Summary
Drug‐induced photosensitivity, the development of phototoxic or photoallergic reactions due to pharmaceuticals and subsequent exposure to ultraviolet or visible light, is an adverse effect of ...growing interest. This is illustrated by the broad spectrum of recent investigations on the topic, ranging from molecular mechanisms and culprit drugs through epidemiological as well as public health related issues to long‐term photoaging and potential photocarcinogenic consequences. The present review summarizes the current state of knowledge on the topic while focusing on culprit drugs and long‐term effects. In total, 393 different drugs or drug compounds are reported to have a photosensitizing potential, although the level of evidence regarding their ability to induce photosensitive reactions varies markedly among these agents. The pharmaceuticals of interest belong to a wide variety of drug classes. The epidemiological risk associated with the use of photosensitizers is difficult to assess due to under‐reporting and geographical differences. However, the widespread use of photosensitizing drugs combined with the potential photocarcinogenic effects reported for several agents has major implications for health and safety and suggests a need for further research on the long‐term effects.
Pluripotent stem cells (PSCs) hold great potential for novel therapeutic approaches to regenerate or replace functionally impaired tissues. Since the introduction of the induced pluripotent stem cell ...technology in 2006, the number of scientific publications on this topic has constantly been increasing. However, so far no therapy based on PSCs has found its way into routine clinical use. In this study, we examined research trends related to clinical trials involving PSCs based on data obtained from ClinicalTrials.gov, the ICTRP database from the World Health Organization, as well as from a search of all individual databases that are included in the ICTRP using a multistep search algorithm. Following a stringent inclusion/exclusion procedure 131 studies remained that could be classified as clinical trials involving PSCs. The magnitude of these studies (77.1%) was observational, which implies that no cells were transplanted into patients, and only a minority of studies (22.9%) were of an interventional study type. The number of clinical trials involving induced pluripotent stem cells (iPSCs, 74.8%) was substantially higher than the one involving embryonic stem cells (ESCs, 25.2%). However, the picture changes completely when focusing on interventional studies, where in the majority (73.3%) of cases ESCs were used. Interestingly, also the study duration was significantly shorter for interventional versus observational trials (
= 0.002). When focusing on the geographical study regions, it became obvious that the greatest part of all observational trials was performed in the USA (41.6%) and in France (16.8%), while the magnitude of interventional studies was performed in Asian countries (China 36.7%, Japan 13.3%, South Korea 10.0%) and in the field of ophthalmology. In summary, these results indicate that only a limited number of trials were focusing on the actual transplantation of PSCs into patients in a rather narrow field of diagnoses. The future will tell us, if the iPSC technology will ultimately overcome the current challenges and will finally make its way into routine clinical use.
•In-situ neutron tomography experiments on heated concrete are used for the first time in this paper to support the results (temperature and 3D moisture distribution) of a fully coupled ...thermo-hydro-mechanical model.•The influence of the experimental boundary condition on the moisture distribution is explored.•A 3D mesoscale extension of the model taking into account explicitly the concrete components (aggregates, cementitious matrix etc.) is proposed.
The exposure of concrete to fire, which often leads to spalling, is a phenomenon that is not yet fully understood. Given the complexity of the thermo-hydro-mechanical phenomena and their strong interaction, a combined numerical-experimental approach is indispensable for understanding the behaviour of concrete at high temperature with respect to spalling. This paper deals with the numerical modeling of moisture distribution in heated concrete, a parameter often linked with spalling, by making use of original experimental data from in-situ neutron tomography. A homogenized continuum model has been employed for investigating various aspects, such as: speed of the drying front, moisture accumulation behind this front, experimental boundary effects etc. In addition, a fully coupled 3D thermo-hydo-mechanical (THM) model on the mesoscale is presented and used for simulating an experiment with a single aggregate for the purpose of investigating the influence of the aggregate on the drying front.
Spalling, which is a phenomenon encountered when high-performance concrete is exposed to high temperature, can lead to large economical damage and can be a major safety hazard. Moisture distribution ...in concrete during exposure to fire is of paramount importance for understanding the complex mechanism of this phenomenon. To capture in its fullness this mechanism, it is crucial to account for the heterogeneous nature of concrete.
In this paper, the first 3D analysis of moisture distribution in concrete at high temperature through in-situ neutron tomography is presented. The world-leading flux at the Institute Laue Langevin in Grenoble, France allowed capturing one 3D scan per minute, which is sufficient to follow the fast dehydration process. The paper describes the experimental setup with the heating system and discusses in detail the framework of the neutron tomography test. Quantitative analysis showing the effect of the aggregate size on the moisture distribution is presented.
The antibody light chain (LC) consists of two domains and is essential for antigen binding in mature immunoglobulins. The two domains are connected by a highly conserved linker that comprises the ...structurally important Arg108 residue. In antibody light chain (AL) amyloidosis, a severe protein amyloid disease, the LC and its N-terminal variable domain (VL) convert to fibrils deposited in the tissues causing organ failure. Understanding the factors shaping the architecture of the LC is important for basic science, biotechnology and for deciphering the principles that lead to fibril formation. In this study, we examined the structure and properties of LC variants with a mutated or extended linker. We show that under destabilizing conditions, the linker modulates the amyloidogenicity of the LC. The fibril formation propensity of LC linker variants and their susceptibility to proteolysis directly correlate implying an interplay between the two LC domains. Using NMR and residual dipolar coupling-based simulations, we found that the linker residue Arg108 is a key factor regulating the relative orientation of the VL and CL domains, keeping them in a bent and dense, but still flexible conformation. Thus, inter-domain contacts and the relative orientation of VL and CL to each other are of major importance for maintaining the structural integrity of the full-length LC.
