Induction of Colonic Aberrant Crypts in Mice by Feeding Apparent N-Nitroso Compounds Derived From Hot Dogs

Nitrite-preserved meats (e.g., hot dogs) may help cause colon cancer because they contain N-nitroso compounds. We tested whether purified hot-dog-derived total apparent N-nitroso compounds (ANC) could induce colonic aberrant crypts, which are putative precursors of colon cancer. We purified ANC precursors in hot dogs and nitrosated them to produce ANC. In preliminary tests, CF1 mice received 1 or 3 i.p. injections of 5mg azoxymethane (AOM)/kg. In Experiments 1 and 2, female A/J mice received ANC in diet. In Experiment 1, ANC dose initially dropped sharply because the ANC precursors had mostly decomposed but, later in Experiment 1 and throughout Experiment 2, ANC remained at 85 nmol/g diet. Mice were killed after 8 (AOM tests) or 17–34 (ANC tests) wk.Median numbers of aberrant crypts in the distal 2 cm of the colon for 1 and 3 AOMinjections, CF1 controls, ANC (Experiment 1), ANC (Experiment 2),and untreated A/J mice were 31, 74, 12, 20, 12, and 5–6, with P < 0.01 for both ANC tests. Experiment 2 showed somewhat increased numbers of colonic mucin-depleted foci in the ANC-treated group. We conclude that hot-dog-derived ANC induced significant numbers of aberrant crypts in the mouse colon

Dimensional accuracy of Electron Beam Melting (EBM) additive manufacture with regard to weight optimized truss structures

The Electron Beam (EBM) additive manufacturing process is well suited to fabricating complex structural designs in Ti–6Al–4V because of the design freedoms it offers combined with strong and consistent material properties. However it has been observed that complications may arise when manufacturing truss-like structures (such as those produced via structural topology optimization) in the form of undersized features on the finished part. The issue appears to affect truss members that are not aligned with the vertical build direction, with an apparent lack of material on the negative surfaces. This effect appears to worsen with a greater angle between the truss member and the build direction, even with the use of support structures. This investigation has characterized and measured the dimensional errors that result from this issue through 3D scanning techniques. Process modifications have then been made which result in significant improvements in dimensional accuracy. This investigation highlights the importance of heat management at features with negative surfaces to yield parts that are dimensionally accurate without introducing excessive internal melt defects in the form of voids and porosity

ANMCO/SIC/SICI-GISE/SICCH Executive Summary of Consensus Document on Risk Stratification in elderly patients with aortic stenosis before surgery or transcatheter aortic valve replacement

Aortic stenosis is one of the most frequent valvular diseases in developed countries, and its impact on public health resources and assistance is increasing. A substantial proportion of elderly people with severe aortic stenosis is not eligible to surgery because of the advanced age, frailty, and multiple co-morbidities. Transcatheter aortic valve implantation (TAVI) enables the treatment of very elderly patients at high or prohibitive surgical risk considered ineligible for surgery and with an acceptable life expectancy. However, a significant percentage of patients die or show no improvement in quality of life (QOL) in the follow-up. In the decision-making process, it is important to determine: (i) whether and how much frailty of the patient influences the risk of procedures; (ii) how the QOL and the individual patient's survival are influenced by aortic valve disease or from other associated conditions; and (iii) whether a geriatric specialist intervention to evaluate and correct frailty or other diseases with their potential or already manifest disabilities can improve the outcome of surgery or TAVI. Consequently, in addition to risk stratification with conventional tools, a number of factors including multi-morbidity, disability, frailty, and cognitive function should be considered, in order to assess the expected benefit of both surgery and TAVI. The pre-operative optimization through a multidisciplinary approach with a Heart Team can counteract the multiple damage (cardiac, neurological, muscular, respiratory, and kidney) that can potentially aggravate the reduced physiological reserves characteristic of frailty. The systematic application in clinical practice of multidimensional assessment instruments of frailty and cognitive function in the screening and the adoption of specific care pathways should facilitate this task

Are We at Risk of Losing the Current Generation of Climate Researchers to Data Science?

Climate model output has progressively increased in size over the past decades and is expected to continue to rise in the future. Consequently, the research time expended by Early Career Researchers (ECRs) on data-intensive activities is displacing the time spent in fostering novel scientific ideas and expanding the frontiers of climate sciences. Here, we highlight an urgent need for a better balance between data-intensive and foundational climate science activities, more open-ended research opportunities that reinforce the scientific freedom of the ECRs, and strong coordinated action to provide infrastructure and resources to the ECRs working in under-resourced environments

Rationale and current perspective for early rhythm control therapy in atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia and an important source for mortality and morbidity on a population level. Despite the clear association between AF and death, stroke, and other cardiovascular events, there is no evidence that rhythm control treatment improves outcome in AF patients. The poor outcome of rhythm control relates to the severity of the atrial substrate for AF not only due to the underlying atrial remodelling process but also due to the poor efficacy and adverse events of the currently available ion-channel antiarrhythmic drugs and ablation techniques. Data suggest, however, an association between sinus rhythm maintenance and improved survival. Hypothetically, sinus rhythm may also lead to a lower risk of stroke and heart failure. The presence of AF, thus, seems one of the modifiable factors associated with death and cardiovascular morbidity in AF patients. Patients with a short history of AF and the underlying heart disease have not been studied before. It is fair to assume that abolishment of AF in these patients is more successful and possibly also safer, which could translate into a prognostic benefit of early rhythm control therapy. Several trials are now investigating whether aggressive early rhythm control therapy can reduce cardiovascular morbidity and mortality and increase maintenance of sinus rhythm. In the present paper we describe the background of these studies and provide some information on their design

The utility of the new generation of humanized mice to study HIV-1 infection: transmission, prevention, pathogenesis, and treatment

Substantial improvements have been made in recent years in the ability to engraft human cells and tissues into immunodeficient mice. The use of human hematopoietic stem cells (HSCs) leads to multi-lineage human hematopoiesis accompanied by production of a variety of human immune cell types. Population of murine primary and secondary lymphoid organs with human cells occurs, and long-term engraftment has been achieved. Engrafted cells are capable of producing human innate and adaptive immune responses, making these models the most physiologically relevant humanized animal models to date. New models have been successfully infected by a variety of strains of Human Immunodeficiency Virus Type 1 (HIV-1), accompanied by virus replication in lymphoid and non-lymphoid organs, including the gut-associated lymphoid tissue, the male and female reproductive tracts, and the brain. Multiple forms of virus-induced pathogenesis are present, and human T cell and antibody responses to HIV-1 are detected. These humanized mice are susceptible to a high rate of rectal and vaginal transmission of HIV-1 across an intact epithelium, indicating the potential to study vaccines and microbicides. Antiviral drugs, siRNAs, and hematopoietic stem cell gene therapy strategies have all been shown to be effective at reducing viral load and preventing or reversing helper T cell loss in humanized mice, indicating that they will serve as an important preclinical model to study new therapeutic modalities. HIV-1 has also been shown to evolve in response to selective pressures in humanized mice, thus showing that the model will be useful to study and/or predict viral evolution in response to drug or immune pressures. The purpose of this review is to summarize the findings reported to date on all new humanized mouse models (those transplanted with human HSCs) in regards to HIV-1 sexual transmission, pathogenesis, anti-HIV-1 immune responses, viral evolution, pre- and post-exposure prophylaxis, and gene therapeutic strategies