Percutaneous autologous venous valve transplantation: short-term feasibility study in an ovine model

BACKGROUND: Limited experience with bioprosthetic venous valve percutaneously inserted into femoral veins in 15 patients has been promising in short-term results only to show disappointing long-term results. Percutaneous autogenous venous valve (PAVV) transplantation was explored in an ovine model as a possible alternative treatment. METHODS: PAVV consisted of a vein segment containing a valve that was attached to a stent template. The stent templates (n = 9) were designed and hand made in our research laboratory. They consist of two stainless steel square stents 13 or 15 mm in diameter to fit the ovine jugular veins (JV), which ranges from 10 to 15 mm in diameter. A valve-containing segment of JV was harvested and attached with sutures and barbs inside the stent template (n = 9). The valve devices were then manually folded and front loaded inside the 4 cm chamber of the 13F delivery sheath and delivered into the contralateral JV by femoral vein approach. Transplanted PAVVs were studied by immediate and 3 months venograms. Animals were euthanized at 3 months, and jugular veins harvested to perform angioscopic evaluations in vitro. RESULTS: PAVV transplantation was successful in all nine animals. Good valve function with no reflux was observed on immediate and 3 months venograms in eight valves. The transplanted maximal JV diameter ranged from 10.2 mm to 15.4 mm (mean 13.1 +/- 1.5 mm). Venoscopic examination revealed intact, flexible, nonthickened valve leaflets in eight specimens. One PAVV exhibited normal function of one leaflet only; the other cusp was accidentally cut during the transplantation procedure. All transplanted autologous valves were free of thrombus and incorporated into the vein wall of the host vessel. CONCLUSION: This study demonstrated that autogenous valve transplants remained patent and competent without long-term anticoagulation for up to 3 months. The percutaneous autogenous venous valve may provide in future minimally invasive treatment for patients with chronic deep venous insufficiency, but long-term studies need to be done to document its continued patency and function.

Animal model for percutaneous creation of traumatic thoracic aortic transection

PURPOSE: This study was conducted to create an animal model for thoracic aortic transection that is suitable for thoracic endograft research. MATERIALS AND METHODS: Percutaneous aortic transection creation was attempted in 12 sheep. A custom collapsible circumferential cutting device was inserted into the proximal descending thoracic aorta via a femoral approach with an 11-F delivery catheter. The device was deployed 2 cm distal to the left subclavian artery origin and rotated 20 times to create aortic transection. Aortic diameters, mean aortic pressures, and heart rates were tested for degrees of difference between measurements before and after the creation of transection. On necropsy, the extent of aortic damage was classified as none, nontransmural, or transmural, and aortic transection was classified as none, partial, or circumferential. RESULTS: On angiography, creation of transmural thoracic aortic transection was successful in 91.7% (11/12) of animals. Aortic transection was circumferential in 54.4% (6/11) of animals and partial in 45.6% (5/11) of animals. Mean aortic diameter was 19.6 +/- 3.4 mm (range 12-24 mm) pre-transection and 25.8 +/- 4.5 mm (range 17.8-33 mm) post-transection (P = .0003). Pre-transection, mean aortic pressure was 79 +/- 13.8 mmHg, and 64.6 +/- 15.8 mmHg 15 min post-transection (P = .041). Pre-transection, mean heart rate was 94.5 +/- 17.2 beats per minute (bpm), and 105.8 +/- 17.2 bpm 15 min post-transection (P = .0057). CONCLUSIONS: Thoracic aortic transection was successfully created percutaneously in most animals. The animals remained in hemodynamically stable condition for as long as 240 minutes after the creation of aortic injury. This percutaneous animal model is straightforward and may be of potential value for future thoracic endograft research.

