Scallop Theorem and Swimming at the Mesoscale.

By comparing theoretical modeling, simulations, and experiments, we show that there exists a swimming regime at low Reynolds numbers solely driven by the inertia of the swimmer itself. This is demonstrated by considering a dumbbell with an asymmetry in coasting time in its two spheres. Despite deforming in a reciprocal fashion, the dumbbell swims by generating a nonreciprocal Stokesian flow, which arises from the asymmetry in coasting times. This asymmetry acts as a second degree of freedom, which allows the scallop theorem to be fulfilled at the mesoscopic scale.

The Impact of Rate Formulations on Stochastic Molecular Motor Dynamics.

Cells are complex structures which require considerable amounts of organization via transport of large intracellular cargo. While passive diffusion is often sufficiently fast for the transport of smaller cargo, active transport is necessary to organize large structures on the short timescales necessary for biological function. The main mechanism of this transport is by cargo attachment to motors which walk in a directed fashion along intracellular filaments. There are a number of models which seek to describe the motion of motors with attached cargo, from detailed microscopic to coarse phenomenological descriptions. We focus on the intermediate-detailed discrete stochastic hopping models, and explore how cargo transport changes depending on the number of motors, motor interaction, system constraints and rate formulations, which are derived from common thermodynamic assumptions. We find that, despite obeying the same detailed balance constraint, the choice of rate formulation considerably affects the characteristics of the overall motion of the system, with one rate formulation exhibiting novel behavior of loaded motor groups moving faster than a single unloaded motor.

Effects of pair bonding on parental behavior and dopamine activity in the nucleus accumbens in male prairie voles.

Male parental care is a vital behavior for the development as well as the physical and mental well-being of the young. However, little is known about the neurochemical regulation of male parental behavior, mainly due to the lack of appropriate animal models. In this study, we used the socially monogamous male prairie vole (Microtus ochrogaster) to investigate the effect of pair-bonding experience on paternal behavior and dopamine (DA) signaling in the nucleus accumbens (NAcc) in the brain. We compared sexually naïve males with males that were pair bonded with a female for two weeks. Our data showed that pair-bonded males displayed enhanced paternal behavior, particularly in pup licking/grooming, associated with increased DA type-1 receptor (D1R) protein expression in the NAcc, compared to sexually naïve males. Site-specific brain microdialysis revealed a significant, but transient, increase in DA release in the NAcc associated with pup exposure in both groups of the males. Further, pharmacological blockade of D1R in the NAcc decreased pup licking/grooming in the pair-bonded males. Together, our data demonstrate that pair-bonding experience with a female facilitated male parental behavior via NAcc D1R mediation in male prairie voles.

Aerogel Cherenkov detector for characterizing the intense flash x-ray source, Cygnus, spectrum.

An aerogel Cherenkov detector is proposed to measure the X-ray energy spectrum from the Cygnus-intense flash X-ray source operated at the Nevada National Security Site. An array of aerogels set at a variety of thresholds between 1 and 3 MeV will be adequate to map out the bremsstrahlung X-ray production of the Cygnus, where the maximum energy of the spectrum is normally around 2.5 MeV. In addition to the Cherenkov radiation from aerogels, one possible competing light-production mechanism is optical transition radiation (OTR), which may be significant in aerogels due to the large number of transitions from SiO2 clusters to vacuum voids. To examine whether OTR is a problem, four aerogel samples were tested using a mono-energetic electron beam (varied in the range of 1-3 MeV) at NSTec Los Alamos Operations. It was demonstrated that aerogels can be used as a Cherenkov medium, where the rate of the light production is about two orders magnitude higher when the electron beam energy is above threshold.

Targeted activation of the hippocampal CA2 area strongly enhances social memory.

