lineage.

A literature review of dopamine in binge eating.

OBJECTIVE: Binge eating, a core diagnostic symptom in binge eating disorder and bulimia nervosa, increases the risk of multiple physiological and psychiatric disorders. The neurotransmitter dopamine is involved in food craving, decision making, executive functioning, and impulsivity personality trait; all of which contribute to the development and maintenance of binge eating. The objective of this paper is to review the associations of dopamine levels/activities, dopamine regulator (e.g., dopamine transporter, degrading enzymes) levels/activities, and dopamine receptor availability/affinity with binge eating. METHODS: A literature search was conducted in PubMed and PsycINFO to obtain human and animal studies published since 2010. RESULTS: A total of 31 studies (25 human, six animal) were included. Among the human studies, there were 12 case-control studies, eight randomized controlled trials, and five cross-sectional studies. Studies used neuroimaging (e.g., positron emission tomography), genetic, and pharmacological (e.g., dopamine transporter inhibitor) techniques to describe or compare dopamine levels/activities, dopamine transporter levels/activities, dopamine degrading enzyme (e.g., catechol-O-methyltransferase) levels/activities, and dopamine receptor (e.g., D1, D2) availability/affinity among participants with and without binge eating. Most human and animal studies supported an altered dopaminergic state in binge eating (26/31, 83.9%); however, results were divergent regarding whether the altered state was hyperdopaminergic (9/26, 34.6%) or hypodopaminergic (17/26, 65.4%). The mixed findings may be partially explained by the variability in sample characteristics, study design, diagnosis criteria, and neuroimaging/genetic/pharmacological techniques used. However, it is possible that instead of being mutually exclusive, the hyperdopaminergic and hypodopaminergic state may co-exist, but in different stages of binge eating or in different individual genotypes. CONCLUSIONS: For future studies to clarify the inconsistent findings, a homogenous sample that controls for confounders that may influence dopamine levels (e.g., psychiatric diseases) is preferable. Longitudinal studies are needed to evaluate whether the hyper- and hypo-dopaminergic states co-exist in different stages of binge eating or co-exist in individual phenotypes. Binge eating is characterized by eating a large amount of food in a short time and a feeling of difficulty to stop while eating. Binge eating is the defining symptom of binge eating disorder and bulimia nervosa, both of which are associated with serious health consequences. Studies have identified several psychological risk factors of binge eating, including a strong desire for food, impaired cognitive skills, and distinct personality traits (e.g., quick action without careful thinking). However, the physiological markers of binge eating remain unclear. Dopamine is a neurotransmitter that is heavily involved in feeding behavior, human motivation, cognitive ability, and personality. Therefore, dopamine is believed to play a critical role in binge eating. This review synthesized study findings related to the levels and activities of dopamine, dopamine regulators, and dopamine receptors in the context of binge eating. The primary finding is that most studies that used neuroimaging, genetic, or drug techniques found an altered dopaminergic state related to binge eating. However, the literature is inconsistent concerning the direction of the alteration. Considering the mixed findings and the limitations in study design, future studies, especially those that include repeated measurements, are needed to clarify the role of dopamine in binge eating.

Personalization of biomechanical simulations of the left ventricle by in-vivo cardiac DTI data: Impact of fiber interpolation methods.

Simulations of cardiac electrophysiology and mechanics have been reported to be sensitive to the microstructural anisotropy of the myocardium. Consequently, a personalized representation of cardiac microstructure is a crucial component of accurate, personalized cardiac biomechanical models. In-vivo cardiac Diffusion Tensor Imaging (cDTI) is a non-invasive magnetic resonance imaging technique capable of probing the heart's microstructure. Being a rather novel technique, issues such as low resolution, signal-to noise ratio, and spatial coverage are currently limiting factors. We outline four interpolation techniques with varying degrees of data fidelity, different amounts of smoothing strength, and varying representation error to bridge the gap between the sparse in-vivo data and the model, requiring a 3D representation of microstructure across the myocardium. We provide a workflow to incorporate in-vivo myofiber orientation into a left ventricular model and demonstrate that personalized modelling based on fiber orientations from in-vivo cDTI data is feasible. The interpolation error is correlated with a trend in personalized parameters and simulated physiological parameters, strains, and ventricular twist. This trend in simulation results is consistent across material parameter settings and therefore corresponds to a bias introduced by the interpolation method. This study suggests that using a tensor interpolation approach to personalize microstructure with in-vivo cDTI data, reduces the fiber uncertainty and thereby the bias in the simulation results.

