Microstructural quantification of collagen fiber orientations and its integration in constitutive modeling of the porcine carotid artery

Background Mechanical characteristics of vascular tissue may play a role in different arterial pathologies, which, amongst others, requires robust constitutive descriptions to capture the vessel wall’s anisotropic and non-linear properties.Specifically, the complex 3D network of collagen and its interaction with other structural elements has a dominating effect of arterial properties at higher stress levels.The aim of this study is to collect quantitative collagen organization as well as mechanical properties to facilitate structural constitutive models for the porcine carotid artery.This helps the understanding of the mechanics of swine carotid arteries, being a standard in clinical hypothesis testing, in endovascular preclinical trials for example. Method Porcine common carotid arteries (n = 10) were harvested and used to (i) characterize the collagen fiber organization with polarized light microscopy, and (ii) the biaxial mechanical properties by inflation testing.The collagen organization was quantified by the Bingham orientation density function (ODF), which in turn was integrated in a structural constitutive model of the vessel wall.A one-layered and thick-walled model was used to estimate mechanical constitutive parameters by least-square fitting the recorded in vitro inflation test results.Finally, uniaxial data published elsewhere were used to validate the mean collagen organization described by the Bingham ODF. Results Thick collagen fibers, i.e.the most mechanically relevant structure, in the common carotid artery are dispersed around the circumferential direction.In addition, almost all samples showed two distinct families of collagen fibers at different elevation, but not azimuthal, angles.Collagen fiber organization could be accurately represented by the Bingham ODF (¿1,2,3=[13.5,0.0,25.2] and ¿1,2,3=[14.7,0.0,26.6]; average error of about 5%), and their integration into a structural constitutive model captured the inflation characteristics of individual carotid artery samples.Specifically, only four mechanical parameters were required to reasonably (average error from 14% to 38%) cover the experimental data over a wide range of axial and circumferential stretches.However, it was critical to account for fibrilar links between thick collagen fibers.Finally, the mean Bingham ODF provide also good approximation to uniaxial experimental data. Conclusions The applied structural constitutive model, based on individually measured collagen orientation densities, was able to capture the biaxial properties of the common carotid artery. Since the model required coupling amongst thick collagen fibers, the collagen fiber orientations measured from polarized light microscopy, alone, seem to be insufficient structural information. Alternatively, a larger dispersion of collagen fiber orientations, that is likely to arise from analyzing larger wall sections, could have had a similar effect, i.e. could have avoided coupling amongst thick collagen fibers.Peer ReviewedPostprint (author's final draft

Retroperitoneoscopic donor nephrectomy: donor outcome and complication rate in comparison with three different techniques

Four surgical techniques for living donor nephrectomy were analyzed retrospectively in terms of perioperative outcome and early complication rate. A total of 182 donor nephrectomies including 69 open (OLDN), 14 fully laparoscopic (LDN), 34 hand-assisted laparoscopic (HLDN) and 65 retroperitoneoscopic (RLDN) nephrectomies were analyzed. There was a significant difference in mean operating time (OPT) between the OLDN (160min) and RLDN (150min) as compared to the LDN (212min) and HLDN group (192min) (P<0.001). Mean warm ischemia time (WIT) was significantly shorter with OLDN (114s), RLDN (121s) and HLDN (128s) when compared to LDN (238s) (P<0.001). Major complication rate was comparable among the groups. Independent of the preferred technique, donor nephrectomy is associated with complication rates. RLDN is comparable to OLDN in terms of OPT, WIT. Learning endoscopic donor nephrectomy could be associated with a higher complication rat