Social cognition enables individuals to understand others' intentions. Social memory is a necessary component of this process, for without it, subsequent encounters are devoid of any historical information. The CA2 area of the hippocampus, particularly the vasopressin 1b receptor (Avpr1b) expressed there, is necessary for memory formation. We used optogenetics to excite vasopressin terminals, originating from the hypothalamic paraventricular nucleus, in the CA2 of mice. This markedly enhanced their social memory if the stimulation occurred during memory acquisition, but not retrieval. This effect was blocked by an Avpr1b antagonist. Finally, this enhanced memory is resistant to the social distraction of an introduced second mouse, important for socially navigating populations of individuals. Our results indicate the CA2 can increase the salience of social signals. Targeted pharmacotherapy with Avpr1b agonists or deep brain stimulation of the CA2 are potential avenues of treatment for those with declining social memory as in various dementias.

Measuring fast stochastic displacements of bio-membranes with dynamic optical displacement spectroscopy.

Stochastic displacements or fluctuations of biological membranes are increasingly recognized as an important aspect of many physiological processes, but hitherto their precise quantification in living cells was limited due to a lack of tools to accurately record them. Here we introduce a novel technique--dynamic optical displacement spectroscopy (DODS), to measure stochastic displacements of membranes with unprecedented combined spatiotemporal resolution of 20 nm and 10 µs. The technique was validated by measuring bending fluctuations of model membranes. DODS was then used to explore the fluctuations in human red blood cells, which showed an ATP-induced enhancement of non-Gaussian behaviour. Plasma membrane fluctuations of human macrophages were quantified to this accuracy for the first time. Stimulation with a cytokine enhanced non-Gaussian contributions to these fluctuations. Simplicity of implementation, and high accuracy make DODS a promising tool for comprehensive understanding of stochastic membrane processes.

Mechanistic investigation of adult myotube response to exercise and drug treatment in vitro using a multiplexed functional assay system.

The ability to accurately measure skeletal muscle functional performance at the single-cell level would be advantageous for exercise physiology studies and disease modeling applications. To that end, this study characterizes the functional response of individual skeletal muscle myotubes derived from adult rodent tissue to creatine treatment and chronic exercise. The observed improvements to functional performance in response to these treatments appear to correlate with alterations in hypertrophic and mitochondrial biogenesis pathways, supporting previously published in vivo and in vitro data, which highlights the role of these pathways in augmenting skeletal muscle output. The developed system represents a multiplexed functional in vitro assay capable of long-term assessment of contractile cellular outputs in real-time that is compatible with concomitant molecular biology analysis. Adoption of this system in drug toxicity and efficacy studies would improve understanding of compound activity on physical cellular outputs and provide more streamlined and predictive data for future preclinical analyses.

A multiplexed chip-based assay system for investigating the functional development of human skeletal myotubes in vitro.

This report details the development of a non-invasive in vitro assay system for investigating the functional maturation and performance of human skeletal myotubes. Data is presented demonstrating the survival and differentiation of human myotubes on microscale silicon cantilevers in a defined, serum-free system. These cultures can be stimulated electrically and the resulting contraction quantified using modified atomic force microscopy technology. This system provides a higher degree of sensitivity for investigating contractile waveforms than video-based analysis, and represents the first system capable of measuring the contractile activity of individual human muscle myotubes in a reliable, high-throughput and non-invasive manner. The development of such a technique is critical for the advancement of body-on-a-chip platforms toward application in pre-clinical drug development screens.

Breaking bonds in male prairie vole: long-term effects on emotional and social behavior, physiology, and neurochemistry.