Reprogramming the topology of the nociceptive circuit in C. elegans reshapes sexual behavior.

The effect of the detailed connectivity of a neural circuit on its function and the resulting behavior of the organism is a key question in many neural systems. Here, we study the circuit for nociception in C. elegans, which is composed of the same neurons in the two sexes that are wired differently. We show that the nociceptive sensory neurons respond similarly in the two sexes, yet the animals display sexually dimorphic behaviors to the same aversive stimuli. To uncover the role of the downstream network topology in shaping behavior, we learn and simulate network models that replicate the observed dimorphic behaviors and use them to predict simple network rewirings that would switch behavior between the sexes. We then show experimentally that these subtle synaptic rewirings indeed flip behavior. Interestingly, when presented with aversive cues, rewired males were compromised in finding mating partners, suggesting that network topologies that enable efficient avoidance of noxious cues have a reproductive "cost." Our results present a deconstruction of the design of a neural circuit that controls sexual behavior and how to reprogram it.

MR elastography inversion by compressive recovery.

Direct inversion (DI) derives tissue shear modulus by inverting the Helmholtz equation. However, conventional DI is sensitive to data quality due to the ill-posed nature of Helmholtz inversion and thus providing reliable stiffness estimation can be challenging. This becomes more problematic in the case of estimating shear stiffness of the lung in which the low tissue density and short T2* result in considerably low signal-to-noise ratio during lung MRE. In the present study, we propose to perform MRE inversion by compressive recovery (MICRo). Such a technique aims to improve the numerical stability and the robustness to data noise of Helmholtz inversion by using prior knowledge on data noise and transform sparsity of the stiffness map. The developed inversion strategy was first validated in simulated phantoms with known stiffness. Next, MICRo was compared to the standard clinical multi-modal DI (MMDI) method forin vivoliver MRE in healthy subjects and patients with different stages of liver fibrosis. After establishing the accuracy of MICRo, we demonstrated the robustness of the proposed technique against data noise in lung MRE with healthy subjects. In simulated phantoms with single-directional or multi-directional waves, MICRo outperformed DI with Romano filter or Savitsky and Golay filter, especially when the stiffness and/or noise level was high. In hepatic MRE application, agreement was observed between MICRo and MMDI. Measuringin vivolung stiffness, MICRo demonstrated its advantages over filtered DI by yielding stable stiffness estimation at both residual volume and total lung capacity. These preliminary results demonstrate the potential value of the proposed technique and also warrant further investigation in a larger clinical population.

An Implementation of Patient-Specific Biventricular Mechanics Simulations With a Deep Learning and Computational Pipeline.

Parameterised patient-specific models of the heart enable quantitative analysis of cardiac function as well as estimation of regional stress and intrinsic tissue stiffness. However, the development of personalised models and subsequent simulations have often required lengthy manual setup, from image labelling through to generating the finite element model and assigning boundary conditions. Recently, rapid patient-specific finite element modelling has been made possible through the use of machine learning techniques. In this paper, utilising multiple neural networks for image labelling and detection of valve landmarks, together with streamlined data integration, a pipeline for generating patient-specific biventricular models is applied to clinically-acquired data from a diverse cohort of individuals, including hypertrophic and dilated cardiomyopathy patients and healthy volunteers. Valve motion from tracked landmarks as well as cavity volumes measured from labelled images are used to drive realistic motion and estimate passive tissue stiffness values. The neural networks are shown to accurately label cardiac regions and features for these diverse morphologies. Furthermore, differences in global intrinsic parameters, such as tissue anisotropy and normalised active tension, between groups illustrate respective underlying changes in tissue composition and/or structure as a result of pathology. This study shows the successful application of a generic pipeline for biventricular modelling, incorporating artificial intelligence solutions, within a diverse cohort.

