Sound transmission loss of periodic Mindlin plates with non-uniformly spaced mass attachmentsa).

The sound transmission loss (STL) of wall partitions, especially in the coincidence region, is investigated. A Mindlin plate with periodically attached masses in a periodic "supercell" pattern is analyzed theoretically and experimentally for sound attenuation. Modeling the masses as points, analytical expressions for predicting the dispersion relation and frequency bandgaps of the plate are developed. The results show that varying the distances between the masses or the masses themselves can lead to the emergence of additional lower-frequency bandgaps and slightly decrease the bandwidth of the primary complete bandgap. Additionally, a triangular periodic pattern of point masses can provide a larger complete bandgap than the conventional rectangular pattern. The results are validated by numerical analyses using the wave and finite element method. Experimental testing is conducted on large-scale plates (2.4 m × 1 m) with periodically attached masses under diffuse field conditions, demonstrating the benefits of utilizing multiple scattering to increase the STL in the coincidence region of the bare plate. The proposed approach is seen to significantly increase the STL of wall partitions in the coincidence region and provides insights into the fundamental principles of sound and vibration attenuation in complex structures based on multiple scattering.

Optimization of a translational murine model of closed-head traumatic brain injury.

Traumatic brain injury (TBI) from closed-head trauma is a leading cause of disability, with limited effective interventions. Many TBI models impact brain parenchyma directly, and are limited by the fact that these forces do not recapitulate clinically relevant closed head injury. However, applying clinically relevant injury mechanics to the intact skull may lead to variability and as a result, preclinical modeling TBI remains a challenge. Current models often do not explore sex differences in TBI, which is critically important for translation to clinical practice. We systematically investigated sources of variability in a murine model of closed-head TBI and developed a framework to reduce variability across severity and sex. We manipulated pressure, dwell time, and displacement to determine effects on motor coordination, spatial learning, and neuronal damage in 10-week-old male and female mice. Increasing pressure beyond 70 psi had a ceiling effect on cellular and behavioral outcomes, while manipulating dwell time only affected behavioral performance. Increasing displacement precisely graded injury severity in both sexes across all outcomes. Physical signs of trauma occurred more frequently at higher displacements. Stratifying severity based on day-1 rotarod performance retained histological relationships and separated both sexes into injury severity cohorts with distinct patterns of behavioral recovery. Utilizing this stratification strategy, within-group rotarod variability over 6 days post-injury was reduced by 50%. These results have important implications for translational research in TBI and provide a framework for using this clinically relevant translational injury model in both male and female mice.

Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.

The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box-binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulated) in the brain, including several GABAA receptor genes that are notably downregulated. Finally, whole-cell patch clamp analysis reveals a significant reduction in both spontaneous and tonic GABAergic inhibitory responses in Xbp1s-expressing neurons. Taken together, our findings unravel a link between XBP1s signaling and seizure occurrence.

Acoustofluidic separation enables early diagnosis of traumatic brain injury based on circulating exosomes.

Traumatic brain injury (TBI) is a global cause of morbidity and mortality. Initial management and risk stratification of patients with TBI is made difficult by the relative insensitivity of screening radiographic studies as well as by the absence of a widely available, noninvasive diagnostic biomarker. In particular, a blood-based biomarker assay could provide a quick and minimally invasive process to stratify risk and guide early management strategies in patients with mild TBI (mTBI). Analysis of circulating exosomes allows the potential for rapid and specific identification of tissue injury. By applying acoustofluidic exosome separation-which uses a combination of microfluidics and acoustics to separate bioparticles based on differences in size and acoustic properties-we successfully isolated exosomes from plasma samples obtained from mice after TBI. Acoustofluidic isolation eliminated interference from other blood components, making it possible to detect exosomal biomarkers for TBI via flow cytometry. Flow cytometry analysis indicated that exosomal biomarkers for TBI increase in the first 24 h following head trauma, indicating the potential of using circulating exosomes for the rapid diagnosis of TBI. Elevated levels of TBI biomarkers were only detected in the samples separated via acoustofluidics; no changes were observed in the analysis of the raw plasma sample. This finding demonstrated the necessity of sample purification prior to exosomal biomarker analysis. Since acoustofluidic exosome separation can easily be integrated with downstream analysis methods, it shows great potential for improving early diagnosis and treatment decisions associated with TBI.