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•Antibody light chains exhibit properties different from the two constituent domains.•The orientation of the two domains is regulated by the connecting linker.•Amyloid formation of variants of the variable domain is inhibited in the light chain.•The stability of the domains is affected in the context of the light chain.•Particularly, the linker residue Arg108 is of special importance.
Objectives This study sought to evaluate long-term in vivo functionality, host cell repopulation, and remodeling of “off-the-shelf” tissue engineered transcatheter homologous heart valves. Background ...Transcatheter valve implantation has emerged as a valid alternative to conventional surgery, in particular for elderly high-risk patients. However, currently used bioprosthetic transcatheter valves are prone to progressive dysfunctional degeneration, limiting their use in younger patients. To overcome these limitations, the concept of tissue engineered heart valves with self-repair capacity has been introduced as next-generation technology. Methods In vivo functionality, host cell repopulation, and matrix remodeling of homologous transcatheter tissue-engineered heart valves (TEHVs) was evaluated up to 24 weeks as pulmonary valve replacements (transapical access) in sheep (n = 12). As a control, tissue composition and structure were analyzed in identical not implanted TEHVs (n = 5). Results Transcatheter implantation was successful in all animals. Valve functionality was excellent displaying sufficient leaflet motion and coaptation with only minor paravalvular leakage in some animals. Mild central regurgitation was detected after 8 weeks, increasing to moderate after 24 weeks, correlating to a compromised leaflet coaptation. Mean and peak transvalvular pressure gradients were 4.4 ± 1.6 mm Hg and 9.7 ± 3.0 mm Hg, respectively. Significant matrix remodeling was observed in the entire valve and corresponded with the rate of host cell repopulation. Conclusions For the first time, the feasibility and long-term functionality of transcatheter-based homologous off-the-shelf tissue engineered heart valves are demonstrated in a relevant pre-clinical model. Such engineered heart valves may represent an interesting alternative to current prostheses because of their rapid cellular repopulation, tissue remodeling, and therewith self-repair capacity. The concept of homologous off-the-shelf tissue engineered heart valves may therefore substantially simplify previous tissue engineering concepts toward clinical translation.
Abstract Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous ...donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control – representing currently used homografts – dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs.
Natural frequencies and damping ratios are important parameters in the design of footbridges against vibrations. Although not normally considered in calculations, non-structural elements such as the ...asphalt pavement and the supports can have a significant influence on the dynamic properties. In this article we present results from vibration tests conducted on four footbridges over the last few years covering a wide range of asphalt temperatures. The experiments show that both the natural frequencies and the damping ratios can change significantly with temperature. In one particular case, a variation in natural frequency of 25% has been observed between high and low asphalt temperatures. An additional damping of around 1% due to the asphalt pavement has been detected. To more clearly understand the experimental results, the bridges were also analysed numerically using a visco-elastic material for the asphalt. The analysis of the experimental results also revealed that other non-structural elements can have a large influence on dynamic properties of bridges. In two cases, the supports did not perform as expected and lead to surprising results.
Martorell hypertensive ischaemic leg ulcer (Martorell HYTILU) is a rare but significant cause of distal leg ulcers. Although hypertension and diabetes are known factors in its development, the ...precise pathogenesis of Martorell HYTILU remains elusive. To reach a better understanding of Martorell HYTILU, transcriptomic analysis was conducted through RNA sequencing and immunohistochemical comparison of Martorell HYTILU (n = 17) with chronic venous ulcers (n = 4) and healthy skin (n = 4). Gene expression analysis showed a marked activation of immune-related pathways in both Martorell HYTILU and chronic venous ulcers compared with healthy skin. Notably, neutrophil activity was substantially higher in Martorell HYTILU. While pathway analysis revealed a mild downregulation of several immune pathways in Martorell HYTILU compared with chronic venous ulcers, keratinization, cornification, and epidermis development were significantly upregulated in Martorell HYTILU. Additionally, STAC2, a gene encoding for a protein promoting the expression of the calcium channel Cav1.1, was significantly upregulated in Martorell HYTILU and was detected perivascularly in situ (Martorell HYTILU n = 24; chronic venous ulcers n = 9, healthy skin n = 11). The high expression of STAC2 in Martorell HYTILU suggests that increased calcium influx plays an important role in the pathogenesis of the disease. Consequently, calcium channel antagonists could be a promising treatment avenue for Martorell HYTILU.
The Histopathology of Leg Ulcers Hofmann, Amun Georg; Deinsberger, Julia; Oszwald, André ...
Dermatopathology (Basel, Switzerland),
03/2024, Letnik:
11, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Ulcerations of the lower extremities are a frequently encountered problem in clinical practice and are of significant interest in public health due to the high prevalence of underlying pathologies, ...including chronic venous disease, diabetes and peripheral arterial occlusive disease. However, leg ulcers can also present as signs and symptoms of various rare diseases and even as an adverse reaction to drugs. In such cases, correct diagnosis ultimately relies on histopathological examination. Apart from the macroscopic presentation, patient history and anatomic location, which are sometimes indicative, most ulcers have very distinct histopathological features. These features are found in different layers of the skin or even associated vessels. In this narrative review, we discuss and highlight the histopathological differences of several types of leg ulcers that can contribute to efficient and accurate diagnosis.
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