Social relationships are essential for many fundamental aspects of life while bond disruption can be detrimental to mental and physical health. Male prairie voles form enduring social bonds with their female partners, allowing the evaluation of partner loss on behavior, physiology, and neurochemistry. Males were evaluated for partner preference formation induced by 24h of mating, and half were separated from their partner for 4 wk. In Experiment 1, partner loss significantly increased anxiety-like behaviors in the elevated plus maze and light-dark box tests and marginally increased depressive-like behaviors in the forced swim test. In addition, while intruder-directed aggression is common in pair bonded prairie voles, separated males were affiliative and lacked aggression toward an unfamiliar female and an intruding male conspecific. Partner loss increased the density of oxytocin-immunoreactivity (-ir), vasopressin-ir, and corticotrophin-releasing hormone-ir cells in the paraventricular nucleus of the hypothalamus and oxytocin-ir cells in the supraoptic nucleus. Tyrosine hydroxylase-ir was not affected. In Experiment 2, partner preference was observed after 2 wk of partner loss but eliminated after 4 wk partner loss. Body weight gain and plasma corticosterone concentrations were elevated throughout the 4 wk. No effects were observed for plasma oxytocin or vasopressin. Together, partner loss elicits anxiety-like and depression-like behaviors, disrupts bond-related behaviors, and alters neuropeptide systems that regulate such behaviors. Thus, partner loss in male prairie voles may provide a model to better understand the behavior, pathology, and neurobiology underlying partner loss and grief.

Correlation of embryonic skeletal muscle myotube physical characteristics with contractile force generation on an atomic force microscope-based bio-microelectromechanical systems device.

Rigorous analysis of muscle function in in vitro systems is needed for both acute and chronic biomedical applications. Forces generated by skeletal myotubes on bio-microelectromechanical cantilevers were calculated using a modified version of Stoney's thin-film equation and finite element analysis (FEA), then analyzed for regression to physical parameters. The Stoney's equation results closely matched the more intensive FEA and the force correlated to cross-sectional area (CSA). Normalizing force to measured CSA significantly improved the statistical sensitivity and now allows for close comparison of in vitro data to in vivo measurements for applications in exercise physiology, robotics, and modeling neuromuscular diseases.

A functional system for high-content screening of neuromuscular junctions in vitro.

High-content phenotypic screening systems are the logical extension of the current efficient, yet low information content, pre-clinical screens for drug discovery. A physiologically accurate in vitro neuromuscular junction (NMJ) screening system would therefore be of tremendous benefit to the study of peripheral neuropathies as well as for basic and applied neuromuscular research. To date, no fully-defined, selective assay system has been developed which would allow investigators to determine the functional output of cultured muscle fibers (myotubes) when stimulated via the NMJ in real time for both acute and chronic applications. Here we present the development of such a phenotypic screening model, along with evidence of NMJ formation and motoneuron initiated neuromuscular transmission in an automated system. Myotubes assembled on silicon cantilevers allowed for measurement of substrate deflection in response to contraction and provided the basis for monitoring the effect of controlled motoneuron stimulation on the contractile behavior. The effect was blocked by treatment with D-tubocurarine, confirming NMJ functionality in this highly multiplexed assay system.

Application of a computerized language lateralization index from FMRI by a group of clinical neuroradiologists.

BACKGROUND AND PURPOSE: Deriving accurate language lateralization from fMRI studies in the clinical context can be difficult, with 10%-20% incorrect conclusions. Most interpretations are qualitative, performed by neuroimaging experts. Quantitative lateralization has been widely described but with little implementation in the clinical setting and is disadvantaged by the use of arbitrary threshold techniques. We investigated the application and utility of a nonthreshold CLI, in a clinical setting, as applied by a group of practicing neuroradiologists. MATERIALS AND METHODS: Twenty-two patients with known language lateralization (11 left and 11 nonleft dominant) had their images reviewed by 8 neuroradiologists in 2 settings, all randomized, once by using a CLI and once without using a CLI. For each review, neuroradiologists recorded their impressions of lateralization for each language sequence, the overall lateralization conclusion, their impression of scan quality and noise, and the subjective confidence in their conclusion. RESULTS: The inter-rater κ for lateralization was 0.64, which increased to 0.70 with the use of CLI. The group accuracy of overall lateralization was 78%, which increased to 81% with the use of a CLI. Using a CLI removed 2 instances of significant errors, with a neuroradiologist's impression of left lateralization in a patient with known right lateralization. Using a CLI had no effect on examinations with conclusions formed with either high confidence or no confidence. CONCLUSIONS: Although the overall clinical benefit of a CLI is modest, the most significant impact is to reduce the most harmful misclassification errors, particularly in fMRI examinations that are suboptimal.