Induction of Neurogenesis and Angiogenesis in a Rat Hemisection Spinal Cord Injury Model With Combined Neural Stem Cell, Endothelial Progenitor Cell, and Biomimetic Hydrogel Matrix Therapy.

Acute spinal cord injury is a devastating injury that may lead to loss of independent function. Stem-cell therapies have shown promise; however, a clinically efficacious stem-cell therapy has yet to be developed. Functionally, endothelial progenitor cells induce angiogenesis, and neural stem cells induce neurogenesis. In this study, we explored using a multimodal therapy combining endothelial progenitor cells with neural stem cells encapsulated in a bioactive biomimetic hydrogel matrix to facilitate stem cell-induced neurogenesis and angiogenesis in a rat hemisection spinal cord injury model. DESIGN: Laboratory experimentation. SETTING: University laboratory. SUBJECTS: Female Fischer 344 rats. INTERVENTIONS: Three groups of rats: 1) control, 2) biomimetic hydrogel therapy, and 3) combined neural stem cell, endothelial progenitor cell, biomimetic hydrogel therapy underwent right-sided spinal cord hemisection at T9-T10. The blinded Basso, Beattie, and Bresnahan motor score was obtained weekly; after 4 weeks, observational histologic analysis of the injured spinal cords was completed. MEASUREMENTS AND MAIN RESULTS: Blinded Basso, Beattie, and Bresnahan motor score of the hind limb revealed significantly improved motor function in rats treated with combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy (p < 0.05) compared with the control group. The acellular biomimetic hydrogel group did not demonstrate a significant improvement in motor function compared with the control group. Immunohistochemistry evaluation of the injured spinal cords demonstrated de novo neurogenesis and angiogenesis in the combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy group, whereas, in the control group, a gap or scar was found in the injured spinal cord. CONCLUSIONS: This study demonstrates proof of concept that multimodal therapy with endothelial progenitor cells and neural stem cells combined with a bioactive biomimetic hydrogel can be used to induce de novo CNS tissue in an injured rat spinal cord.

ApoE mimetic improves pathology and memory in a model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by Aß plaques. Current treatments are purely symptomatic despite decades of intensive research interest. Notably, patients with the APOE4 allele are at increased risk for developing AD. One hypothesis regarding the mechanism by which the APOE4 allele might increase AD risk is loss of adaptive function, raising the possibility that the exogenous administration of apoE mimetics would have therapeutic effects. In this study, we utilized a previously characterized murine model of AD containing human APP, PS1 and APOE4TR, the APP/PS1/APOETR mouse. We treated male APP/PS1/APOETR mice with the apoE mimetic CN-105 or vehicle for 40d, beginning either at 14-18 or 25-28 weeks of age. After termination of treatment we tested animals in both Morris water maze and contextual fear conditioning, and examined soluble Aß by biochemistery and Aß deposition in cortex by unbiased stereology. We found that transient treatment with CN-105 for 40d beginning at 14-18 weeks reduced Aß pathology and rescued memory deficits in male APP/PS1/APOETR mice. Notably, delaying treatment onset to 25-28 weeks did not produce as robust an effect. These results suggest CN-105 treatment in a mouse model of AD results in a reduction in AD pathology and improved behavioral outcomes when administered early in the course of disease. As CN-105 has an excellent safety profile and is already in clinical trials, these findings raise the possibility that CN-105 represents a novel and translatable therapeutic strategy for AD.

Implementation of Continuous Video-Electroencephalography at a Community Hospital Enhances Care and Reduces Costs.

