An arteriovenous mock circulatory loop and accompanying bond graph model for in vitro study of peripheral intravascular bioartificial organs.

BACKGROUND: Silicon nanopore membrane-based implantable bioartificial organs are dependent on arteriovenous implantation of a mechanically robust and biocompatible hemofilter. The hemofilter acts as a low-resistance, high-flow network, with blood flow physiology similar to arteriovenous shunts commonly created for hemodialysis access. A mock circulatory loop (MCL) that mimics shunt physiology is an essential tool for refinement and durability testing of arteriovenous implantable bioartificial organs and silicon blood-interfacing membranes. We sought to develop a compact and cost-effective MCL to replicate flow conditions through an arteriovenous shunt and used data from the MCL and swine to inform a bond graph mathematical model of the physical setup. METHODS: Flow physiology through bioartificial organ prototypes was obtained in the MCL and during extracorporeal attachment to swine for biologic comparison. The MCL was tested for stability overtime by measuring pressurewave variability over a 48-h period. Data obtained in vitro and extracorporeally informed creation of a bond graph model of the MCL. RESULTS: The arteriovenous MCL was a cost-effective, portable system that reproduced flow rates and pressures consistent with a pulsatile arteriovenous shunt as measured in swine. MCL performance was stable over prolonged use, providing a cost-effective simulator for enhanced testing of peripherally implanted bioartificial organ prototypes. The corresponding bond graph model recapitulates MCL and animal physiology, offering a tool for further refinement of the MCL system.

Pumping liquid metal at high temperatures up to 1,673 kelvin.

Heat is fundamental to power generation and many industrial processes, and is most useful at high temperatures because it can be converted more efficiently to other types of energy. However, efficient transportation, storage and conversion of heat at extreme temperatures (more than about 1,300 kelvin) is impractical for many applications. Liquid metals can be very effective media for transferring heat at high temperatures, but liquid-metal pumping has been limited by the corrosion of metal infrastructures. Here we demonstrate a ceramic, mechanical pump that can be used to continuously circulate liquid tin at temperatures of around 1,473-1,673 kelvin. Our approach to liquid-metal pumping is enabled by the use of ceramics for the mechanical and sealing components, but owing to the brittle nature of ceramics their use requires careful engineering. Our set-up enables effective heat transfer using a liquid at previously unattainable temperatures, and could be used for thermal storage and transport, electric power production, and chemical or materials processing.

Beyond emergency surgery: redefining acute care surgery.

BACKGROUND: Considerable debate exists regarding the definition, skill set, and training requirements for the new specialty of acute care surgery (ACS). We hypothesized that a patient subset could be identified that requires a level of care beyond general surgical training and justifies creation of this new specialty. MATERIALS AND METHODS: Reviewed patient admissions over 1-y to the only general surgical service at a level I trauma center-staffed by trauma and/or critical care trained physicians. Patients classified as follows: trauma, ACS, emergency general (EGS), or elective surgery. ACS patients are nonelective, nontrauma patients with significantly altered physiology requiring intensive care unit admission and/or specific complex operative interventions. Differences in demographics, hospital course, and outcomes were analyzed. RESULTS: In-patient service evaluated approximately 5500 patients, including 3300 trauma patients. A total of 2152 admissions include 37% trauma, 30% elective, 28% EGS, and 4% ACS. ACS and trauma patients were more likely to require multiple operations (ACS relative risk [RR] = 11.5; trauma RR = 5.7, P < 0.0001), have longer hospital and intensive care unit length of stay, and higher mortality (P < 0.0001). They were less likely to be discharged home (ACS RR = 0.75; trauma RR = 0.67, P < 0.0001) compared with that of the EGS group. EGS and elective patients were most similar to each other in multiple areas. CONCLUSIONS: ACS and EGS patients represent distinct patient cohorts, as reflected by significant differences in critical care needs, likelihood of multiple operations, and need for postdischarge rehabilitation. The skills required to care for ACS patients, including ability to rescue from complications and provide critical care, differ from those required for EGS patients and supports development of ACS training and regionalization of care.

Localized SDF-1α Delivery Increases Pro-Healing Bone Marrow-Derived Cells in the Supraspinatus Muscle Following Severe Rotator Cuff Injury.

