Tachol1 QTL on mouse chromosome 1 is responsible for hypercholesterolemia and diet-induced obesity.

Hypercholesterolemia raises the risk for cardiovascular complications and overall health. Hypercholesterolemia is common, affecting 10% of the general population of the US, and heritable. Most individuals with hypercholesterolemia have a polygenic predisposition to the condition. Previously we identified a quantitative trait locus, Tachol1, linked to hypercholesterolemia on mouse chromosome 1 (Chr1) in a cross between C57BL/6J (B6) and TALLYHO/JngJ (TH) mice, a polygenic model for human obesity, type 2 diabetes and hyperlipidemia. Subsequently, using congenic mice that carry a TH-derived genomic segment of Chr1 on a B6 background, we demonstrated that the distal segment of Chr1, where Tachol1 maps, is necessary to cause hypercholesterolemia, as well as diet-induced obesity. In this study, we generated overlapping subcongenic lines to the distal segment of congenic region and characterized subcongenic mice carrying the smallest TH region of Tachol1, ~ 16.2 Mb in size (B6.TH-Chr1-16.2 Mb). Both male and female B6.TH-Chr1-16.2 Mb mice showed a significantly increased plasma total cholesterol levels compared to B6 on both chow and high fat (HF) diet. B6.TH-Chr1-16.2 Mb mice also had greater fat mass than B6 on HF diet, without increasing food intake. The gene and protein expression levels of absent in melanoma 2 (Aim2) gene were significantly upregulated in B6.TH-Chr1-16.2 Mb mice compared to B6. In summary, we confirmed the effect of Tachol1 on hypercholesterolemia and diet-induced obesity using subcongenic analysis.

Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives.

Introduction: Parathyroid carcinoma (PC) is an extremely rare entity, with a frequency of 0.005% of all malignancies. Most data related to this rare disease are limited to case series and a few database studies. We present a large database study that aims to investigate the demographic, clinical, and pathological factors, prognosis, and survival of PC. Methods: Data of parathyroid carcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) diagnosed between 1975 and 2016. Results: PC had a slightly higher incidence in men (52.2%, p < 0.005), the majority of cases affected Caucasians (75.4%, p < 0.005), and the mean age at diagnosis was 62 years. Histologically, 99.7% were adenocarcinomas not otherwise specified (p < 0.005), well-differentiated (p < 0.005), and 2−4 cm (p < 0.001) in size among the patients with available data. In cases with staging provided, most PC were organ-confined (36.8%, p < 0.001). Lymph nodes were positive in 25.2% of cases where lymph node status was reported. The main treatment modality was surgery (97.2%), followed by radiation alone (2%), and very few received chemotherapy alone (0.8%), p < 0.005. Five-year follow-up was available for 82.7% of the cases. Those who underwent surgery only or radiation alone had 5-year survivals of 83.8% and 72.2%, respectively (p < 0.037). Multivariable analysis identified tumor size >4 cm, age > 40 years, male sex, Caucasian race, distant spread, and poorly differentiated grade as independent risk factors for mortality (p < 0.001). Conclusion: PC is a very rare tumor mostly affecting Caucasian individuals in the fifth decade. Older age, poor histologic differentiation, and distant metastasis are associated with a worse prognosis. Surgical resection offers the best survival outcome. To better understand the pathogenesis and factors affecting survival, all PC patients should be enrolled in national and international registries.

EURADOS STRATEGIC RESEARCH AGENDA 2020: VISION FOR THE DOSIMETRY OF IONISING RADIATION.