A three dimensional finite element model for arterial clamping

Motivation and Introduction Arterial clamps are chosen to compress arteries during surgery so that blood flow is arrested. Arterial compression, however, may lead to injuries of the vessel wall, which are associated with a variety of severe short-term and long-term complications. For example, clamp induced injuries may cause spontaneous occlusion of the vessel after the operation, which leads to infarction of the downstream tissues. Therefore, surgeons require arterial clamps that allow efficient compression and cause only minimal injury. Severity and distribution of injuries depend on ͑i͒ the arterial type ͓1,2͔, the geometry and the nonlinear and anisotropic material behavior of the clamped multi-layered artery, ͑ii͒ the design of the chosen clamp ͓3-7͔ and ͑iii͒ the applied clamping forces ͓2,6,8,9͔. The optimization of this mechanical problem requires a numerical model, which considers appropriately all decisive factors. Yet, such a model is not available in the literature to date. Appropriate numerical models may lead to substantial improvements of arterial clamp designs, and thus are of potential interest for surgeons and clamp suppliers. In the past the demand for appropriate arterial clamps has led to a great variety of different designs and techniques. A suitable clamp design provides easy handling, good vessel grip and efficient vessel occlusion, and it is aimed to minimize arterial injuries. Clamps are named after their inventors as, for example, Blalock, Cooley, DeBakey, Fogarty, Potts, Satinsky, etc. They are available in different sizes with straight, curved or angled branches. Their jaws may be plain or have spikes, and they may be silicone filled. The existing designs are based on surgical intuition rather than on mechanical considerations. Consequently, the effects of clamping and the suitability of clamp designs have been investigated by means of experimental studies rather than by mechanical analyses. To the authors&apos; knowledge, only ͓10͔ presented a mathematical approach with the goal to determine the minimum vascular occlusive force. However, this simplifying analytical model does not consider the crucial constitutive behavior of arterial walls. Thus, it is incapable of calculating wall stresses. Despite the clinical significance of arterial clamping there are relatively few studies, which are concerned with its local effects. Most of the experimental investigations are animal studies and focus on morphological changes. The observed injuries range from mild damage, which involves only the intima, to severe damage with total disruptions of the media, layer delaminations and even total wall disruptions with associated bleeding. In addition, long-term changes such as stenoses ͓11͔ and intimal hyperplasia-excessive thickening of the intima due to tissue growth ͓1͔-have been observed. Beside structural changes also functional changes of clamped arteries have been investigated, for example, the ability to relax or contract upon application of certain drugs ͓7,8͔ and the ability to inhibit blood clotting ͓12,13͔. The influences of the clamping force ͓2,6,8,9͔ and of the duration of clamping ͓14͔ have been studied. Moreover, comparisons of different types of arteries ͓2͔ and different clamp designs ͓3-7͔ in regard to clamp induced wall injury have been performed. These studies have identified the types and the consequences of clamp induced injuries and thus have demonstrated the importance of proper clamp designs. However, experimental studies are afflicted with a number of disadvantages. They are expensive and time-consuming and it is disputable if results of animal arteries are representative for human arteries. The significance of experimental studies is definitely restricted to the chosen arteries, instruments and clamping conditions. A fundamental shortcoming is that the results of existing experimental studies do not provide insights into the mechanical process of arterial clamping. The latter is determined by the three-dimensional stress-strain distributions in the clamped arterial wall. To overcome these shortcomings we developed a threedimensional finite element model for arterial clamping. The essential approach is to model the artery as a two-layer fiber-reinforced material with the fibers corresponding to the collagenous component of the material. The two layers represent the media ͑the middle layer of the artery͒ and the adventitia ͑the outer layer͒. Th

A homeostatic-driven turnover remodelling constitutive model for healing in soft tissues

Remodelling of soft biological tissue is characterized by interacting biochemical and biomechanical events, which change the tissue's microstructure, and, consequently, its macroscopic mechanical properties. Remodelling is a well-defined stage of the healing process, and aims at recovering or repairing the injured extracellular matrix. Like other physiological processes, remodelling is thought to be driven by homeostasis, i.e. it tends to re-establish the properties of the uninjured tissue. However, homeostasis may never be reached, such that remodelling may also appear as a continuous pathological transformation of diseased tissues during aneurysm expansion, for example. A simple constitutive model for soft biological tissues that regards remodelling as homeostatic-driven turnover is developed. Specifically, the recoverable effective tissue damage, whose rate is the sum of a mechanical damage rate and a healing rate, serves as a scalar internal thermodynamic variable. In order to integrate the biochemical and biomechanical aspects of remodelling, the healing rate is, on the one hand, driven by mechanical stimuli, but, on the other hand, subjected to simple metabolic constraints. The proposed model is formulated in accordance with continuum damage mechanics within an open-system thermodynamics framework. The numerical implementation in an in-house finite-element code is described, particularized for Ogden hyperelasticity. Numerical examples illustrate the basic constitutive characteristics of the model and demonstrate its potential in representing aspects of remodelling of soft tissues. Simulation results are verified for their plausibility, but also validated against reported experimental data.Peer ReviewedPostprint (author's final draft

Retroperitoneoscopy-Assisted Cryoablation of Renal Tumors Using Multiple 1.5 mm Ultrathin Cryoprobes: A Preliminary Report

Abstract Objectives: Laparoscopic cryoablation has recently been proposed as a minimally invasive nephron-sparing treatment for selected patients. We report on our experience with a retroperitoneoscopic technique using multiple ultrathin cryoprobes. Methods: Seven patients underwent retroperitoneoscopic renal cryoablation for solid renal masses. Mean tumor size on the CT scan was 2.6 (1.5-3.5) cm. A double freeze-thaw cycle of renal cryoablation was performed under realtime ultrasound monitoring using a total of six 1.5-mm cryoprobes simultaneously. Results: Cryoablation was technically successful in all patients without any need for conversion. Mean duration of surgery was 161 (130-195) minutes and mean blood loss was 107 (50-250) ml. Perioperative biopsy of the tumor confirmed renal cell carcinoma in four patients and angiomyolipoma in two patients; it was inconclusive in one case. Mean follow-up for 13.6 (4-22) months showed no evidence of residual tumor or recurrence. Conclusions: Retroperitoneoscopy-assisted cryosurgical ablation using multiple ultrathin 1.5-mm cryoprobes is a minimally invasive treatment that is suitable to treat small renal tumors.