To examine how the chemotactic agent stromal cell-derived factor-1alpha (SDF-1α) modulates the unique cellular milieu within rotator cuff muscle following tendon injury, we developed an injectable, heparin-based microparticle platform to locally present SDF-1α within the supraspinatus muscle following severe rotator cuff injury. SDF-1α loaded, degradable, N-desulfated heparin-based microparticles were fabricated, injected into a rat model of severe rotator cuff injury, and were retained for up to 7 days at the site. The resultant inflammatory cell and mesenchymal stem cell populations were analyzed compared to uninjured contralateral controls and, after 7 days, the fold-change in anti-inflammatory, M2-like macrophages (CD11b+CD68+CD163+, 4.3X fold-change) and mesenchymal stem cells (CD29+CD44+CD90+, 3.0X, respectively) was significantly greater in muscles treated with SDF-1α loaded microparticles than unloaded microparticles or injury alone. Our results indicate that SDF-1α loaded microparticles may be a novel approach to shift the cellular composition within the supraspinatus muscle and create a more pro-regenerative milieu, which may provide a platform to improve muscle repair following rotator cuff injury in the future.

Robust Control of a Cable-Driven Soft Exoskeleton Joint for Intrinsic Human-Robot Interaction.

A novel, cable-driven soft joint is presented for use in robotic rehabilitation exoskeletons to provide intrinsic, comfortable human-robot interaction. The torque-displacement characteristics of the soft elastomeric core contained within the joint are modeled. This knowledge is used in conjunction with a dynamic system model to derive a sliding mode controller (SMC) to implement low-level torque control of the joint. The SMC controller is experimentally compared with a baseline feedback-linearised proportional-derivative controller across a range of conditions and shown to be robust to un-modeled disturbances. The torque controller is then tested with six healthy subjects while they perform a selection of activities of daily living, which has validated its range of performance. Finally, a case study with a participant with spastic cerebral palsy is presented to illustrate the potential of both the joint and controller to be used in a physiotherapy setting to assist clinical populations.

Robotic assessment of neuromuscular characteristics using musculoskeletal models: A pilot study.

OBJECTIVE: Non-invasive neuromuscular characterization aims to provide greater insight into the effectiveness of existing and emerging rehabilitation therapies by quantifying neuromuscular characteristics relating to force production, muscle viscoelasticity and voluntary neural activation. In this paper, we propose a novel approach to evaluate neuromuscular characteristics, such as muscle fiber stiffness and viscosity, by combining robotic and HD-sEMG measurements with computational musculoskeletal modeling. This pilot study investigates the efficacy of this approach on a healthy population and provides new insight on potential limitations of conventional musculoskeletal models for this application. METHODS: Subject-specific neuromuscular characteristics of the biceps and triceps brachii were evaluated using robot-measured kinetics, kinematics and EMG activity as inputs to a musculoskeletal model. RESULTS: Repeatability experiments in five participants revealed large variability within each subjects evaluated characteristics, with almost all experiencing variation greater than 50% of full scale when repeating the same task. CONCLUSION: The use of robotics and HD-sEMG, in conjunction with musculoskeletal modeling, to quantify neuromuscular characteristics has been explored. Despite the ability to predict joint kinematics with relatively high accuracy, parameter characterization was inconsistent i.e. many parameter combinations gave rise to minimal kinematic error. SIGNIFICANCE: The proposed technique is a novel approach for in vivo neuromuscular characterization and is a step towards the realization of objective in-home robot-assisted rehabilitation. Importantly, the results have confirmed the technical (robot and HD-sEMG) feasibility while highlighting the need to develop new musculoskeletal models and optimization techniques capable of achieving consistent results across a range of dynamic tasks.

Predicting tumor responses to mitomycin C on the basis of DT-diaphorase activity or drug metabolism by tumor homogenates: implications for enzyme-directed bioreductive drug development.