Characterization and optimization of a simple, repeatable system for the long term in vitro culture of aligned myotubes in 3D.

Increased recent research activity in exercise physiology has dramatically improved our understanding of skeletal muscle development and physiology in both health and disease. Advances in bioengineering have enabled the development of biomimetic 3D in vitro models of skeletal muscle which have the potential to further advance our understanding of the fundamental processes that underpin muscle physiology. As the principle structural protein of the extracellular matrix, collagen-based matrices are popular tools for the creation of such 3D models but the custom nature of many reported systems has precluded their more widespread adoption. Here we present a simple, reproducible iteration of an established 3D in vitro model of skeletal muscle, demonstrating both the high levels of reproducibility possible in this system and the improved cellular architecture of such constructs over standard 2D cell culture techniques. We have used primary rat muscle cells to validate this simple model and generate comparable data to conventional established cell culture techniques. We have optimized culture parameters for these cells which should provide a template in this 3D system for using muscle cells derived from other donor species and cell lines.

Effect of a prescan patient-radiologist encounter on functional MR image quality.

BACKGROUND AND PURPOSE: A substantial number of clinical fMRI examinations inadequately assess language localization or lateralization, usually due to patient movement and suboptimal participation. We hypothesized that a prescan interview of the patient by the radiologist would reduce the fraction of nondiagnostic scans. MATERIALS AND METHODS: A single noise score for each acquisition was produced from time-series data on the basis of a weighted sum of 22 factors. Scores were recorded as the following quartiles: 0-5 = excellent, 5-10 = adequate, 10-15= marginal, and >15 = unacceptable. This measure was evaluated for 202 consecutive fMRI patients: 96 without and 106 with a physician prescan interview. The data were analyzed to compute the fraction of all nondiagnostic sequences and entire studies and were compared between the 2 groups. Image-noise characteristics included the SDs of linear and angular displacements of the head and the number of time-series outliers caused by focal motion. RESULTS: Of 999 sequences acquired, 539 had a prescan interview. The mean noise score significantly decreased for both individual sequence (from 7.9 to 6.3, P = <.001) and study-based (from 7.7 to 6.2, P = .05) methods. The fraction of sequences or studies scored as unacceptable decreased for sequence-based (from 15.2% to 10.9%, P = .04) and study-based (from 9.4% to 1.9%, P = .02) analyses. SDs of head motion decreased for linear (by 12%-14%, P < .01) and angular displacement (by 38%-48%, P < .001). The number of time-series spikes decreased by 10% (P = .004). CONCLUSIONS: We report that a prescan physician-patient interview modestly but significantly reduces fMRI noise scores. These results support the newly added billable costs of professional intervention before fMRI scans.

A randomised controlled trial of subcutaneous sodium salicylate therapy for osteoarthritis of the thumb.

BACKGROUND: Current treatment for osteoarthritis (OA) is limited. Many patients with OA of the hand have areas of tender subcutaneous thickening in the forearm and upper scapular region. A pilot study showed an improvement in pain from OA at the first carpometacarpal joint after injection of such areas with 0.5% sodium salicylate or saline, an inexpensive treatment that can be administered by general practitioners and nurses. The study indicated that a randomised, sham-controlled trial was justified. METHODS: 40 patients with OA of the first carpometacarpal joint were randomised to receive either injections of sodium salicylate into tender, thickened areas of subcutaneous tissue on the forearm (baseline) and upper scapular region (week 1) or sham injections consisting of pressure without skin penetration. Blinded assessments were made at weeks 3, 7 and 13 after baseline. RESULTS: Pain and tenderness during follow-up were both significantly lower in the active treatment group compared with the sham group: 19% and 14% greater reduction in mean visual analogue scale (VAS) score, respectively (p=0.007 and 0.02, baseline mean 5.65 and 5.35 cm, average difference in change from baseline VAS 1.9 and 1.4 cm, 95% CI 0.6 to 3.2 and 0.2 to 2.5). Active and sham injections were painful, the former significantly more so; however, there was no significant correlation between the pain of active injections and response. CONCLUSION: The data show that subcutaneous sodium salicylate injections are an effective symptomatic treatment for OA of the thumb. The results provide a basis for further physiological and therapeutic research in this area.