BACKGROUND: Despite data indicating the importance of continuous video-electroencephalography (cvEEG) monitoring, adoption has been slow outside major academic centers. Barriers to adoption include the need for technologists, equipment, and cvEEG readers. Advancements in lower-cost lead placement templates and commercial systems with remote review may reduce barriers to allow community centers to implement cvEEG. Here, we report our experience, lessons learned, and financial impact of implementing a community hospital cvEEG-monitoring program. METHODS: We implemented an adult cvEEG service at Duke Regional Hospital (DRH), a community hospital affiliate, in June of 2012. Lead placement templates were used in the implementation to reduce the impact on technologists by using other bedside providers for EEG initiation. Utilization of the service, study quality, and patient outcomes were tracked over a 3-year period following initiation of service. RESULTS: Service was implemented at essentially no cost. Utilization varied from a number of factors: intensive care unit (ICU) attending awareness, limited willingness of bedside providers to perform lead placement, and variation in practice of the consulting neurologists. A total of 92 studies were performed on 88 patients in the first 3 years of the program, 24 in year one, 27 in year two, and 38 in year three, showing progressive adoption. Seizures were seen in 25 patients (27%), 19 were in status, of which 18 were successfully treated. Transfers to the main hospital, Duke University Medical Center, were prevented for 53 patients, producing an estimated cost savings of $145,750. The retained patients produced a direct contribution margin of about $75,000, and the margin was just over $100,000 for the entire monitored cohort. CONCLUSION: ICU cvEEG service is feasible and practical to implement at the community hospital level. Service was initiated at little to no cost and clearly enhanced care, increased breadth of care, increased ICU census, and reduced transfers. The system allowed for successful management of ICU patients with underlying seizures and eliminated interfacility transfers, producing a savings of $145,750. The savings combined with the retained patient revenue produced a total revenue of over $250,000 with additional revenue in professional services as well. These results suggest expansion of cvEEG monitoring to community ICUs is practical, financially sustainable, improves the level and quality of care, and reduces costs.

Prediction of sound transmission through, and radiation from, panels using a wave and finite element method.

This paper describes the extension of a wave and finite element (WFE) method to the prediction of noise transmission through, and radiation from, infinite panels. The WFE method starts with a conventional finite element model of a small segment of the panel. For a given frequency, the mass and stiffness matrices of the segment are used to form the structural dynamic stiffness matrix. The acoustic responses of the fluids surrounding the structure are modelled analytically. The dynamic stiffness matrix of the segment is post-processed using periodic structure theory, and coupled with those of the fluids. The total dynamic stiffness matrix is used to obtain the response of the medium to an incident acoustic pressure. Excitation of the structure by oblique plane waves and a diffuse sound field are considered. The response to structural excitation and the consequent radiation are determined. Since the size of the WFE model is small, computational times are small. Various example applications are presented to illustrate the approach, including a thin isotropic panel, an antisymmetric, cross-ply sandwich panel and a symmetric panel with an orthotropic core.

Diagnostic Accuracy of Electrographic Seizure Detection by Neurophysiologists and Non-Neurophysiologists in the Adult ICU Using a Panel of Quantitative EEG Trends.

PURPOSE: To evaluate the sensitivity and specificity of a panel of quantitative EEG (qEEG) trends for seizure detection in adult intensive care unit (ICU) patients when reviewed by neurophysiologists and non-neurophysiologists. METHODS: One hour qEEG panels (n = 180) were collected retrospectively from 45 ICU patients and were distributed to 5 neurophysiologists, 7 EEG technologists, and 5 Neuroscience ICU nurses for evaluation of seizures. Each panel consisted of the following qEEG tools, displayed separately for left and right hemisphere electrodes: rhythmicity spectrogram (rhythmic run detection and display; Persyst Inc), color density spectral array, EEG asymmetry index, and amplitude integrated EEG. The reviewers did not have access to the raw EEG data. RESULTS: For the reviewer's ability to detect the presence of seizures on qEEG panels when compared with the gold standard of independent raw EEG review, the sensitivities and specificities are as follows: neurophysiologists 0.87 and 0.61, EEG technologists 0.80 and 0.80, and Neuroscience ICU nurses 0.87 and 0.61, respectively. There was no statistical difference among the three groups regarding sensitivity. CONCLUSIONS: Quantitative EEG display panels are a promising tool to aid detection of seizures by non-neurophysiologists as well as by neurophysiologists. However, even when used as a panel, qEEG trends do not appear to be adequate as the sole method for reviewing continuous EEG data.

Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.

Female sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone's effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury.

Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice.

The human APOE4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Apolipoprotein E is secreted as part of a high-density lipoprotein-like particle by glial cells in the brain for the primary purpose of transport of lipophilic compounds involved in the maintenance of synapses. Previous studies examining synaptic integrity in the amygdala of human apoE targeted replacement (TR) mice showed a decrease in spontaneous excitatory synaptic activity, dendritic arbor, and spine density associated with apoE4 compared with apoE3 and apoE2 in adult male mice. In the present study, we assessed how APOE genotype affects synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in human apoE3, E4, and E2/4 TR mice at the age of 18-20 months. In contrast to adult mice, we found that aged apoE4 TR mice exhibited the highest level of excitatory synaptic activity compared with other cohorts. Additionally, apoE4 mice had significantly greater spontaneous inhibitory activity than all other cohorts. Taken together, there was a significant interaction between genotypes when comparing inhibition relative to excitation; there was a simple main effect of frequency type with an imbalance toward inhibition in apoE4 mice but not in apoE3 or apoE2/4 mice. These results suggest that apoE isoforms differentially influence synaptic transmission throughout the life span, where aging coupled with apoE4 expression, results in an imbalance in maintaining integrity of synaptic transmission.

A wave finite element analysis of the passive cochlea.

Current models of the cochlea can be characterized as being either based on the assumed propagation of a single slow wave, which provides good insight, or involve the solution of a numerical model, such as in the finite element method, which allows the incorporation of more detailed anatomical features. In this paper it is shown how the wave finite element method can be used to decompose the results of a finite element calculation in terms of wave components, which allows the insight of the wave approach to be brought to bear on more complicated numerical models. In order to illustrate the method, a simple box model is considered, of a passive, locally reacting, basilar membrane interacting via three-dimensional fluid coupling. An analytic formulation of the dispersion equation is used initially to illustrate the types of wave one would expect in such a model. The wave finite element is then used to calculate the wavenumbers of all the waves in the finite element model. It is shown that only a single wave type dominates the response until this peaks at the best place in the cochlea, where an evanescent, higher order fluid wave can make a significant contribution.

Estrogen metabolism within the lung and its modulation by tobacco smoke.

Although estrogen and the enzymes responsible for its metabolism have been detected within the lung, the ability of this tissue to metabolize estrogen has not been demonstrated previously. The goal of this study was to characterize the profile of estrogen metabolites within the murine lung and to determine the effect of tobacco smoke exposure on metabolite levels. Use of liquid chromatography-tandem mass spectrometry led to the detection of three estrogens (E1, E2 and E3) and five estrogen metabolites (2-OHE1, 4-OHE1, 4-OHE2, 2-OMeE1 and 2-OMeE2) within the perfused lung, with 4-OHE1 being the most abundant species. Levels of 4-OHEs, carcinogenic derivatives produced primarily by cytochrome P450 1B1 (Cyp1b1), were 2-fold higher in females than males. Deletion of Cyp1b1 in females led to a dramatic reduction (21-fold) in 4-OHEs, whereas levels of 2-OHE1 and the putative protective estrogen metabolite 2-OMeE2 were increased (2.4- and 5.0-fold, respectively) (P = 0.01). Similar quantitative differences in estrogen metabolite levels were observed between Cyp1b1 null and wild-type males. Exposure of female mice to tobacco smoke for 8 weeks (2h per day, 5 days per week) increased the levels of 4-OHE1 (4-fold) and 2-OHE2 (2-fold) within the lung while reducing the total concentration of 2-OMeEs to 70% of those of unexposed controls. These data suggest that tobacco smoke accelerates the production of 4-OHEs within the lung; carcinogenic metabolites that could potentially contribute to lung tumor development. Thus, inhibition of CYP1B1 may represent a promising strategy for the prevention and treatment of lung cancer.