Magnetic Resonance Elastography Reconstruction for Anisotropic Tissues.

Elastography has become widely used clinically for characterising changes in soft tissue mechanics that are associated with altered tissue structure and composition. However, some soft tissues, such as muscle, are not isotropic as is assumed in clinical elastography implementations. This limits the ability of these methods to capture changes in anisotropic tissues associated with disease. The objective of this study was to develop and validate a novel elastography reconstruction technique suitable for estimating the linear viscoelastic mechanical properties of transversely isotropic soft tissues. We derived a divergence-free formulation of the governing equations for acoustic wave propagation through a linearly transversely isotropic viscoelastic material, and transformed this into a weak form. This was then implemented into a finite element framework, enabling the analysis of wave input data and tissue structural fibre orientations, in this case based on diffusion tensor imaging. To validate the material constants obtained with this method, numerous in silico phantom experiments were run which encompassed a range of variations in wave input directions, material properties, fibre structure and noise. The method was also tested on ex vivo muscle and in vivo human volunteer calf muscles, and compared with a previous curl-based inversion method. The new method robustly extracted the transversely isotropic shear moduli (G⊥', G∥', G″) from the in silico phantom tests with minimal bias, including in the presence of experimentally realistic levels of noise in either fibre orientation or wave data. This new method performed better than the previous method in the presence of noise. Anisotropy estimates from the ex vivo muscle phantom agreed well with rheological tests. In vivo experiments on human calf muscles were able to detect increases in muscle shear moduli with passive muscle stretch. This new reconstruction method can be applied to quantify tissue mechanical properties of anisotropic soft tissues, such as muscle, in health and disease.

Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin.

For complex diseases in which multiple mediators contribute to overall disease pathogenesis by distinct or redundant mechanisms, simultaneous blockade of multiple targets may yield better therapeutic efficacy than inhibition of a single target. However, developing two separate monoclonal antibodies for clinical use as combination therapy is impractical, owing to regulatory hurdles and cost. Multi-specific, antibody-based molecules have been investigated; however, their therapeutic use has been hampered by poor pharmacokinetics, stability and manufacturing feasibility. Here, we describe a generally applicable model of a dual-specific, tetravalent immunoglobulin G (IgG)-like molecule--termed dual-variable-domain immunoglobulin (DVD-Ig)--that can be engineered from any two monoclonal antibodies while preserving activities of the parental antibodies. This molecule can be efficiently produced from mammalian cells and exhibits good physicochemical and pharmacokinetic properties. Preclinical studies of a DVD-Ig protein in an animal disease model demonstrate its potential for therapeutic application in human diseases.

C. elegans Males Integrate Food Signals and Biological Sex to Modulate State-Dependent Chemosensation and Behavioral Prioritization.