Mitomycin C (MMC) is a clinically used anticancer drug that is reduced to cytotoxic metabolites by cellular reductases via a process known as bioreductive drug activation. The identification of key enzymes responsible for drug activation has been investigated extensively with the ultimate aim of tailoring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable interest has been centered upon the enzyme DT-diaphorase (DTD) although conflicting reports of good and poor correlations between enzyme activity and response in vitro and in vivo have been published. The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts. DTD levels were measured in 45 human tumor xenografts that had been characterized previously in terms of their sensitivity to MMC in vitro and in vivo (the in vivo response profile to MMC was taken from work published previously). A poor correlation between DTD activity and antitumor activity in vitro as well as in vivo was obtained. This study also assessed the predictive value of an alternative approach based upon the ability of tumor homogenates to metabolize MMC. This approach is based on the premise that the overall rate of MMC metabolism may provide a better indicator of response than single enzyme measurements. MMC metabolism was evaluated in tumor homogenates (clarified by centrifugation at 1000 x g for 1 min) by measuring the disappearance of the parent compound by HPLC. In responsive [T/C <10% (T/C defined as the relative size of treated and control tumors)] and resistant (T/C >50%) tumors, the mean half life of MMC was 75+/-48.3 and 280+/-129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005). In conclusion, these results unequivocally demonstrate that response to MMC in vivo cannot be predicted on the basis of DTD activity. Measurement of MMC metabolism by tumor homogenates on the other hand may provide a better indicator of tumor response, and further studies are required to determine whether this approach has real clinical potential in terms of individualizing patient chemotherapy.

Human APC2 localization and allelic imbalance.

A second adenomatous polyposis coli (APC)-like gene, APC2/APCL, was recently described and localized to chromosome 19. We have fine mapped APC2 to a small region of chromosome 19p13.3 containing markers D19S883 and WI-19632, a region commonly lost in a variety of cancers, particularly ovarian cancer. Interphase fluorescence in situ hybridization analysis revealed an APC2 allelic imbalance in 19 of 20 ovarian cancers screened and indicates that APC2 could be a potential tumor suppressor gene in ovarian cancer. When overexpressed in SKOV3 ovarian cancer cells, which express low levels of APC2, exogenous APC2 localized to the Golgi apparatus, actin-containing structures, and occasionally to microtubules. Antibodies against the NH2 terminus of human APC2 show that endogenous APC2 is diffusely distributed in the cytoplasm and colocalizes with both the Golgi apparatus and actin filaments. APC2 remained associated with actin filaments after treatment with the actin-disrupting agent, cytochalasin D. These results suggest that APC2 is involved in actin-associated events and could influence cell motility or adhesion through interaction with actin filaments, as well as functioning independently or in cooperation with APC to down-regulate beta-catenin signaling.

Solvent-dependent precipitation of prion protein.

The misfolded isoform of the prion protein (PrP(Sc)) possesses many unusual physiochemical properties. Previously, we and others reported on the differential partitioning of PrP(Sc) from plasma derived therapeutic proteins during their purification processes. To understand the driving force behind these partitioning differences, we investigated the effects of various solvent conditions on the precipitation of PrP(Sc). In a physiological buffer, PrP(Sc) remained in the supernatant after low speed centrifugation. At pH 5, PrP(Sc) precipitation was nearly complete regardless of the salt content. PrP(Sc) could also be precipitated at pH 8 by adding ethanol, but this precipitation was salt dependent. Based on these observations, an empirical mathematical model was constructed in which the PrP(Sc) precipitation trends were fully described as a function of solvent pH, salt, and ethanol concentration. This model consistently predicted PrP(Sc) partitioning during cold ethanol precipitation steps used in plasma protein purification processes, as shown by experimentally determined distributions of PrP(Sc) and transmissible spongiform encephalopathy (TSE) infectivity. These results indicate that pH, salt, and ethanol content are the major solvent factors determining the precipitation of the infectious PrP(Sc) in these processes and may provide a useful tool for assessing the differential partitioning of PrP(Sc) in a given solvent environment.

The effect of flexor digitorum profundus tendon shortening on jersey finger surgical repair: a cadaveric biomechanical study.

Delayed diagnosis of jersey finger injuries often results in retraction of the flexor digitorum profundus tendon. Current practice recommends limiting tendon advancement to 1 cm in delayed repairs. The purpose of this study was to investigate the biomechanical consequences of tendon shortening on the force required to form a fist. The flexor digitorum profundus muscle was isolated in ten cadaveric forearms and the force required to form a fist was recorded. Simulated jersey finger injuries to the ring finger were then created and repaired. The forces required to pull the fingertips to the palm after serial tendon advancements were measured. There was a near linear increase in the force required for making a fist with shortening up to 2.5 cm. The force required to make a fist should be taken into account when considering the limit of 'safe' tendon shortening in delayed repair of jersey finger injuries.