Since 2012, the European Radiation Dosimetry Group (EURADOS) has developed its Strategic Research Agenda (SRA), which contributes to the identification of future research needs in radiation dosimetry in Europe. Continued scientific developments in this field necessitate regular updates and, consequently, this paper summarises the latest revision of the SRA, with input regarding the state of the art and vision for the future contributed by EURADOS Working Groups and through a stakeholder workshop. Five visions define key issues in dosimetry research that are considered important over at least the next decade. They include scientific objectives and developments in (i) updated fundamental dose concepts and quantities, (ii) improved radiation risk estimates deduced from epidemiological cohorts, (iii) efficient dose assessment for radiological emergencies, (iv) integrated personalised dosimetry in medical applications and (v) improved radiation protection of workers and the public. This SRA will be used as a guideline for future activities of EURADOS Working Groups but can also be used as guidance for research in radiation dosimetry by the wider community. It will also be used as input for a general European research roadmap for radiation protection, following similar previous contributions to the European Joint Programme for the Integration of Radiation Protection Research, under the Horizon 2020 programme (CONCERT). The full version of the SRA is available as a EURADOS report (www.eurados.org).

Transcriptomically Guided Mesendoderm Induction of Human Pluripotent Stem Cells Using a Systematically Defined Culture Scheme.

Human pluripotent stem cells (hPSCs) are an essential cell source in tissue engineering, studies of development, and disease modeling. Efficient, broadly amenable protocols for rapid lineage induction of hPSCs are of great interest in the stem cell biology field. We describe a simple, robust method for differentiation of hPSCs into mesendoderm in defined conditions utilizing single-cell seeding (SCS) and BMP4 and Activin A (BA) treatment. BA treatment was readily incorporated into existing protocols for chondrogenic and endothelial progenitor cell differentiation, while fine-tuning of BA conditions facilitated definitive endoderm commitment. After prolonged differentiation in vitro or in vivo, BA pretreatment resulted in higher mesoderm and endoderm levels at the expense of ectoderm formation. These data demonstrate that SCS with BA treatment is a powerful method for induction of mesendoderm that can be adapted for use in mesoderm and endoderm differentiation.

A Retrospective Study of the Incidence and Management of Complications Associated With Regional Nerve Blocks in Equine Dental Patients.

Regional anesthesia of the equine head is commonly performed to allow oral extraction of diseased teeth in the standing horse. The use of 4 blocks (infraorbital nerve, maxillary nerve, mental nerve, and mandibular nerve) is well documented for desensitization of dental quadrants for oral surgery for exodontia, but descriptions of associated complications are limited. A total of 270 regional nerve blocks were performed on 162 equine patients in a second opinion referral hospital setting. Criteria for inclusion in the study included a 24-hour stay in hospital, that the blocks be performed by one clinician and at minimum, a 2-week follow-up examination be performed. A total of 8 complications were identified in 7 patients representing a 2.96% incidence of complication. Complications included supraorbital hematoma (3), local hematoma (2), lingual self-trauma (2), and nerve block failure to desensitize (1). Treatment and management of complications are discussed. Complications associated with regional anesthesia may be reduced by reducing anesthetic volumes, precise needle placement, familiarity with the facial anatomy relevant to nerve blocks, adequate restraint, aseptic technique, postprocedural muzzling, and the use of a newly opened bottle of local anesthetic.

Transcatheter Mitral Valve-in-Ring Implantation.

Failed surgical mitral valve repair using an annuloplasty ring has traditionally been treated with surgical valve replacement or repair1. For patients at high risk for repeat open heart surgery, placement of a trans-catheter aortic valve (i.e., TAVI valve) within the mitral ring (i.e., Mitral-Valve-in-Ring, MViR) has emerged as a novel alternative treatment strategy2-5 . We describe our experience of a failed mitral valve repair that was successfully treated with a TAVI valve delivered via the trans-septal approach, and summarise the data relating to this emerging treatment strategy.

Sarcoid of the Upper Humerus Found Incidentally on MR Images Obtained for Work-Up of Rotator Cuff Tear Where Compromised Tissue Quality Was a Concern for Surgical Success.

