Inducing pluripotency in the domestic cat (Felis Catus)

Domestic cats suffer from a range of inherited genetic diseases, many of which display similarities with equivalent human conditions. Developing cellular models for these inherited diseases would enable drug discovery, benefiting feline health and welfare as well as enhancing the potential of cats as relevant animal models for translation to human medicine. Advances in our understanding of these diseases at the cellular level have come from the use of induced pluripotent stem cells (iPSCs). iPSCs are capable of differentiating into derivatives of all three germ layers, therefore overcoming the limitations of primary differentiated cells and the ethical concerns of using embryonic stem cells. No studies however report the generation of iPSCs from domestic cats (fiPSCs). Feline adipose derived fibroblasts were infected with amphotropic retrovirus containing the coding sequences for human Oct4, Sox2, Klf4, cMyc and Nanog. Isolated iPSC clones were expanded on mouse inactivated embryonic fibroblasts in the presence of feline leukaemia inhibitory factor (LIF). Retroviral delivery of human pluripotent genes gave rise to putative fiPSC colonies within 5-7 days. These iPS-like cells required foetal bovine serum and feline LIF for maintenance. Colonies were domed with refractile edges, similar to mouse iPSCs. Immunocytochemistry demonstrated positive staining for stem cell markers: alkaline phosphatase, Oct4, Sox2, Nanog and SSEA1. Cells were negative for SSEA4. Expression of endogenous feline Nanog was confirmed by qPCR. The cells were able to differentiate in vitro into cells representative of the three germ layers. These results confirm the generation of the first induced pluripotent cells from domestic cats. These cells will provide valuable models to study genetic diseases and explore novel therapeutic strategies

Large Animal Models in Regenerative Medicine and Tissue Engineering: To Do or Not to Do

Rapid developments in Regenerative Medicine and Tissue Engineering has witnessed an increasing drive toward clinical translation of breakthrough technologies. However, the progression of promising preclinical data to achieve successful clinical market authorisation remains a bottleneck. One hurdle for progress to the clinic is the transition from small animal research to advanced preclinical studies in large animals to test safety and efficacy of products. Notwithstanding this, to draw meaningful and reliable conclusions from animal experiments it is critical that the species and disease model of choice is relevant to answer the research question as well as the clinical problem. Selecting the most appropriate animal model requires in-depth knowledge of specific species and breeds to ascertain the adequacy of the model and outcome measures that closely mirror the clinical situation. Traditional reductionist approaches in animal experiments, which often do not sufficiently reflect the studied disease, are still the norm and can result in a disconnect in outcomes observed between animal studies and clinical trials. To address these concerns a reconsideration in approach will be required. This should include a stepwise approach using in vitro and ex vivo experiments as well as in silico modeling to minimize the need for in vivo studies for screening and early development studies, followed by large animal models which more closely resemble human disease. Naturally occurring, or spontaneous diseases in large animals remain a largely untapped resource, and given the similarities in pathophysiology to humans they not only allow for studying new treatment strategies but also disease etiology and prevention. Naturally occurring disease models, particularly for longer lived large animal species, allow for studying disorders at an age when the disease is most prevalent. As these diseases are usually also a concern in the chosen veterinary species they would be beneficiaries of newly developed therapies. Improved awareness of the progress in animal models is mutually beneficial for animals, researchers, human and veterinary patients. In this overview we describe advantages and disadvantages of various animal models including domesticated and companion animals used in regenerative medicine and tissue engineering to provide an informed choice of disease-relevant animal models

Lowering of blood pressure after nitrate-rich vegetable consumption is abolished with the co-ingestion of thiocyanate-rich vegetables in healthy normotensive males