The role of expectancy and volition in smooth pursuit eye movements.

The most important factor allowing the generation of pursuit eye movements prior to target onset is confidence in the likelihood of imminent target appearance. We show how these anticipatory pursuit responses are essentially ballistic motor primitives and how the signal that drives them in normally defined by stored information concerning target speed, duration and direction. But we also show how static cues may be used to grade the level of these motor primitives 'on-line'. We further demonstrate that, when concatenated, these graded motor primitives can be rapidly combined to form predictive smooth movement trajectories in response to complex multi-ramp sequences.

Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

OBJECTIVES: To test the hypotheses that virtual outreach would reduce offers of hospital follow-up appointments and reduce numbers of medical interventions and investigations, reduce numbers of contacts with the health care system, have a positive impact on patient satisfaction and enablement, and lead to improvements in patient health status. To perform an economic evaluation of virtual outreach. DESIGN: A randomised controlled trial comparing joint teleconsultations between GPs, specialists and patients with standard outpatient referral. It was accompanied by an economic evaluation. SETTING: The trial was centred on the Royal Free Hampstead NHS Trust, London, and the Royal Shrewsbury Hospital Trust in Shropshire. The project teams recruited and trained a total of 134 GPs from 29 practices and 20 consultant specialists. PARTICIPANTS: In total, 3170 patients were referred, of whom 2094 consented to participate in the study and were eligible for inclusion. In all, 1051 patients were randomised to the virtual outreach group and 1043 to standard outpatient appointments. The patients were followed 6 months after their index consultation. INTERVENTIONS: Patients randomised to virtual outreach underwent a joint teleconsultation, in which they attended the general practice surgery where they and their GP consulted with a hospital specialist via a videolink between the hospital and the practice. MAIN OUTCOME MEASURES: Outcome measures included offers of follow-up outpatient appointments, numbers of tests, investigations, procedures, treatments and contacts with primary and secondary care, patient satisfaction (Ware Specific Visit Questionnaire), enablement (Patient Enablement Instrument) and quality of life (Short Form-12 and Child Health Questionnaire). An economic evaluation of the costs and consequences of the intervention was undertaken. Sensitivity analysis was used to test the robustness of the results. RESULTS: Patients in the virtual outreach group were more likely to be offered a follow-up appointment. Significant differences in effects were observed between the two sites and across different specialities. Virtual outreach increased the offers of follow-up appointments more in Shrewsbury than in London, and more in ENT and orthopaedics than in the other specialities. Fewer tests and investigations were ordered in the virtual outreach group, by an average of 0.79 per patient. In the 6-month period following the index consultation, there were no significant differences overall in number of contacts with general practice, outpatient visits, accident and emergency contacts, inpatient stays, day surgery and inpatient procedures or prescriptions between the randomised groups. Tests of interaction indicated that virtual outreach decreased the number of tests and investigations, particularly in patients referred to gastroenterology, and increased the number of outpatient visits, particularly in those referred to orthopaedics. Patient satisfaction was greater after a virtual outreach consultation than after a standard outpatient consultation, with no heterogeneity between specialities or sites. However, patient enablement after the index consultation, and the physical and psychological scores of the Short Form-12 for adults and the scores on the Child Health Questionnaire for children under 16, did not differ between the randomised groups at 6 months' follow-up. NHS costs over 6 months were greater for the virtual outreach consultations than for conventional outpatients, pound 724 and pound 625 per patient, respectively. The index consultation accounted for this excess. Cost and time savings to patients were found. Estimated productivity losses were also less in the virtual outreach group. CONCLUSIONS: Virtual outreach consultations result in significantly higher levels of patient satisfaction than standard outpatient appointments and lead to substantial reductions in numbers of tests and investigations, but they are variably associated with increased rates of offer of follow-up according to speciality and site. Changes in costs and technological advances may improve the relative position of virtual consultations in future. The extent to which virtual outreach is implemented will probably be dependent on factors such as patient demand, costs, and the attitudes of staff working in general practice and hospital settings. Further research could involve long-term follow-up of patients in the virtual outreach trial to determine downstream outcomes and costs; further study into the effectiveness and costs of virtual outreach used for follow-up appointments, rather than first-time referrals; and whether the costs of virtual outreach could be substantially reduced without adversely affecting the quality of the consultation if nurses or other members of the primary care team were to undertake the hosting of the joint teleconsultations in place of the GP. Qualitative work into the attitudes of the patients, GPs and hospital specialists would also be valuable.