Sarcoidosis is an idiopathic systemic inflammatory disorder characterized histologically by noncaseating granulomas. The pathogenesis likely includes genetic, immunologic, and environmental factors. The lungs, skin, and eyes are most commonly affected. Although bone involvement is possible, sarcoidosis of the humerus is rare, with few cases reported. Furthermore, we are unaware of any reports of sarcoidosis of the upper humerus with a coexisting rotator cuff tear. We report the case of a 50-year-old female with sarcoidosis of the humerus and a coexisting tear of the supraspinatus tendon. Her medical history includes type 2 diabetes, depression, and fatigue. She had chronic shoulder pain that worsened after her dog jerked on the leash. Radiographs were grossly normal. Subsequent magnetic resonance imaging (MRI) demonstrated a possible small full-thickness rotator cuff tear. Multiple rounded lesions were also noted within the proximal humerus. A biopsy demonstrated noncaseating granulomas, confirming the diagnosis of sarcoidosis. There was concern that her sarcoid lesions would compromise bone quality, limiting options for surgical repair of her rotator cuff tear. However, it was determined that her lesion did not involve cortical bone, and surgery was performed. During surgery, the supraspinatus tendon was found to be partially torn and was treated with arthroscopic debridement and acromioplasty. An excellent result was ultimately achieved after her rheumatologist started adalimumab injections. This case demonstrates that there can be a rare incidental finding of osseous sarcoid lesions in the upper humerus where the bone might be compromised in the location of a planned rotator cuff repair.

Rotator cuff tear following long-standing axillary neuropathy in a female motocross racer.

A 'terrible triad' of anterior shoulder dislocation, axillary nerve damage and rotator cuff tear has been previously described. However, we are unaware of any report of anterior shoulder dislocation, humeral fracture, axillary neuropathy and subsequent rotator cuff tear requiring surgery when the axillary neuropathy was deemed permanent. We report the case of a 20-year-old woman who fell in a motocross accident and had an anterior shoulder dislocation, humeral fracture and axillary neuropathy. The fracture was treated surgically with open reduction and internal fixation. The axillary nerve injury was ultimately permanent. Thirteen months after the motocross accident, the patient sustained a rotator cuff tear from seemingly minor trauma. However, several months of aggressive physical therapy preceded the rotator cuff tear. The tear was repaired and the patient was followed for 5 years after the initial injury. She returned to competing in motocross, even though the axillary neuropathy remained complete and permanent.

The work programme of EURADOS on internal and external dosimetry.

Since the early 1980s, the European Radiation Dosimetry Group (EURADOS) has been maintaining a network of institutions interested in the dosimetry of ionising radiation. As of 2017, this network includes more than 70 institutions (research centres, dosimetry services, university institutes, etc.), and the EURADOS database lists more than 500 scientists who contribute to the EURADOS mission, which is to promote research and technical development in dosimetry and its implementation into practice, and to contribute to harmonisation of dosimetry in Europe and its conformance with international practices. The EURADOS working programme is organised into eight working groups dealing with environmental, computational, internal, and retrospective dosimetry; dosimetry in medical imaging; dosimetry in radiotherapy; dosimetry in high-energy radiation fields; and harmonisation of individual monitoring. Results are published as freely available EURADOS reports and in the peer-reviewed scientific literature. Moreover, EURADOS organises winter schools and training courses on various aspects relevant for radiation dosimetry, and formulates the strategic research needs in dosimetry important for Europe. This paper gives an overview on the most important EURADOS activities. More details can be found at www.eurados.org .

EURADOS IC2012N: FURTHER INFORMATION DERIVED FROM AN EURADOS INTERNATIONAL COMPARISON OF NEUTRON PERSONAL DOSEMETERS.

In 2012, the European Radiation Dosimetry Group (EURADOS) performed an intercomparison for neutron dosemeters that are intended to measure personal dose equivalent, Hp(10). A total of 31 participants registered with 34 dosimetry systems. The irradiation tests were chosen to provide the participants with useful information on their dosimetry systems, i.e. linearity, reproducibility, responses for different energies and angles and to simulated workplace fields. This paper gives details of the extensive information derived from the exercise.

EURADOS strategic research agenda: vision for dosimetry of ionising radiation.