A diet rich in vegetables is known to provide cardioprotection. However, it is unclear how the consumption of different vegetables might interact to influence vascular health. This study tested the hypothesis that nitrate-rich vegetable consumption would lower systolic blood pressure but that this effect would be abolished when nitrate-rich and thiocyanate-rich vegetables are co-ingested. On four separate occasions, and in a randomised cross-over design, eleven healthy males reported to the laboratory and consumed a 750 mL vegetable smoothie that was either: low in nitrate (~ 0.3 mmol) and thiocyanate (~ 5 μmol), low in nitrate and high in SCN- (~ 72 μmol), high in nitrate (~ 4 mmol) and low in SCN- and high in nitrate and SCN-. Blood pressure as well as plasma and salivary [thiocyanate], [nitrate] and [nitrite] were assessed before and 3 hours after smoothie consumption. Plasma [nitrate] and [nitrite] and salivary [nitrate] were not different after consuming the two high-nitrate smoothies, but salivary [nitrite] was higher after consuming the high-nitrate low-thiocyanate smoothie (1183 ± 625 µM) compared to the high-nitrate high-thiocyanate smoothie (941 ± 532 µM; P<0.001). Systolic blood pressure was only lowered after consuming the high-nitrate low-thiocyanate smoothie (-3 ± 5 mmHg; P<0.05). The acute consumption of vegetables high in nitrate and low in thiocyanate lowered systolic blood pressure. However, when the same dose of nitrate-rich vegetables was co-ingested with thiocyanate-rich vegetables the increase in salivary [nitrite] was smaller and systolic blood pressure was not lowered. These findings might have implications for optimising dietary guidelines aimed at improving cardiovascular health

Randomized Controlled Trial to Evaluate an Internet‐Based Self‐Management Program in Systemic Sclerosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148240/1/acr23595.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148240/2/acr23595_am.pd

Care in the time of catastrophe: citizenship, community and the ecological imagination

Published without an abstract

Catching Element Formation In The Act

Gamma-ray astronomy explores the most energetic photons in nature to address some of the most pressing puzzles in contemporary astrophysics. It encompasses a wide range of objects and phenomena: stars, supernovae, novae, neutron stars, stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays and relativistic-particle acceleration, and the evolution of galaxies. MeV gamma-rays provide a unique probe of nuclear processes in astronomy, directly measuring radioactive decay, nuclear de-excitation, and positron annihilation. The substantial information carried by gamma-ray photons allows us to see deeper into these objects, the bulk of the power is often emitted at gamma-ray energies, and radioactivity provides a natural physical clock that adds unique information. New science will be driven by time-domain population studies at gamma-ray energies. This science is enabled by next-generation gamma-ray instruments with one to two orders of magnitude better sensitivity, larger sky coverage, and faster cadence than all previous gamma-ray instruments. This transformative capability permits: (a) the accurate identification of the gamma-ray emitting objects and correlations with observations taken at other wavelengths and with other messengers; (b) construction of new gamma-ray maps of the Milky Way and other nearby galaxies where extended regions are distinguished from point sources; and (c) considerable serendipitous science of scarce events -- nearby neutron star mergers, for example. Advances in technology push the performance of new gamma-ray instruments to address a wide set of astrophysical questions.Comment: 14 pages including 3 figure

Effects of self-paced interval and continuous training on health markers in women

This is the final version of the article. Available from Springer Verlag via the DOI in this record.PURPOSE: To compare the effects of self-paced high-intensity interval and continuous cycle training on health markers in premenopausal women. METHODS: Forty-five inactive females were randomised to a high-intensity interval training (HIIT; n = 15), continuous training (CT; n = 15) or an inactive control (CON; n = 15) group. HIIT performed 5 × 5 min sets comprising repetitions of 30-s low-, 20-s moderate- and 10-s high-intensity cycling with 2 min rest between sets. CT completed 50 min of continuous cycling. Training was completed self-paced, 3 times weekly for 12 weeks. RESULTS: Peak oxygen uptake (16 ± 8 and 21 ± 12%), resting heart rate (HR) (-5 ± 9 and -4 ± 7 bpm) and visual and verbal learning improved following HIIT and CT compared to CON (P  0.05). No outcome variable changed in the CON group (P > 0.05). CONCLUSIONS: Twelve weeks of self-paced HIIT and CT were similarly effective at improving cardiorespiratory fitness, resting HR and cognitive function in inactive premenopausal women, whereas blood pressure, submaximal HR, well-being and body mass adaptations were training-type-specific. Both training methods improved established health markers, but the adaptations to HIIT were evoked for a lower time commitment.The study was supported by FIFA-Medical Assessment and Research Centre (F-MARC)

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3&nbsp;years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0&nbsp;years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores &gt;2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores &gt;2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score &gt;2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores &gt;2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores &gt;2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007