The effect of cell density on the maturation and contractile ability of muscle derived cells in a 3D tissue-engineered skeletal muscle model and determination of the cellular and mechanical stimuli required for the synthesis of a postural phenotype.

The successful engineering of a truly biomimetic model of skeletal muscle could have a significant impact on a number of biomedical disciplines. Although a variety of techniques are currently being developed, there is, as of yet, no widely available and easily reproducible culture system for the synthesis of 3D artificial muscle tissues. In attempting to generate such a model it is essential to optimise any protocol in order to generate a tissue that best represents the in vivo environment. Since the maturation of muscle derived cells in culture is critically dependent on density, a major factor to be addressed in the development of these models is the ideal concentration at which to seed cells in order to generate an optimal response. In studying the effect of cell density on the performance of cells in an established 3D collagen based model of skeletal muscle, we demonstrate that an optimum density does exist in terms of peak force generation and myogenic gene expression data. Greater densities however, lead to the formation of a more physiologically relevant tissue with a phenotype characteristic of slow, postural muscle.

Richter transformation of chronic lymphocytic leukemia presenting as a dural-based non-hodgkin lymphoma mass.

Richter transformation is defined as a diffuse large cell lymphoma, occurring by transformation of chronic lymphocytic leukemia (CLL). We present a 64-year-old man with a history of CLL and a left parieto-occipital transtentorial extra-axial mass. The patient underwent CT and MR imaging, demonstrating a large dural-based mass with extracranial extension, which occluded the left transverse sinus. Biopsy of the mass proved a pathologic diagnosis of diffuse large cell non-Hodgkin lymphoma, consistent with Richter transformation of CLL.

Building a learning community on-line: the first step towards a national virtual learning environment in orthodontics.

Virtual learning environments (VLEs) are attractive solutions for the delivery of education on-line. Orthodontic education online has the potential to alleviate some of the problems caused by increasing demands on academic staff, the impact of the European work time directives and changes in junior doctors' hours. All act to constrain the effective training of orthodontic postgraduates. The design of a VLE is driven by modern concepts in learning and teaching, the structure, content and assessment methods will help determine the range of behaviours any programme hopes to encourage. This paper aims to provide information on how a modular specialist-training programme in the United Kingdom has been developed and enhanced by a VLE.

Which factors influence willingness-to-pay for orthognathic treatment?

The aims of this interview-based questionnaire study were to establish which factors influence willingness-to-pay (WTP) for orthognathic treatment and to compare WTP values, from both members of the general public and orthognathic patients, with the actual cost of treatment, the hypothesis being that the more highly valued the intervention, the higher the WTP value. Data were collected from 88 orthognathic patients and a convenience sample of 100 adults using the so-called 'payment card' method. Demographic data were recorded, as well as ability to pay, incisor relationship, occupation, and level of education. In addition, the resources used in orthognathic treatment were estimated for five patients who participated in the study. The results showed that there was a significant difference between the mean WTP values for the public and patient groups. Patients were prepared to pay [see symbol in tex]2750 more than members of the general public. In addition, a significant relationship was found between WTP and incisor relationship in the patient group, with Class II division 1 patients prepared to pay [see symbol in text]3130 more than those with Class III malocclusions. Ability to pay did not significantly affect WTP. The mean total costs estimated for orthognathic treatment were lower than the mean patient WTP value and similar to the mean WTP value for the public group. In terms of cost-benefit, it appears that orthognathic treatment provides 'good value for money'. This study also showed that both patients and the general public were prepared to place a monetary value on the correction of dentofacial deformity and that this form of economic evaluation is a useful tool in monitoring health care in the UK.