Since autumn 2012, the European Radiation Dosimetry Group (EURADOS) has been developing its Strategic Research Agenda (SRA), which is intended to contribute to the identification of future research needs in radiation dosimetry in Europe. The present article summarises-based on input from EURADOS Working Groups (WGs) and Voting Members-five visions in dosimetry and defines key issues in dosimetry research that are considered important for the next decades. The five visions include scientific developments required towards (a) updated fundamental dose concepts and quantities, (b) improved radiation risk estimates deduced from epidemiological cohorts, (c) efficient dose assessment for radiological emergencies, (d) integrated personalised dosimetry in medical applications and (e) improved radiation protection of workers and the public. The SRA of EURADOS will be used as a guideline for future activities of the EURADOS WGs. A detailed version of the SRA can be downloaded as a EURADOS report from the EURADOS website (www.eurados.org).

Yeast cell wall supplementation alters aspects of the physiological and acute phase responses of crossbred heifers to an endotoxin challenge.

A study was conducted to determine the effect of feeding yeast cell wall (YCW) products on the physiological and acute phase responses of crossbred, newly-received feedlot heifers to an endotoxin challenge. Heifers (n = 24; 219 ± 2.4 kg) were separated into treatment groups receiving either a control diet (n = 8), YCW-A (2.5 g/heifer/d; n = 8) or YCW-C (2.5 g/heifer/d; n = 8) and were fed for 52 d. On d 37 heifers were challenged i.v. with LPS (0.5 µg/kg body mass) and blood samples were collected from -2 h to 8 h and again at 24 h relative to LPS challenge. There was an increase in vaginal temperature in all heifers post-LPS, with YCW-C maintaining a lower vaginal temperature post-LPS than control and YCW-A heifers. Sickness behavior scores increased post-LPS in all heifers, but were not affected by treatment. Cortisol concentrations were greatest in control heifers post-LPS compared with YCW-A or YCW-C heifers. Concentrations of IFN-γ and TNF-α increased post-LPS, but were not affected by treatment. Serum IL-6 concentrations increased post-LPS and were greater in control heifers than YCW-A and YCW-C heifers. These data indicate that YCW supplementation can decrease the physiological and acute phase responses of newly-received heifers following an endotoxin challenge.

Doses and risks from uranium are not increased significantly by interactions with natural background photon radiation.

The impact of depleted uranium (DU) on human health has been the subject of much conjecture. Both the chemical and radiological aspects of its behaviour in the human body have previously been investigated in detail, with the radiological impact being assumed to be linked to the alpha decay of uranium. More recently, it has been proposed that the accumulation in tissue of high-Z materials, such as DU, may give rise to enhanced local energy deposition in the presence of natural background photon radiation due to the high photoelectric interaction cross sections of high-Z atoms. It is speculated that, in addition to producing short-range photoelectrons, these events will be followed by intense Auger and Coster-Kronig electron emission, thereby causing levels of cell damage that are unaccounted for in conventional models of radiological risk. In this study, the physical and biological bases of these claims are investigated. The potential magnitudes of any effect are evaluated and discussed, and compared with the risks from other radiological or chemical hazards. Monte Carlo calculations are performed to estimate likely energy depositions due to the presence of uranium in human tissues in photon fields: whole body doses, organ doses in anthropomorphic phantoms and nano-/micro-dosimetric scenarios are each considered. The proposal is shown generally to be based on sound physics, but overall the impact on human health is expected to be negligible.

Individual monitoring for external radiation at accelerator facilities.

Individual monitoring at accelerator facilities is discussed, within the framework set out by the International Commission on Radiological Protection and with reference to the implementation of the recommendations of that body within the European Basic Safety Standards. Legislation in other parts of the world may differ, but a worldwide perspective on this subject would be too exhaustive. The fields at accelerator facilities are contrasted in terms of particle type and energy with those encountered at more conventional sites within the nuclear fuel cycle, medical applications and general industry. The implications for individual monitoring are discussed in relation to the dose quantities for these accelerator fields and also with respect to the personal dosemeters options.

Analysis of the CONRAD computational problems expressing only stochastic uncertainties: neutrons and protons.