Dynamic integration of internal and external cues is essential for flexible, adaptive behavior. In C. elegans, biological sex and feeding state regulate expression of the food-associated chemoreceptor odr-10, contributing to plasticity in food detection and the decision between feeding and exploration. In adult hermaphrodites, odr-10 expression is high, but in well-fed adult males, odr-10 expression is low, promoting exploratory mate-searching behavior. Food-deprivation transiently activates male odr-10 expression, heightening food sensitivity and reducing food leaving. Here, we identify a neuroendocrine feedback loop that sex-specifically regulates odr-10 in response to food deprivation. In well-fed males, insulin-like (insulin/IGF-1 signaling [IIS]) and transforming growth factor ß (TGF-ß) signaling repress odr-10 expression. Upon food deprivation, odr-10 is directly activated by DAF-16/FoxO, the canonical C. elegans IIS effector. The TGF-ß ligand DAF-7 likely acts upstream of IIS and links feeding to odr-10 only in males, due in part to the male-specific expression of daf-7 in ASJ. Surprisingly, these responses to food deprivation are not triggered by internal metabolic cues but rather by the loss of sensory signals associated with food. When males are starved in the presence of inedible food, they become nutritionally stressed, but odr-10 expression remains low and exploratory behavior is suppressed less than in starved control males. Food signals are detected by a small number of sensory neurons whose activity non-autonomously regulates daf-7 expression, IIS, and odr-10. Thus, adult C. elegans males employ a neuroendocrine feedback loop that integrates food detection and genetic sex to dynamically modulate chemoreceptor expression and influence the feeding-versus-exploration decision.

The Makorin lep-2 and the lncRNA lep-5 regulate lin-28 to schedule sexual maturation of the C. elegans nervous system.

Sexual maturation must occur on a controlled developmental schedule. In mammals, Makorin3 (MKRN3) and the miRNA regulators LIN28A/B are key regulators of this process, but how they act is unclear. In C. elegans, sexual maturation of the nervous system includes the functional remodeling of postmitotic neurons and the onset of adult-specific behaviors. Here, we find that the lin-28-let-7 axis (the 'heterochronic pathway') determines the timing of these events. Upstream of lin-28, the Makorin lep-2 and the lncRNA lep-5 regulate maturation cell-autonomously, indicating that distributed clocks, not a central timer, coordinate sexual differentiation of the C. elegans nervous system. Overexpression of human MKRN3 delays aspects of C. elegans sexual maturation, suggesting the conservation of Makorin function. These studies reveal roles for a Makorin and a lncRNA in timing of sexual differentiation; moreover, they demonstrate deep conservation of the lin-28-let-7 system in controlling the functional maturation of the nervous system.

Development of an in vitro potency bioassay for therapeutic IL-13 antagonists: the A-549 cell bioassay.

Interleukin 13 is a key cytokine that mediates airway hyper-responsiveness and mucus over-production, and several anti-IL-13 therapeutic antibodies are currently in clinical development for the treatment of asthma. Conventional cell-based bioassays for evaluating neutralization potencies of IL-13 antagonists are semi-quantitative or with a low sensitivity. Here, we report the development of a highly sensitive bioassay to assess the potency of IL-13 antagonists using human lung epithelial A-549 cells that produce thymus and activation-regulated chemokine (TARC) in response to IL-13 stimulation. The A-549 cells were responsive to both wild type and a variant form of recombinant human IL-13 in a concentration-dependent manner, with a 16 to 24 h exposure time found to be within the linear portion of the bioassay response range. The Effective Concentration at 50% of the maximal response (ED50) of IL-13 determined for the assay was 1-5 ng/mL. With this level of IL-13, an anti-IL-13 antibody B-B13 yielded an approximate median Inhibitory Concentration (IC50) value of 0.2 nM. Bioassay optimization was performed to achieve best assay condition and sensitivity. Additionally, IL-13 antagonist potency against natural human IL-13 was also investigated in the A-549 cell bioassay.

Estimation of transversely isotropic material properties from magnetic resonance elastography using the optimised virtual fields method.

Magnetic resonance elastography (MRE) has been used to estimate isotropic myocardial stiffness. However, anisotropic stiffness estimates may give insight into structural changes that occur in the myocardium as a result of pathologies such as diastolic heart failure. The virtual fields method (VFM) has been proposed for estimating material stiffness from image data. This study applied the optimised VFM to identify transversely isotropic material properties from both simulated harmonic displacements in a left ventricular (LV) model with a fibre field measured from histology as well as isotropic phantom MRE data. Two material model formulations were implemented, estimating either 3 or 5 material properties. The 3-parameter formulation writes the transversely isotropic constitutive relation in a way that dissociates the bulk modulus from other parameters. Accurate identification of transversely isotropic material properties in the LV model was shown to be dependent on the loading condition applied, amount of Gaussian noise in the signal, and frequency of excitation. Parameter sensitivity values showed that shear moduli are less sensitive to noise than the other parameters. This preliminary investigation showed the feasibility and limitations of using the VFM to identify transversely isotropic material properties from MRE images of a phantom as well as simulated harmonic displacements in an LV geometry.

