In vivo studies of an implantable energy convertor for skeletal muscle powered cardiac assist

A device that harnesses the mechanical energy of skeletal muscle contracting in a linear configuration has been implanted in goats. This energy convertor transforms muscle work to hydraulic energy that could drive a variety of cardiac assist devices. The device is mounted with a rib clamp and plate affixed to the sternum by cortical bone screws. A transcutaneous hydraulic line carries a silicon based working fluid to an external system that controls the muscle load. In 60 to 70 kg goats, the latissimus dorsi insertion was reattached to the energy convertor. A Telectronics myostimulator with intramuscular electrodes stimulated the latissimus dorsi. In acute implants, hydraulic pressures in excess of 150 psi were obtained. Chronic implantation of the device allowed system evaluation in the conscious unanesthetized animal. Two weeks after implant, hydraulic pressures in excess of 200 psi were obtained and energy transferred to the external loading system exceeded 1 J per contraction. Six weeks after implant, the device continued to cycle freely. These initial results are very promising and suggest an implantable energy convertor is feasible. Development of an energy convertor is an important step toward tether-free skeletal muscle powered cardiac assist devices.     

The effect of prior austenite grain size on the transformation behaviour of C-Mn-Ni weld metal

The influence of prior austenite grain size on the transformation behaviour and microstructural development of C-Mn-Ni weld metals was investigated. It was found that increasing the grain size depressed the start temperature of grain-boundary ferrite and slightly increased the acicular ferrite start temperature. The microstructural products also changed from a boundary-dominated effect in the small grain sizes, to an intragranular-dominated effect in the large grain sizes, and at the same time, the morphology of the acicular ferrite was seen to change to a larger aspect ratio.     

Diverse Fab specific for acetylcholine receptor epitopes from a myasthenia gravis thymus combinatorial library

The muscle weakness in myasthenia gravis (MG) is caused by heterogeneous high-affinity IgG autoantibodies to the nicotinic acetylcholine receptor (AChR), a complex ion channel glycoprotein. These antibodies are clearly responsible for reducing AChR numbers at the neuromuscular junction in myasthenia; however, the origins, diversity, specificity and pathogenicity of individual antibodies have not yet been established. We have cloned and characterized four different AChR-specific Fab from an MG patient's thymus by screening an IgG1/kappa gene combinatorial lambda phage library with soluble human AChR labeled with [125I] alpha-bungarotoxin. Unlike most previously cloned human antibodies, all four Fab immunoprecipitated soluble human muscle AChR. Two Fab strongly inhibited binding of mAb to the main immunogenic region on the alpha subunits and one Fab bound to an epitope on the fetal-specific gamma subunit. In sensitivity and fine specificity, these Fab resembled the anti-AChR antibodies found in many MG patients, including the donor. The closest germline counterparts for their heavy chains were in VH families 1, 3 and 4; however, there were many differences consistent with an antigen-driven response of diverse B cell clones. The combinatorial approach holds promise for further analysis of human autoantibodies.     

Development of a new 304L austenitic welding consumable containing tungsten

The transformation behaviour and kinetics of a duplex weld metal, in which tungsten was substituted for molybdenum, have been studied at 600, 700 and 800 C. Despite a low carbon level (0.037wt%), the material exhibited exceptional resistance against intermetallic formation during ageing. The Charpy impact toughness at room temperature was consistently superior compared to a standard molybdenum containing 316 weld metal. The results suggest that suitable development of the tungsten-bearing 304 consumable could lead to significant improvements in weld-metal properties.     

Microstructure and phase transformations in duplex 316 submerged arc weld metal,an ageing study at 700° C

The transformation of metastable-ferrite has been studied in two duplex stainless steel weld metals. The kinetics and the nature of the equilibrium phases produced, depend upon the localized microsegregation of chromium and molybdenum to the-ferrite laths in the as-welded state. A transformation model is proposed which suggests that a longer term stability of the-ferrite may be achieved by alterations in the basic 316L composition used for the production of submerged arc weld metals.     

A study on the rate of degradation of the bioabsorbable polymer polyglycolic acid (PGA)

As part of a study to characterise bioabsorbable scaffolds for tissue engineering an investigation has been conducted into the rate of degradation of polyglycolic acid (PGA). This is one of the most commonly used bioabsorbable materials and has been used in sutures since the 60s and more recently in cell scaffolds, drug delivery devices and bone fixation pins. This study looks at the influence that surface-to-volume ratio i.e. thickness of material, has on degradation. By degrading various thicknesses of PGA in a buffer saline solution over 24 days and testing their properties at regular intervals, a knowledge of how surface-to-volume ratio affects degradation was developed. Properties such as weight loss, crystallinity, molecular weight and structural integrity were measured. Results showed that rate of mass loss was dependent on sample thickness but crystallinity, melting point and molecular weight were independent of thickness.     

Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing

Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70–80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner.     

SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration

The challenge of developing gene therapies for genetic forms of blindness is heightened by the heterogeneity of these conditions. However, mechanistic commonalities indicate key pathways that may be targeted in a gene-independent approach. Mitochondrial dysfunction and axon degeneration are common features of many neurodegenerative conditions including retinal degenerations. Here we explore the neuroprotective effect afforded by the absence of sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a prodegenerative NADase, in a rotenone-induced mouse model of retinal ganglion cell loss and visual dysfunction. Sarm1 knockout mice retain visual function after rotenone insult, displaying preservation of photopic negative response following rotenone treatment in addition to significantly higher optokinetic response measurements than wild type mice following rotenone. Protection of spatial vision is sustained over time in both sexes and is accompanied by increased RGC survival and additionally preservation of axonal density in optic nerves of Sarm1^−/− mice insulted with rotenone. Primary fibroblasts extracted from Sarm1^−/− mice demonstrate an increased oxygen consumption rate relative to those from wild type mice, with significantly higher basal, maximal and spare respiratory capacity. Collectively, our data indicate that Sarm1 ablation increases mitochondrial bioenergetics and confers histological and functional protection in vivo in the mouse retina against mitochondrial dysfunction, a hallmark of many neurodegenerative conditions including a variety of ocular disorders.