Hierarchical Markov Random Fields Applied to Model Soft Tissue Deformations on Graphics Hardware

Many methodologies dealing with prediction or simulation of soft tissue deformations on medical image data require preprocessing of the data in order to produce a different shape representation that complies with standard methodologies, such as mass–spring networks, finite element method s (FEM). On the other hand, methodologies working directly on the image space normally do not take into account mechanical behavior of tissues and tend to lack physics foundations driving soft tissue deformations. This chapter presents a method to simulate soft tissue deformations based on coupled concepts from image analysis and mechanics theory. The proposed methodology is based on a robust stochastic approach that takes into account material properties retrieved directly from the image, concepts from continuum mechanics and FEM. The optimization framework is solved within a hierarchical Markov random field (HMRF) which is implemented on the graphics processor unit (GPU See Graphics processing unit ).

Effect of vascular targeting agent in rat tumor model: dynamic contrast-enhanced versus diffusion-weighted MR imaging

PURPOSE: To compare dynamic contrast material-enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of combretastatin A4 phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADC(low); b = 0, 50, and 100 sec/mm(2)) and high b gradient values (ADC(high); b = 500, 750, and 1000 sec/mm(2)). The difference between ADC(low) and ADC(high) was used as a surrogate measure of tissue perfusion (ADC(low) - ADC(high) = ADC(perf)). From the dynamic contrast-enhanced MR images, the volume transfer constant k and the initial slope of the contrast enhancement-time curve were calculated. For statistical analyses, a paired two-tailed Student t test and linear regression analysis were used. RESULTS: Early after administration of combretastatin, all perfusion-related parameters (k, initial slope, and ADC(perf)) decreased significantly (P < .001); at 9 days after combretastatin administration, they increased significantly (P < .001). Changes in ADC(perf) were correlated with changes in k (R(2) = 0.46, P < .001) and the initial slope (R(2) = 0.67, P < .001). CONCLUSION: Both dynamic contrast-enhanced MR imaging and diffusion-weighted MR imaging allow monitoring of perfusion changes induced by vascular targeting agents in tumors. Diffusion-weighted imaging provides additional information about intratumoral cell viability versus necrosis after administration of combretastatin.

Prediction of residential radon exposure of the whole Swiss population: comparison of model-based predictions with measurement-based predictions

Radon plays an important role for human exposure to natural sources of ionizing radiation. The aim of this article is to compare two approaches to estimate mean radon exposure in the Swiss population: model-based predictions at individual level and measurement-based predictions based on measurements aggregated at municipality level. A nationwide model was used to predict radon levels in each household and for each individual based on the corresponding tectonic unit, building age, building type, soil texture, degree of urbanization, and floor. Measurement-based predictions were carried out within a health impact assessment on residential radon and lung cancer. Mean measured radon levels were corrected for the average floor distribution and weighted with population size of each municipality. Model-based predictions yielded a mean radon exposure of the Swiss population of 84.1 Bq/m(3) . Measurement-based predictions yielded an average exposure of 78 Bq/m(3) . This study demonstrates that the model- and the measurement-based predictions provided similar results. The advantage of the measurement-based approach is its simplicity, which is sufficient for assessing exposure distribution in a population. The model-based approach allows predicting radon levels at specific sites, which is needed in an epidemiological study, and the results do not depend on how the measurement sites have been selected.

Nonviral Gene Delivery of Growth and Differentiation Factor 5 to Human Mesenchymal Stem Cells Injected into a 3D Bovine Intervertebral Disc Organ Culture System