Cytokine production of CD8+ immune T cells but not of CD4+ T cells from Toxoplasma gondii-infected mice is polarized to a type 1 response following stimulation with tachyzoite-infected macrophages.

To examine whether cytokine production of CD4(+)immune T cells and CD8(+)immune T cells in Toxoplasma gondii-infected mice differ in their responses to infected cells and to soluble antigens of the parasite, we compared the production of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, and IL-10 by the immune T cell populations following in vitro stimulation with tachyzoite-infected macrophages and tachyzoite lysate antigens (TLA). Both CD4(+)and CD8(+)immune T cells produced large amounts of IFN-gamma in response to either infected macrophages or TLA, but the CD4(+)T cells produced greater amounts of the cytokine than did the CD8(+)T cells with both stimulations. Both T cell populations also produced IL-2 after stimulation with infected macrophages, whereas only CD4(+)T cells did when stimulated with TLA. CD4(+)immune T cells also produced large amounts of IL-4 and IL-10 after stimulation with infected macrophages, but CD8(+)T cells did not. These results indicate that CD4(+)immune T cells produce IFN-gamma, IL-2, IL-4, and IL-10 in response to infected macrophages, whereas CD8(+)immune T cells produce predominantly IFN-gamma and IL-2. Since IL-4 and IL-10 could suppress IFN-gamma-mediated protective mechanisms against the parasite, the production of these cytokines by CD4(+)immune T cells in response to infected cells could negatively affect their protective activity in vivo.

Anxiety and stress in the postpartum: is there more to postnatal distress than depression?

BACKGROUND: Postnatal depression has received considerable research and clinical attention, however anxiety and stress in the postpartum has been relatively ignored. Along with the widespread use of the Edinburgh Postnatal Depression Scale (EPDS), depression has become the marker for postnatal maladjustment. Symptoms of anxiety tend to be subsumed within diagnoses of depression, which can result in anxiety being minimized or overlooked in the absence of depression. Some researchers have identified the need to distinguish between postnatal depression and anxiety, and to discern cases where depression and anxiety co-exist. The aim of this study was to assess the prevalence of postnatal distress using the EPDS and the Depression Anxiety Stress Scales (DASS-21). METHOD: As part of a larger cross-sectional study, the EPDS and DASS-21 were administered to a convenience sample of 325 primiparous mothers, who ranged in age from 18 to 44 years (M = 32 years). Recruited through mother's groups and health centres in Melbourne Australia, inclusion was limited to mothers whose babies were aged between 6 weeks and 6 months. Analyses included comparisons between the classifications of women according to the EPDS and the DASS-21, and an exploration of the extent to which the EPDS identified anxious-depressed women. RESULTS: The EPDS identified 80 women (25%) as possibly depressed (using a cut-off of over 9), of which the DASS-21 corroborated 58%. In the total sample, 61 women (19%) were classified by the DASS-21 to be depressed. Using broader criteria for distress, it was revealed by the DASS-21 that a further 33 women (10%) showed symptoms of anxiety and stress without depression. A total of 41 women (13%) had symptoms of anxiety either in isolation or in combination with depression. The DASS-21 identified 7% of the sample as being both anxious and depressed. This at-risk sub-group had higher mean EPDS and DASS-depression scores than their depressed-only counterparts. CONCLUSION: The prevalence of anxiety and stress in the present study points to the importance of assessing postnatal women for broader indicators of psychological morbidity than that of depression alone. The DASS-21 appears to be a useful instrument for this purpose.