Within the scope of CONRAD (A Coordinated Action for Radiation Dosimetry) Work Package 4 on Computational Dosimetry jointly collaborated with the other research actions on internal dosimetry, complex mixed radiation fields at workplaces and medical staff dosimetry. Besides these collaborative actions, WP4 promoted an international comparison on eight problems with their associated experimental data. A first set of three problems, the results of which are herewith summarised, dealt only with the expression of the stochastic uncertainties of the results: the analysis of the response function of a proton recoil telescope detector, the study of a Bonner sphere neutron spectrometer and the analysis of the neutron spectrum and dosimetric quantity H(p)(10) in a thermal neutron facility operated by IRSN Cadarache (the SIGMA facility). A second paper will summarise the results of the other five problems which dealt with the full uncertainty budget estimate. A third paper will present the results of a comparison on in vivo measurements of the (241)Am bone-seeker nuclide distributed in the knee. All the detailed papers will be presented in the WP4 Final Workshop Proceedings.

Evaluation of individual dosimetry in mixed neutron and photon radiation fields (EVIDOS). Part I: Scope and methods of the project.

Supported by the European Commission, the EVIDOS project started in November 2001 with the broad goal of evaluating state of the art dosimetry techniques in representative workplaces of the nuclear industry. Seven European institutes joined efforts with end users at nuclear power plants, at fuel processing and reprocessing plants, and at transport and storage facilities. A comprehensive programme was devised to evaluate capabilities and limitations of standard and innovative personal dosemeters in relation to the mixed neutron-photon fields of concern to the nuclear industry. This paper describes the criteria behind the selection of dosimetry techniques and workplaces that were analysed, as well as the organisation of the measurement campaigns. Particular emphasis was placed on the evaluation of a variety of electronic personal dosemeters, either commercially available or previously developed by the partners. The estimates provided by these personal dosemeters were compared to reference values of dose equivalent quantities derived from spectrometry and fluence-to-dose equivalent conversion coefficients. Spectrometry was performed both with conventional multisphere and with some original instrumentation providing energy and direction resolution, based on silicon detectors and superheated drop detectors mounted on or in spherical moderators. The results were collected in a large, searchable database and are intended to be used in the harmonisation of dosimetric procedures for mixed radiation fields and for the approval of dosimetry services in Europe.

Evaluation of individual dosimetry in mixed neutron and photon radiation fields (EVIDOS). Part II: Conclusions and recommendations.

The paper presents the main conclusions and recommendations derived from the EVIDOS project, which is supported by the European Commission within the 5th Framework Programme. EVIDOS aims at evaluating state of the art neutron dosimetry techniques in representative workplaces of the nuclear industry with complex mixed neutron-photon radiation fields. This analysis complements a series of individual papers which present detailed results and it summarises the main findings from a practical point of view. Conclusions and recommendations are given concerning characterisation of radiation fields, methods to derive radiation protection quantities and dosemeter results.

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part I: Neutrons and uncertainties.

The QUADOS EU cost shared action conducted an intercomparison on the usage of numerical methods in radiation protection and dosimetry. The eight problems proposed were intended to test the usage of Monte Carlo and deterministic methods by assessing the accuracy with which the codes are applied and also the methods used to evaluate uncertainty in the answer gained through these methods. The overall objective was to spread good practice through the community and give users information on how to assess the uncertainties associated with their calculated results.

Electronic neutron personal dosemeters: their performance in mixed radiation fields in nuclear power plants.

This work describes spectral distributions of neutrons obtained as function of energy and direction at four workplace fields at the Krümmel reactor in Germany. Values of personal dose equivalent H(p)(10) and effective dose E are determined for different directions of a person's orientation in these fields and readings of personal neutron dosemeters--especially electronic dosemeters--are discussed with respect to H(p)(10) and E.

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part II: Photons, electrons and protons.

'QUADOS', a concerted action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on a discussion of lessons learned from the participation in solving the photon and charged particle problems. The lessons learned from the participation in solving the neutron problems are presented in a companion paper (in this issue).