Intervertebral disc (IVD) cell therapy with unconditioned 2D expanded mesenchymal stem cells (MSC) is a promising concept yet challenging to realize. Differentiation of MSCs by nonviral gene delivery of growth and differentiation factor 5 (GDF5) by electroporation mediated gene transfer could be an excellent source for cell transplantation. Human MSCs were harvested from bone marrow aspirate and GDF5 gene transfer was achieved by in vitro electroporation. Transfected cells were cultured as monolayers and as 3D cultures in 1.2% alginate bead culture. MSC expressed GDF5 efficiently for up to 21 days. The combination of GDF5 gene transfer and 3D culture in alginate showed an upregulation of aggrecan and SOX9, two markers for chondrogenesis, and KRT19 as a marker for discogenesis compared to untransfected cells. The cells encapsulated in alginate produced more proteoglycans expressed in GAG/DNA ratio. Furthermore, GDF5 transfected MCS injected into an IVD papain degeneration organ culture model showed a partial recovery of the GAG/DNA ratio after 7 days. In this study we demonstrate the potential of GDF5 transfected MSC as a promising approach for clinical translation for disc regeneration.

What are the implications of changing treatment delivery models for patients with inflammatory bowel disease: a discussion paper.

An integrated model of care has been used effectively to manage chronic diseases; however, there is limited, yet encouraging evidence on its introduction in the management of inflammatory bowel disease (IBD), a chronic gastrointestinal condition. Here, the rationale for and implications of introducing an integrated model of care for patients with IBD are discussed, with a particular focus on psychology input, patient-centred care, efficiency as perceived by patients and doctors, financial implications and the possible means of model introduction. This is a discussion paper on the integrated model of care for IBD against a background of what has been learned from an integrated model of care established in other chronic conditions. Although limited, the emerging data on an integrated model of care in IBD are encouraging with respect to patient outcomes and savings in healthcare costs. In other conditions, the model has been well received by both patients and practitioners, although the loss of autonomy by doctors is listed among its drawbacks. The cost-effectiveness data are now sufficiently convincing to recommend the model's acceptance in principle. The model should be promoted at the policy level rather than by individual practitioners to facilitate equal access for patients with IBD on a larger scale than currently.

Secondary prevention in the clinical management of patients with cardiovascular diseases. Core components, standards and outcome measures for referral and delivery

Despite major improvements in diagnostics and interventional therapies, cardiovascular diseases remain a major health care and socio-economic burden both in western and developing countries, in which this burden is increasing in close correlation to economic growth. Health authorities and the general population have started to recognize that the fight against these diseases can only be won if their burden is faced by increasing our investment on interventions in lifestyle changes and prevention. There is an overwhelming evidence of the efficacy of secondary prevention initiatives including cardiac rehabilitation in terms of reduction in morbidity and mortality. However, secondary prevention is still too poorly implemented in clinical practice, often only on selected populations and over a limited period of time. The development of systematic and full comprehensive preventive programmes is warranted, integrated in the organization of national health systems. Furthermore, systematic monitoring of the process of delivery and outcomes is a necessity. Cardiology and secondary prevention, including cardiac rehabilitation, have evolved almost independently of each other and although each makes a unique contribution it is now time to join forces under the banner of preventive cardiology and create a comprehensive model that optimizes long term outcomes for patients and reduces the future burden on health care services. These are the aims that the Cardiac Rehabilitation Section of the European Association for Cardiovascular Prevention & Rehabilitation has foreseen to promote secondary preventive cardiology in clinical practice.

Impact of epinephrine and norepinephrine on two dynamic indices in a porcine hemorrhagic shock model

