Equivalence and Insurance van den Hurk, Arthur
European business organization law review,
03/2024, Volume:
25, Issue:
1
Journal Article
Peer reviewed
Open access
The concept of equivalence is present in various forms in the Solvency II framework, the EU prudential regulatory framework for insurance and reinsurance. While equivalence in Solvency II does not ...grant, or should not be equated to, market access for market participants that make use of the equivalence instruments within Solvency II, equivalence plays an important role in insurance, in particular in the solvency capital calculation at group level, in group supervision and for the recognition of reinsurance under Solvency II. The conclusion can be drawn that equivalence is an essential building block of the current framework. The application of equivalence in the framework and in practice is discussed in this contribution, and while the application might be complex, it is indispensable. At the same time, other mechanisms, either within the Solvency II framework or more broadly at international level, influence the current state and might affect the evolution of equivalence going forward. While, inherently, there is a political component to equivalence as well, the instruments remain firmly based in (detailed) Solvency II rules and are applied accordingly in practice.
Purpose: We developed and phenotyped a pigmented knockout rat model for lecithin retinol acyltransferase (LRAT) using CRISPR/Cas9. The introduced mutation (c.12delA) is based on a patient group ...harboring a homologous homozygous frameshift mutation in the LRAT gene (c.12delC), causing a dysfunctional visual (retinoid) cycle. Methods: The introduced mutation was confirmed by DNA and RNA sequencing. The expression of Lrat was determined on both the RNA and protein level in wildtype and knockout animals using RT-PCR and immunohistochemistry. The retinal structure and function, as well as the visual behavior of the Lrat−/− and control rats, were characterized using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), electroretinography (ERG) and vision-based behavioral assays. Results: Wildtype animals had high Lrat mRNA expression in multiple tissues, including the eye and liver. In contrast, hardly any expression was detected in Lrat−/− animals. LRAT protein was abundantly present in wildtype animals and absent in Lrat−/− animals. Lrat−/− animals showed progressively reduced ERG potentials compared to wildtype controls from two weeks of age onwards. Vison-based behavioral assays confirmed reduced vision. Structural abnormalities, such as overall retinal thinning, were observed in Lrat−/− animals. The retinal thickness in knockout rats was decreased to roughly 80% by four months of age. No functional or structural differences were observed between wildtype and heterozygote animals. Conclusions: Our Lrat−/− rat is a new animal model for retinal dystrophy, especially for the LRAT-subtype of early-onset retinal dystrophies. This model has advantages over the existing mouse models and the RCS rat strain and can be used for translational studies of retinal dystrophies.
The retinal pigment epithelium (RPE) and the adjacent light-sensitive photoreceptors form a single functional unit lining the back of the eye. Both cell layers are essential for normal vision. RPE ...degeneration is usually followed by photoreceptor degeneration and vice versa. There are currently almost no effective therapies available for RPE disorders such as Stargardt disease, specific types of retinitis pigmentosa, and age-related macular degeneration. RPE replacement for these disorders, especially in later stages of the disease, may be one of the most promising future therapies. There is, however, no consensus regarding the optimal RPE source, delivery strategy, or the optimal experimental host in which to test RPE replacement therapy. Multiple RPE sources, delivery methods, and recipient animal models have been investigated, with variable results. So far, a systematic evaluation of the (variables influencing) efficacy of experimental RPE replacement parameters is lacking. Here we investigate the effect of RPE transplantation on vision and vision-based behavior in animal models of retinal degenerated diseases. In addition, we aim to explore the effect of RPE source used for transplantation, the method of intervention, and the animal model which is used.
In this study, we systematically identified all publications concerning transplantation of RPE in experimental animal models targeting the improvement of vision (e.g., outcome measurements related to the morphology or function of the eye). A variety of characteristics, such as species, gender, and age of the animals but also cell type, number of cells, and other intervention characteristics were extracted from all studies. A risk of bias analysis was performed as well. Subsequently, all references describing one of the following outcomes were analyzed in depth in this systematic review: a-, b-, and c-wave amplitudes, vision-based, thickness analyses based on optical coherence tomography (OCT) data, and transplant survival based on scanning laser ophthalmoscopy (SLO) data. Meta-analyses were performed on the a- and b-wave amplitudes from electroretinography (ERG) data as well as data from vision-based behavioral assays.
original research articles met the inclusion criteria after two screening rounds. Overall, most studies were categorized as unclear regarding the risk of bias, because many experimental details were poorly reported. Twenty-three studies reporting one or more of the outcome measures of interest were eligible for either descriptive (thickness analyses based on OCT data;
= 2) or meta-analyses. RPE transplantation significantly increased ERG a-wave (Hedges' g 1.181 (0.471-1.892),
= 6) and b-wave (Hedges' g 1.734 (1.295-2.172),
= 42) amplitudes and improved vision-based behavior (Hedges' g 1.018 (0.826-1.209),
= 96). Subgroup analyses revealed a significantly increased effect of the use of young and adolescent animals compared to adult animals. Moreover, transplanting more cells (in the range of 10
versus in the range of 10
) resulted in a significantly increased effect on vision-based behavior as well. The origin of cells mattered as well. A significantly increased effect was found on vision-based behavior when using ARPE-19 and OpRegen
RPE.