Volitional selection of direction in the generation of anticipatory ocular smooth pursuit in humans.

Anticipatory smooth pursuit eye movements cannot normally be generated in the absence of a moving target. However, repeated presentation of identical target motion stimuli, preceded by warning cues, leads to the build up of anticipatory smooth pursuit prior to target onset. These anticipatory responses arguably depend more on motor habit than cognitive expectations. Here, we show that directional cues, concomitant with a timing cue, may be used to initiate predictive (velocity scaled) movements in response to target stimuli of random direction. Furthermore, we show stored velocity and timing information may be directionally transferred, thus allowing predictive movements in a novel direction. This demonstrates the internal origin of these movements and their volitional as opposed to reflexive nature.

Education and training of practice nurses.

Seventeen nurses in eight rural general practices participated in a distance education project. Low-cost videoconferencing equipment was assessed for its suitability in two training sessions, concerning asthma and travel immunization. The intended learning outcomes were reached and although initially apprehensive, the nurses quickly became accustomed to the medium. Videoconferencing has now become an accepted part of in-service training. Technical reliability remains the most important problem.

Client perceptions of the polysomnography experience and compliance with therapy.

A grounded theory approach was used to generate theory about clients' perceptions of polysomnography, and the relationships between these perceptions and compliance with therapy. Interviews were conducted with two groups of clients: those who complied with recommended therapy (Continuous Positive Airways Pressure) and those who did not. Compliance with suggested therapy appeared to be related to the degree of benefit derived by the client. In addition, there were problems with the process of diagnosis and follow-up that impacted on client satisfaction and may have influenced their compliance. These findings have highlighted issues which have been used to generate theories that will be tested in future research.

Obesity and symptomatic osteoarthritis of the knee.

Given the growing prevalence of obesity around the world and its association with osteoarthritis of the knee, orthopaedic surgeons need to be familiar with the management of the obese patient with degenerative knee pain. The precise mechanism by which obesity leads to osteoarthritis remains unknown, but is likely to be due to a combination of mechanical, humoral and genetic factors. Weight loss has clear medical benefits for the obese patient and seems to be a logical way of relieving joint pain associated with degenerative arthritis. There are a variety of ways in which this may be done including diet and exercise, and treatment with drugs and bariatric surgery. Whether substantial weight loss can delay or even reverse the symptoms associated with osteoarthritis remains to be seen. Surgery for osteoarthritis in the obese patient can be technically more challenging and carries a risk of additional complications. Substantial weight loss before undertaking total knee replacement is advisable. More prospective studies that evaluate the effect of significant weight loss on the evolution of symptomatic osteoarthritis of the knee are needed so that orthopaedic surgeons can treat this patient group appropriately.

5-Lipoxygenase expression in benign and malignant canine prostate tissues.

5-Lipoxygenase (5-LO) is overexpressed in human prostate carcinomas (PCs), and its inhibition decreases proliferation and induces apoptosis in prostate cancer cell lines. We hypothesized that 5-LO would be overexpressed in canine PC compared with benign prostate tissue and may be important in the pathogenesis of the disease. Immunoblot analysis of canine PC and benign prostatic hyperplasia (BPH) tissues demonstrated 5-LO expression in both. 5-LO immunohistochemical staining was not significantly different within the stromal or epithelial components of canine primary PC, BPH or suppurative prostatitis, suggesting that differential expression of this enzyme does not occur in these conditions. The percentage of tumour cells expressing 5-LO was significantly lower in metastatic PC lesions compared with primary PC (P < 0.0001). This decreased expression may indicate down-regulation or altered expression of the enzyme with progression of canine PC to a metastatic phenotype.