Abstract BACKGROUND: Pulse pressure variations (PPVs) and stroke volume variations (SVVs) are dynamic indices for predicting fluid responsiveness in intensive care unit patients. These hemodynamic markers underscore Frank-Starling law by which volume expansion increases cardiac output (CO). The aim of the present study was to evaluate the impact of the administration of catecholamines on PPV, SVV, and inferior vena cava flow (IVCF). METHODS: In this prospective, physiologic, animal study, hemodynamic parameters were measured in deeply sedated and mechanically ventilated pigs. Systemic hemodynamic and pressure-volume loops obtained by inferior vena cava occlusion were recorded. Measurements were collected during two conditions, that is, normovolemia and hypovolemia, generated by blood removal to obtain a mean arterial pressure value lower than 60 mm Hg. At each condition, CO, IVCF, SVV, and PPV were assessed by catheters and flow meters. Data were compared between the conditions normovolemia and hypovolemia before and after intravenous administrations of norepinephrine and epinephrine using a nonparametric Wilcoxon test. RESULTS: Eight pigs were anesthetized, mechanically ventilated, and equipped. Both norepinephrine and epinephrine significantly increased IVCF and decreased PPV and SVV, regardless of volemic conditions (p < 0.05). However, epinephrine was also able to significantly increase CO regardless of volemic conditions. CONCLUSION: The present study demonstrates that intravenous administrations of norepinephrine and epinephrine increase IVCF, whatever the volemic conditions are. The concomitant decreases in PPV and SVV corroborate the fact that catecholamine administration recruits unstressed blood volume. In this regard, understanding a decrease in PPV and SVV values, after catecholamine administration, as an obvious indication of a restored volemia could be an outright misinterpretation.

Preliminary study on carprofen concentration measurements after transcutaneous treatment with Vetdrop® in a microfracture joint defect model in sheep.

BackgroundThe present preliminary study describes concentration time courses of the NSAID carprofen in the plasma and synovial fluid in a microfrature sheep model after transcutaneous treatments with a novel application device (Vetdrop®). To treat circumscribed inflammatory processes a transcutaneous application device could potentially be beneficial. After transcutaneous application normally lower systemic concentrations are measured which may reduce the incidence of side effects, whereas efficacy is still maintained.In this study carprofen was used based on its capacity to provide analgesia after orthopaedic procedures in sheep and it is considered that it may have a positive influence on the healing of cartilage in low concentrations.ResultsIn all transcutaneously treated animals, carprofen plasma concentrations exceeded those of synovial fluid, although plasma levels remained significantly reduced (300-fold) as compared to carprofen administered intravenously. Furthermore, in contrast to the intravenously treated animals, a modest accumulation of carprofen in plasma and synovial fluid was observed in the transcutaneously treated animals over the 6-week treatment period.ConclusionsThe transcutaneously administered carprofen using the Vetdrop® device penetrated the skin and both, plasma- and synovial concentrations could be measured repeatedly over time. This novel device may be considered a valuable transcutaneous drug delivery system.

Complete digital workflow for the production of implant-supported single-unit monolithic crowns.

OBJECTIVES The aim of this case series was to introduce a complete digital workflow for the production of monolithic implant crowns. MATERIAL AND METHODS Six patients were treated with implant-supported crowns made of resin nano ceramic (RNC). Starting with an intraoral optical scan (IOS), and following a CAD/CAM process, the monolithic crowns were bonded either to a novel prefabricated titanium abutment base (group A) or to a CAD/CAM-generated individualized titanium abutment (group B) in premolar or molar sites on a soft tissue level dental implant. Economic analyses included clinical and laboratory steps. An esthetic evaluation was performed to compare the two abutment-crown combinations. RESULTS None of the digitally constructed RNC crowns required any clinical adaptation. Overall mean work time calculations revealed obvious differences for group A (65.3 min) compared with group B (86.5 min). Esthetic analysis demonstrated a more favorable outcome for the prefabricated bonding bases. CONCLUSIONS Prefabricated or individualized abutments on monolithic RNC crowns using CAD/CAM technology in a model-free workflow seem to provide a feasible and streamlined treatment approach for single-edentulous space rehabilitation in the posterior region. However, RNC as full-contour material has to be considered experimental, and further large-scale clinical investigations with long-term follow-up observation are necessary.