Maximum tumor diameter adjusted to the risk profile predicts biochemical recurrence after radical prostatectomy

Currently, no consensus exists on the best method for tumor quantification in prostate cancer (PCA), and its prognostic value remains controversial. We evaluated how a newly defined maximum tumor diameter (MTD) might contribute to the prediction of biochemical recurrence (BCR) in a consecutive series of PCA patients treated with radical prostatectomy (RP). Patients with PCA who underwent RP without neoadjuvant therapy at a single center were included for analysis. MTD was defined as the largest diameter of all identified tumors in all three dimensions (i.e., length, width, or depth) of the prostate ("Basel technique”). Cox regression models addressed the association of MTD with BCR in three risk groups (low risk—prostate-specific antigen (PSA)  20ng/ml or pT3 or GS ≥ 8) and whole cohort. Within a median follow-up of 44months (interquartile range (IQR) 23-66), 48 patients (9.4%) in the intermediate-risk and high-risk groups experienced BCR. In multivariate Cox regression analysis, PSA, pathological stage (pT stage), GS, positive surgical margins (PSMs), and MTD > 19.5mm were independent predictors for BCR (p 24.5mm) was the only independent predictor of BCR in the intermediate-risk group (hazard ratio (HR) 9.933, 95% confidence interval (CI) 2.070-47.665; p < 0.05). MTD is an independent risk factor of BCR in PC patients after RP. The combination of the MTD with other well-known prognostic factors after RP may improve decision-making concerning follow-up intensity or adjuvant treatment

Potential feedbacks between loss of biosphere integrity and climate change

Non-technical abstract Individual organisms on land and in the ocean sequester massive amounts of the carbon emitted into the atmosphere by humans. Yet the role of ecosystems as a whole in modulating this uptake of carbon is less clear. Here, we study several different mechanisms by which climate change and ecosystems could interact. We show that climate change could cause changes in ecosystems that reduce their capacity to take up carbon, further accelerating climate change. More research on – and better governance of – interactions between climate change and ecosystems is urgently required. Technical abstract Individual responses of terrestrial and marine species to future climate change will affect the capacity of the land and ocean to store carbon. How system-level changes in the integrity of the biosphere interact with climate change is more uncertain. Here, we explore the consequences of different hypotheses on the interactions between the climate–carbon system and the integrity of the terrestrial and marine biospheres. We investigate mechanisms including impairment of terrestrial ecosystem functioning due to lagged ecosystem responses, permafrost thaw, terrestrial biodiversity loss and impacts of changes in marine biodiversity on the marine biological pump. To investigate climate–biosphere interactions involving complex concepts such as biosphere integrity, we designed and implemented conceptual representations of these climate–biosphere interactions in a stylized climate–carbon model. We find that all four classes of interactions amplify climate change, potentially contributing up to an additional 0.4°C warming across all representative concentration pathway scenarios by the year 2100 and potentially turning the terrestrial biosphere into a net carbon source, although uncertainties are large. The results of this preliminary quantitative study call for more research on – and better integrated governance of – the interactions between climate change and biosphere integrity, the two core ‘planetary boundaries’.The research leading to these results has received funding from the Stordalen Foundation via the Planetary Boundary Research Network (PB.net), the Earth League’s EarthDoc programme, the Leibniz Association (project DOMINOES), European Research Council Synergy project Imbalance-P (grant ERC-2013-SyG-610028), European Research Council Advanced Investigator project ERA (grant ERC-2016-ADG-743080), Deutsche Forschungsgemeinschaft (DFG BE 6485/1-1), Project Grant 2014-589 from the Swedish Research Council Formas and a core grant to the Stockholm Resilience Centre by Mistra

Comparable Autoantibody Serum Levels against Amyloid- and Inflammation-Associated Proteins in Parkinson’s Disease Patients and Controls

Naturally occurring autoantibodies (NAbs) against a number of potentially disease-associated cellular proteins, including Amyloid-beta1-42 (Abeta1-42), Alpha-synuclein (Asyn), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and S100 calcium binding protein B (S100B) have been suggested to be associated with neurodegenerative disorders, in particular Alzheimer's (AD) and Parkinson's disease (PD). Whereas the (reduced) occurrence of specific NAbs in AD is widely accepted, previous literature examining the relation of these NAb titres between PD patients and controls, as well as comparing these levels with demographic and clinical parameters in PD patients have produced inconsistent findings. We therefore aimed, in a cross-sectional approach, to determine serum titres of the above NAbs in a cohort of 93 PD patients (31 of them demented) and 194 controls. Levels were correlated with demographic and clinical variables, cerebrospinal fluid Abeta1-42, total tau and phospho-tau levels, as well as with single nucleotide polymorphisms (SNPs) of genes which either have been reported to influence the immune system, the amyloid cascade or the occurrence of PD (ApoE, GSK3B, HLA-DRA, HSPA5, SNCA, and STK39). The investigated NAb titres were neither significantly associated with the occurrence of PD, nor with demographic and clinical parameters, neurodegenerative markers or genetic variables. These results argue against a major potential of blood-borne parameters of the adaptive immune system to serve as trait or state markers in PD

Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors

Introduction Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). Materials and Methods IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: 3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. Results PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Discussion Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders