Features of a rare peripheral primitive neuroectodermal tumour arising from the thoracic spine in a juvenile canine patient.

Peripheral primitive neuroectodermal tumours are rare tumours in juveniles. The current patient was a paraplegic 8-month-old Scottish deerhound with a suspected pulmonary mass. Radiographically, there was a large extrapleural mass within the mid-left hemithorax. On MRI, the mass was mainly hyperintense on T2-weighted images, isointense on T1-weighted images and was heterogeneously strongly contrast enhancing with a multilobulated appearance, spinal cord compression, paraspinal musculature invasion and intrathoracic extension. Those changes were confirmed on post-mortem, and the mass diagnosed based on immunohistochemistry.

Effectiveness of PennHIP and Orthopedic Foundation for Animals measurements of hip joint quality for breeding selection to reduce hip dysplasia in a population of purpose-bred detection dogs.

OBJECTIVE: To examine the effectiveness of applying selective pressure to improve hip joint quality in purpose-bred detection dogs by use of PennHIP distraction index (DI) values along with Orthopedic Foundation for Animals (OFA) hip joint scores and to determine whether age, sex, coat color, breed, and body weight were associated with hip joint quality. ANIMALS: 615 purpose-bred detection dogs assessed for hip joint quality. PROCEDURES: Orthopedic records of 615 purpose-bred detection dogs (569 Labrador Retrievers and 46 Labrador Retriever-German Wirehaired Pointer crossbred dogs) from 2000 through 2017 were analyzed. From 2000 to 2014, hip joint quality scores were determined by OFA evaluation only (429 dogs). Beginning in 2015, both PennHIP and OFA evaluations were used to select male and female breeding stock (179 dogs; 7 dogs were removed from analysis because they did not undergo both evaluations). Selection threshold DI value for sires and dams was ≤ 0.30; all had hip joint scores of excellent or good by OFA standards. Standard ventrodorsal hip joint-extended and stress (compression and distraction) pelvic radiographs were submitted for OFA and PennHIP evaluations. RESULTS: Hip joint quality scores were unchanged by use of OFA measurements only. When both PennHIP and OFA measurements were used for the selection of breeding stock, hip joint quality scores improved significantly. Sex and age were significant predictors of DI values. CONCLUSIONS AND CLINICAL RELEVANCE: PennHIP DI values were an effective measurement of hip joint quality for selecting breeding stock, and the addition of DI values to OFA measurements significantly improved hip joint quality in a population of purpose-bred dogs.

Growing skull fracture in a red-tailed hawk (Buteo jamaicensis).

Growing skull fractures have been reported in humans for many years, usually resulting from injury to the soft skull during the rapid growth period of an infant's life. Nestling raptors have thin, fragile skulls, a rapid growth rate, and compete aggressively for food items. Skull trauma may occur, which may lead to the development of a growing skull fracture. Growing skull fractures may be under-diagnosed in raptor rehabilitation facilities that do not have access to advanced technologic equipment. Three-dimensional (3-D) computed tomography was used to diagnose a growing skull fracture in a red-tailed hawk (Buteo jamaicensis). The lesion was surgically repaired and the animal was eventually returned to the wild. This is the first report of a growing skull fracture in an animal. In this case, 3-D computed topographic imaging was utilized to diagnose a growing skull fracture in a red-tailed hawk, surgical repair was performed, and the bird recovered completely and was ultimately released.

Exploring the benefits and challenges of establishing a DRI-like process for bioactives.

Bioactives can be defined as: "Constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status" (Office of Disease Prevention and Health Promotion, Office of Public Health and Science, Department of Health and Human Services in Fed Reg 69:55821-55822, 2004). Although traditional nutrients, such as vitamins, minerals, protein, essential fatty acids and essential amino acids, have dietary reference intake (DRI) values, there is no such evaluative process for bioactives. For certain classes of bioactives, substantial scientific evidence exists to validate a relationship between their intake and enhanced health conditions or reduced risk of disease. In addition, the study of bioactives and their relationship to disease risk is a growing area of research supported by government, academic institutions, and food and supplement manufacturers. Importantly, consumers are purchasing foods containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects. This conference, Bioactives: Qualitative Nutrient Reference Values for Life-stage Groups?, explored why it is important to have a DRI-like process for bioactives and challenges for establishing such a process.

Nutrient reference values for bioactives: new approaches needed? A conference report.

Nutrients can be classified as either "essential" or "non-essential," the latter are also termed bioactive substances. Whereas the absence of essential nutrients from the diet results in overt deficiency often times with moderate to severe physiological decrements, the absence of bioactive substances from the diet results in suboptimal health. Nutrient reference values are set by Codex Alimentarius and regulatory bodies in many countries, mostly for essential nutrients with recommended daily intakes. The IOM in the United States has defined a set of four DRIs that, when data are appropriate, include an EAR, a RDA that is derived from the EAR, an AI for nutrients without appropriate data to identify an EAR, and an UL. From the RDA, the United States derives a labeling value called the DV, which applies to older children and most adults. In Codex, the equivalents of the DVs are the NRVs to be used in calculating percentage values on food labels. Nothing in the IOM documents specifies that labeling values can be set only for what have been defined to date as essential nutrients. Indeed, the US Food and Drug Administration sets a labeling value for dietary fiber based on the IOM AI for this ingredient. This conference explores the definitions, concepts, and data on two of the best examples of bioactive substances that, perhaps, should have NRVs: lutein and zeaxanthin, and n-3 long-chain polyunsaturated fatty acids.

A review of calcium supplements and cardiovascular disease risk.

A group of academic and industry experts in the fields of nutrition, cardiology, epidemiology, food science, bone health, and integrative medicine examined the data on the relationship between calcium supplement use and risk of cardiovascular events, with an emphasis on 4 of the Bradford Hill criteria for causal inference: strength, consistency, dose-response, and biological plausibility. Results from 2 epidemiological studies and a meta-analysis of randomized, controlled clinical trials, including a subgroup analysis from the Women's Health Initiative, have prompted concern about a potential association between calcium supplement use and a small increase in the risk of adverse cardiovascular events. However, a number of issues with the studies, such as inadequate compliance with the intervention, use of nontrial calcium supplements, potential bias in event ascertainment, and lack of information on and adjustment for known cardiovascular risk determinants, suggest that bias and confounding cannot be excluded as explanations for the reported associations. Findings from other cohort studies also suggest no detrimental effect of calcium from diet or supplements, with or without vitamin D, on cardiovascular disease risk. In addition, little evidence exists for plausible biological mechanisms to link calcium supplement use with adverse cardiovascular outcomes. The authors do not believe that the evidence presented to date regarding the hypothesized relationship between calcium supplement use and increased cardiovascular disease risk is sufficient to warrant a change in the Institute of Medicine recommendations, which advocate use of supplements to promote optimal bone health in individuals who do not obtain recommended intakes of calcium through dietary sources.

Niacin: chemical forms, bioavailability, and health effects.

Elevated low-density lipoprotein cholesterol (LDL-C) has been the main target of lipid-altering therapy to reduce cardiovascular risk associated with dyslipidemia. Residual cardiovascular risk remains, however, after achievement of goal LDL-C levels and is associated in part with other risk markers of cardiovascular disease, including low high-density lipoprotein cholesterol (HDL-C), high lipoprotein a, and hypertriglyceridemia. Niacin is considered a valuable agent for therapy to modify high LDL-C as well as low HDL-C, high lipoprotein a, and hypertriglyceridemia. The forms of niacin available in the marketplace include unbound niacin, or free nicotinic acid (NA); extended-release NA, a form of NA that is released gradually over a period of time; inositol hexanicotinate, six molecules of NA covalently bonded to one molecule of inositol; and nicotinamide, or niacinamide, the amide form of NA, which is readily bioavailable. This review is designed to assist healthcare professionals in evaluating the form(s) of niacin best suited for a particular therapeutic goal. Further, it provides a literature-based evaluation of risk for NA, extended-release NA, inositol hexanicotinate, and nicotinamide.

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress.

Nutrition issues in Codex: health claims, nutrient reference values and WTO agreements: a conference report.

BACKGROUND: Codex documents may be used as educational and consensus materials for member governments. Also, the WTO SPS Agreement recognizes Codex as the presumptive international authority on food issues. Nutrient bioavailability is a critical factor in determining the ability of nutrients to provide beneficial effects. Bioavailability also influences the quantitative dietary requirements that are the basis of nutrient intake recommendations and NRVs. HEALTH CLAIMS: Codex, EFSA and some national regulatory authorities have established guidelines or regulations that will permit several types of health claims. The scientific basis for claims has been established by the US FDA and EFSA, but not yet by Codex. Evidence-based nutrition differs from evidence-based medicine, but the differences are only recently gaining recognition. Health claims on foods may provide useful information to consumers, but many will interpret the information to mean that they can rely upon the food or nutrient to eliminate a disease risk. NUTRIENT REFERENCE VALUES: NRVs are designed to provide a quantitative basis for comparing the nutritive values of foods, helping to illustrate how specific foods fit into the overall diet. The INL-98 and the mean of adult male and female values provide NRVs that are sufficient when used as targets for individual intakes by most adults. WORLD TRADE ORGANIZATION AGREEMENTS: WTO recognizes Codex as the primary international authority on food issues. Current regulatory schemes based on recommended dietary allowances are trade restrictive. A substantial number of decisions by the EFSA could lead to violation of WTO agreements.

Under the law, FDA must grant different standards for new dietary ingredients and food additives.

The FDA's draft Guidance on notifications for new dietary ingredients attempts to narrow the scope of "old" dietary ingredients that do not require notification to FDA and repeats some mistakes from the past by going beyond what is required or permitted by the Food, Drug & Cosmetic Act, as amended by the Dietary Supplements Health and Education Act of 1994. The draft Guidance attempts to apply the notification requirement to new supplements, not just new ingredients, and it expands the working definition of "chemically altered" to include many changes that were not foreseen in the Congressional Record in 1994. Through these misinterpretations, FDA attempts to impose a food additives-like safety standard, and gain de facto premarket approval against the overt wishes of Congress.

High-resolution computed tomography bronchial lumen to pulmonary artery diameter ratio in anesthetized ventilated cats with normal lungs.

High-resolution computed tomography (CT) is the preferred noninvasive tool for diagnosing bronchiectasis in people. A criterion for evaluating dilation of the bronchus is the bronchial lumen to pulmonary artery diameter (bronchoarterial ratio [BA ratio]). A ratio of > 1.0 in humans or > 2.0 in dogs has been suggested as a threshold for identifying bronchiectasis. The purpose of this study was to establish the BA ratio in normal cats. Fourteen specific pathogen-free cats were selected for analysis of thoracic CT images. The BA ratios of the lobar bronchi of the left cranial (cranial and caudal parts), right cranial, right middle, left caudal, and right caudal lung lobes were measured. The mean of the mean BA ratio of all lung lobes was 0.71 +/- 0.05. Individual BA ratios ranged from 0.5 to 1.11. Comparing individual lobes for each cat, there was no significant difference (P = 0.145) in mean BA ratio between lung lobes. A mean BA ratio for these normal cats was 0.71 +/- 0.1, which suggests an upper cut-off normal value > 0.91 (mean +/- 2 standard deviations) between normal and abnormal cats.

Highest Observed Intake: definition, regulatory uses and provisional values.

For nutrients and related substances, the Tolerable Upper Intake Level (UL) has become the internationally accepted risk assessment method. The major limitation of the UL method as applied by authoritative groups thus far is that no UL has been set for nutrients without established adverse effects. In contrast to the limitations inherent in the UL method, an alternative approach is available; it identifies a risk assessment value termed the Highest Observed Intake (HOI). In the absence of a UL, the HOI is the highest intake with adequate data to show, with acceptable confidence, the absence of adverse effects up to that intake. With this concept defined and accepted in a report by the authoritative international organizations FAO and WHO, a complete risk assessment for the nutrients and related substances would have to identify UL values for those with known adverse effects and HOI values for those without known adverse effects. The need for the HOI concept and value is illustrated by the unjustified policy and regulatory actions taken in relation to vitamin B12. Regulatory utility is explained and tentative HOI values are identified for several vitamins and non-essential nutrients. Endorsement of the concept and development of HOI values by authoritative bodies is likely to be required for broad acceptance and use.