Precision of fit of implant-supported screw-retained 10-unit computer-aided-designed and computer-aided-manufactured frameworks made from zirconium dioxide and titanium: an in vitro study

OBJECTIVE To analyze the precision of fit of implant-supported screw-retained computer-aided-designed and computer-aided-manufactured (CAD/CAM) zirconium dioxide (ZrO) frameworks. MATERIALS AND METHODS Computer-aided-designed and computer-aided-manufactured ZrO frameworks (NobelProcera) for a screw-retained 10-unit implant-supported reconstruction on six implants (FDI positions 15, 13, 11, 21, 23, 25) were fabricated using a laser (ZrO-L, N = 6) and a mechanical scanner (ZrO-M, N = 5) for digitizing the implant platform and the cuspid-supporting framework resin pattern. Laser-scanned CAD/CAM titanium (TIT-L, N = 6) and cast CoCrW-alloy frameworks (Cast, N = 5) fabricated on the same model and designed similar to the ZrO frameworks were the control. The one-screw test (implant 25 screw-retained) was applied to assess the vertical microgap between implant and framework platform with a scanning electron microscope. The mean microgap was calculated from approximal and buccal values. Statistical comparison was performed with non-parametric tests. RESULTS No statistically significant pairwise difference was observed between the relative effects of vertical microgap between ZrO-L (median 14 μm; 95% CI 10-26 μm), ZrO-M (18 μm; 12-27 μm) and TIT-L (15 μm; 6-18 μm), whereas the values of Cast (236 μm; 181-301 μm) were significantly higher (P < 0.001) than the three CAD/CAM groups. A monotonous trend of increasing values from implant 23 to 15 was observed in all groups (ZrO-L, ZrO-M and Cast P < 0.001, TIT-L P = 0.044). CONCLUSIONS Optical and tactile scanners with CAD/CAM technology allow for the fabrication of highly accurate long-span screw-retained ZrO implant-reconstructions. Titanium frameworks showed the most consistent precision. Fit of the cast alloy frameworks was clinically inacceptable.

Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.

Towards a new model of care: integrating mental health, substance use, and somatic care

Although research and clinical interventions for patients with dual disorders have been described since as early as the 1980s, the day-to-day treatment of these patients remains problematic and challenging in many countries. Throughout this book, many approaches and possible pathways have been outlined. Based upon these experiences, some key points can be extracted in order to guide to future developments. (1) New diagnostic approaches are warranted when dealing with patients who have multiple problems, given the limitations of the current categorical systems. (2) Greater emphasis should be placed on secondary prevention and early intervention for children and adolescents at an increased risk of later-life dual disorders. (3) Mental, addiction, and somatic care systems can be integrated, adopting a patient-focused approach to care delivery. (4) Recovery should be taken into consideration when defining treatment intervention and outcome goals. (5) It is important to reduce societal risk factors, such as poverty and early childhood adversity. (6) More resources are needed to provide adequate mental health care in the various countries. The development of European guidance initiatives would provide benefits in many of these areas, making it possible to ensure a more harmonized standard of care for patients with dual disorders.

The immunology of the porcine skin and its value as a model for human skin.

The porcine skin has striking similarities to the human skin in terms of general structure, thickness, hair follicle content, pigmentation, collagen and lipid composition. This has been the basis for numerous studies using the pig as a model for wound healing, transdermal delivery, dermal toxicology, radiation and UVB effects. Considering that the skin also represents an immune organ of utmost importance for health, immune cells present in the skin of the pig will be reviewed. The focus of this review is on dendritic cells, which play a central role in the skin immune system as they serve as sentinels in the skin, which offers a large surface area exposed to the environment. Based on a literature review and original data we propose a classification of porcine dendritic cell subsets in the skin corresponding to the subsets described in the human skin. The equivalent of the human CD141(+) DC subset is CD1a(-)CD4(-)CD172a(-)CADM1(high), that of the CD1c(+) subset is CD1a(+)CD4(-)CD172a(+)CADM1(+/low), and porcine plasmacytoid dendritic cells are CD1a(-)CD4(+)CD172a(+)CADM1(-). CD209 and CD14 could represent markers of inflammatory monocyte-derived cells, either dendritic cells or macrophages. Future studies for example using transriptomic analysis of sorted populations are required to confirm the identity of these cells.