Slow motor neuron stimulation of locust skeletal muscle: model and measurement.

The isometric force response of the locust hind leg extensor tibia muscle to stimulation of a slow extensor tibia motor neuron is experimentally investigated, and a mathematical model describing the response presented. The measured force response was modelled by considering the ability of an existing model, developed to describe the response to the stimulation of a fast extensor tibia motor neuron and to also model the response to slow motor neuron stimulation. It is found that despite large differences in the force response to slow and fast motor neuron stimulation, which could be accounted for by the differing physiology of the fibres they innervate, the model is able to describe the response to both fast and slow motor neuron stimulation. Thus, the presented model provides a potentially generally applicable, robust, simple model to describe the isometric force response of a range of muscles.

Wave motion and dispersion phenomena: veering, locking and strong coupling effects.

The dispersion curves describe wave propagation in a structure, each branch representing a wave mode. As frequency varies the wavenumbers change and a number of dispersion phenomena may occur. This paper characterizes, analyzes, and quantifies these phenomena in general terms and illustrates them with examples. Two classes of phenomena occur. Weak coupling phenomena-veering and locking-arise when branches of the dispersion curves interact. These occur in the vicinity of the frequency at which, for undamped waveguides, the dispersion curves in the uncoupled waveguides would cross: if two dispersion curves (representing either propagating or evanescent waves) come close together as frequency increases then the curves either veer apart or lock together, forming a pair of attenuating oscillatory waves, which may later unlock into a pair of either propagating or evanescent waves. Which phenomenon occurs depends on the product of the gradients of the dispersion curves. The wave mode shapes which describe the deformation of the structure under the passage of a wave change rapidly around this critical frequency. These phenomena also occur in damped systems unless the levels of damping of the uncoupled waveguides are sufficiently different. Other phenomena can be attributed to strong coupling effects, where arbitrarily light stiffness or gyroscopic coupling changes the qualitative nature of the dispersion curves.

Interaction between sex and apolipoprotein e genetic background in a murine model of intracerebral hemorrhage.

Emerging evidence suggests sex and apolipoprotein E (APOE) genotype separately modify outcomes after intracerebral hemorrhage (ICH). We test the hypothesis that an interaction exists between sex and APOE polymorphism in modifying outcomes after ICH and is altered by administration of exogenous apoE-mimetic peptide. To define the effects of sex and APOE polymorphism in ICH, we created collagenase-induced ICH in male and female APOETR mice (targeted replacement mice homozygous for APOE3 or APOE4 alleles; n=12/group) and assessed performance on Rotarod (RR) and Morris water maze (MWM). To evaluate hematoma formation, we used hematoxylin and eosin staining at 24 h after injury (n=8/group). Using separate cohorts (n=12/group), apoE-mimetic peptide (COG1410 at 2 mg/kg) was administered after ICH, and mice were assessed by RR and MWM. Female mice outperformed male mice via RR and MWM by over 190% improvement through 7 days (RR) and 32 days (MWM) of testing after ICH (p<0.01). Female APOE3TR mice demonstrated improved function compared with all other groups (p<0.05) without any difference in hematoma volume at 24 h after injury in any group. Administration of a therapeutic apoE-mimetic peptide improved RR latencies through 7 days after ICH in male and female APOE4TR mice and MWM latencies over days 28-32 after ICH in male APOE4TR mice (p<0.05). Sex and APOE polymorphism influence functional outcomes in our murine model of ICH. Moreover, administration of exogenous apoE-mimetic peptide after injury differentially modifies the interaction between sex and APOE polymorphism.

A comparison of models of the isometric force of locust skeletal muscle in response to pulse train inputs.