This systematic review shows that RPE transplantation in animal models for retinal degeneration significantly increases a- and b- wave amplitudes and improves vision-related behavior. These effects appear to be more pronounced in young animals, when the number of transplanted cells is larger and when ARPE-19 and OpRegen
RPE cells are used. We further emphasize that there is an urgent need for improving the reporting and methodological quality of animal experiments, to make such studies more comparable.
The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were ...systematically injected with various doses of sodium iodate (SI). After injection, the retinal structure and visual function were non-invasively characterized over time to obtain in-depth data on the suitability of these models for studying experimental therapies for retinal degenerative diseases, such as dry AMD.
SI was injected into the tail vein (i.v.) using a series of doses (0-70 mg/kg) in adolescent C57BL/6J mice and Brown Norway rats. The retinal structure and function were assessed non-invasively at baseline (day 1) and at several time points (1-3, 5, and 10-weeks) post-injection by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and electroretinography (ERG).
After the SI injection, retinal degeneration in mice and rats yielded similar results. The lowest dose (10 mg/kg) resulted in non-detectable structural or functional effects. An injection with 20 mg/kg SI did not result in an evident retinal degeneration as judged from the OCT data. In contrast, the ERG responses were temporarily decreased but returned to baseline within two-weeks. Higher doses (30, 40, 50, and 70 mg/kg) resulted in moderate to severe structural RPE and retinal injury and decreased the ERG amplitudes, indicating visual impairment in both mice and rat strains.
After the SI injections, we observed dose-dependent structural and functional pathological effects on the retinal pigment epithelium (RPE) and retina in the pigmented mouse and rat strains that were used in this study. Similar effects were observed in both species. In particular, a dose of 30 mg/kg seems to be suitable for future studies on developing experimental therapies. These relatively easily induced non-inherited models may serve as useful tools for evaluating novel therapies for RPE-related retinal degenerations, such as AMD.
BACKGROUND
In retrospective studies, it has been shown that differences in storage variables of platelet (PLT) concentrates (PCs) are partially donor dependent. It was our aim to prospectively ...determine the donor effect on PLT quality.
STUDY DESIGN AND METHODS
Based on quality control data of outdated apheresis PCs, male donors were selected with at least one PC with a pH value of more than 7.0 (“good,” n = 6) or one PC with a pH value of less than 6.7 (“poor,” n = 6) on Day 8. These donors donated a PC (Trima Accel, Terumo) and completed a short questionnaire about their health and lifestyle. PCs were stored for 12 days and analyzed at regular intervals for in vitro quality.
RESULTS
Donor characteristics were comparable, except that zero of six good and four of six poor donors reported high blood pressure and/or high cholesterol/fat and/or use of medicines. Lactate production in good PCs was lower than that in poor PCs (0.09 ± 0.03 mmol/day/1011 PLTs vs. 0.13 ± 0.04 mmol/day/1011 PLTs, p < 0.05) resulting in a higher pH from Day 5 onward. At the end of storage, the good PCs showed lower CD62P expression, lower phosphatidylserine exposure, and higher mitochondrial membrane potential. PLT functional properties were only slightly different. Despite having lower pH, the poor PCs also fulfilled European Guidelines during 7‐day storage.
CONCLUSION
Platelet storage performance is consistent when donors are dichotomized as having good or poor storing PLTs. Metabolic differences are perhaps due to different functionality of the mitochondria. More research is needed to establish the underlying causes and the implications for donors and blood products.
Spatio-temporal variation of hydrological processes that have a strong lagged autocorrelation (memory), such as soil moisture, snow accumulation and the antecedent hydro-climatic conditions, ...significantly impact the peaks of flood waves. Ignoring these memory processes leads to biased estimates of floods and high river levels that are sensitive to the occurrence of these compounding hydro-meteorological processes. Here, we investigate the role of memory in hydrological and meteorological systems at different temporal scales for the Rhine basin. We simulate the hydrological regime of the Rhine river basin using a distributed hydrological model (SPHY) forced with 1950–2000 atmospheric conditions from an ensemble simulation with a high resolution (0.11°/12 km) regional climate model (RACMO2). The findings show that meltwater from antecedent anomalous snowfall results in a time shift of the discharge peak. Soil moisture modulates the rainfall-runoff relationship and generates a strong runoff response at high soil moisture levels and buffers the generation of runoff peaks at low levels. Additionally, our results show that meteorological autocorrelation (manifesting itself by the occurrence of clustered precipitation events) has a strong impact on the magnitude of peak discharge. Removing meteorological autocorrelation at time scales longer than five days reduces peak discharge by 80% relative to the reference climate. At time scales longer than 30 days this meteorological autocorrelation loses its significant role in generating high discharge levels.
Oligodinucleotides containing CpG motifs stimulate vertebrate immune cells in vitro, have proven efficacy in murine disease models and are currently being tested in human clinical trials as therapies ...for cancer, allergy, and infectious disease. As there are no known immunostimulatory motifs for veterinary species, the potential of CpG DNA as a veterinary pharmaceutical has not been investigated. Here, optimal CpG motifs for seven veterinary and three laboratory species are described. The preferential recognition of a GTCGTT motif was strongly conserved across two vertebrate phyla, although a GACGTT motif was optimal for inbred strains of mice and rabbits. In a subsequent adjuvanticity trial, the in vitro screening methodology was validated in sheep, representing the first demonstration of CpG DNA efficacy in a veterinary species. These results should provide candidate immunostimulant and therapeutic drugs for veterinary use and enable the testing of CpG DNA in large animal models of human disease.
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