Muscle models are an important tool in the development of new rehabilitation and diagnostic techniques. Many models have been proposed in the past, but little work has been done on comparing the performance of models. In this paper, seven models that describe the isometric force response to pulse train inputs are investigated. Five of the models are from the literature while two new models are also presented. Models are compared in terms of their ability to fit to isometric force data, using Akaike's and Bayesian information criteria and by examining the ability of each model to describe the underlying behaviour in response to individual pulses. Experimental data were collected by stimulating the locust extensor tibia muscle and measuring the force generated at the tibia. Parameters in each model were estimated by minimising the error between the modelled and actual force response for a set of training data. A separate set of test data, which included physiological kick-type data, was used to assess the models. It was found that a linear model performed the worst whereas a new model was found to perform the best. The parameter sensitivity of this new model was investigated using a one-at-a-time approach, and it found that the force response is not particularly sensitive to changes in any parameter.

Subject-specific musculoskeletal parameters of wrist flexors and extensors estimated by an EMG-driven musculoskeletal model.

An EMG-driven musculoskeletal model is implemented to estimate subject-specific musculoskeletal parameters such as the optimal physiological muscle length, the tendon slack length and the maximum isometric muscle force of flexor and extensor muscle groups crossing the wrist, as well as biomechanical indexes to quantify the muscle operating range, the stiffness of the musculotendon actuators, and the contribution of the muscle fibres to the joint moment. Twelve healthy subjects (11 males and 1 female, mean age 31.1±8.7 years) were instructed to perform isometric maximum voluntary contractions of wrist flexors and extensors. Recorded EMGs were used as input to the model and the root mean square error (RMSE) between measured and predicted torque was minimised to estimate the subject-specific musculotendon parameters. The model was validated and the RMSE and the normalised RMSE calculated during estimation and validation phases are compared. Estimated subject-specific musculoskeletal parameters vary in a physiological range, while the biomechanical indexes are in agreement with previously published data. The proposed methodology proved to be effective for the in vivo estimation of physiological parameters of the musculotendon complex and has potential as an investigative tool to distinguish aetiological differences among subjects affected by musculoskeletal disorders.

Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid ß (Aß) peptides, Aß1-40 (Aß40) and Aß1-42 (Aß42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Aß, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterol-enriched diet) presents with Aß-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function. Strikingly, these electroretinographic deficits are abrogated in a dose-dependent manner by systemic administration of an antibody targeting the C termini of Aß40 and Aß42. Concomitant reduction in the levels of Aß and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-Aß40/42 antibody immunotherapy and visual protection. These observations are consistent with the reduction in amyloid plaques and improvement of cognitive function in mouse models of Alzheimer's disease treated with anti-Aß antibodies. They also implicate Aß in the pathogenesis of AMD and identify Aß as a viable therapeutic target for its treatment.

Modelling the isometric force response to multiple pulse stimuli in locust skeletal muscle.

An improved model of locust skeletal muscle will inform on the general behaviour of invertebrate and mammalian muscle with the eventual aim of improving biomedical models of human muscles, embracing prosthetic construction and muscle therapy. In this article, the isometric response of the locust hind leg extensor muscle to input pulse trains is investigated. Experimental data was collected by stimulating the muscle directly and measuring the force at the tibia. The responses to constant frequency stimulus trains of various frequencies and number of pulses were decomposed into the response to each individual stimulus. Each individual pulse response was then fitted to a model, it being assumed that the response to each pulse could be approximated as an impulse response and was linear, no assumption were made about the model order. When the interpulse frequency (IPF) was low and the number of pulses in the train small, a second-order model provided a good fit to each pulse. For moderate IPF or for long pulse trains a linear third-order model provided a better fit to the response to each pulse. The fit using a second-order model deteriorated with increasing IPF. When the input comprised higher IPFs with a large number of pulses the assumptions that the response was linear could not be confirmed. A generalised model is also presented. This model is second-order, and contains two nonlinear terms. The model is able to capture the force response to a range of inputs. This includes cases where the input comprised of higher frequency pulse trains and the assumption of quasi-linear behaviour could not be confirmed.