Scientific issues related to Codex Alimentarius goals: a review of principles, with examples.

The Codex Alimentarius provides the food standards and guidelines recognized by the World Trade Organization as the primary authority for use in settlement of related trade disputes. Codex bases its decisions primarily on scientific principles and evidence, although other legitimate factors such as economic and societal values may be considered. Codex has two primary aims: to protect consumers' health and assure fair practices in food trade. Codex documents may provide templates for individual nations but are not binding for domestic policies. Despite many advances over the last couple of decades, misunderstandings and controversies have interfered with important aspects of progress which Codex needs to accomplish, especially in the areas of claims of benefits related to food or nutrient consumption and the establishment of the safety of these items. Claims for health benefits should be based on the totality of available scientific evidence, including observational data collected from large populations as well as the results from randomized clinical trials. Safety should be evaluated by risk assessment on high quality experimental data, with anecdotal information having a lesser role. Regulatory policy would be improved if "history of safe use" were to be better defined and described.

Magnetic resonance imaging of radiation-induced thymic atrophy as a model for pathologic changes in acute feline immunodeficiency virus infection.

The development of a protocol to reproducibly induce thymic atrophy, as occurs in feline immunodeficiency virus (FIV) infection and other immunosuppressive diseases, and to consistently estimate thymic volume, provides a valuable tool in the search of innovative and novel therapeutic strategies. Magnetic resonance imaging (MRI) using the short tau inversion recovery (STIR) technique, with fat suppression properties, was determined to provide an optimized means of locating, defining, and quantitatively estimating thymus volume in young cats. Thymic atrophy was induced in four, 8-10-week-old kittens with a single, directed 500 cGy dose of 6 MV X-rays from a clinical linear accelerator, and sequential MR images of the cranial mediastinum were collected at 2, 7, 14, and 21 days post irradiation (PI). Irradiation induced a severe reduction in thymic volume, which was decreased, on average, to 47% that of normal, by 7 days PI. Histopathology confirmed marked, diffuse thymic atrophy, characterized by reduced thymic volume, decreased overall cellularity, increased apoptosis, histiocytosis, and reduced distinction of the corticomedullary junction, comparable to that seen in acute FIV infection. Beginning on day 7 PI, thymic volumes rebounded slightly and continued to increase over the following 14 days, regaining 3-35% of original volume. These findings demonstrate the feasibility and advantages of using this non-invasive, in vivo imaging technique to measure and evaluate changes in thymic volume in physiologic and experimental situations. All experimental protocols in this study were approved by the Institutional Animal Care and Use Committee (IACUC) at Auburn University.

Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy.

Preclinical studies and initial clinical trials have documented the feasibility of adenoassociated virus (AAV)-mediated gene therapy for hemophilia B. In an 8-year study, inhibitor-prone hemophilia B dogs (n = 2) treated with liver-directed AAV2 factor IX (FIX) gene therapy did not have a single bleed requiring FIX replacement, whereas dogs undergoing muscle-directed gene therapy (n = 3) had a bleed frequency similar to untreated FIX-deficient dogs. Coagulation tests (whole blood clotting time [WBCT], activated clotting time [ACT], and activated partial thromboplastin time [aPTT]) have remained at the upper limits of the normal ranges in the 2 dogs that received liver-directed gene therapy. The FIX activity has remained stable between 4% and 10% in both liver-treated dogs, but is undetectable in the dogs undergoing muscle-directed gene transfer. Integration site analysis by linear amplification-mediated polymerase chain reaction (LAM-PCR) suggested the vector sequences have persisted predominantly in extrachromosomal form. Complete blood count (CBC), serum chemistries, bile acid profile, hepatic magnetic resonance imaging (MRI) and computed tomography (CT) scans, and liver biopsy were normal with no evidence for tumor formation. AAV-mediated liver-directed gene therapy corrected the hemophilia phenotype without toxicity or inhibitor development in the inhibitor-prone null mutation dogs for more than 8 years.

Expanded approach to tolerable upper intake guidelines for nutrients and bioactive substances.

The original tolerable upper intake level (UL) method greatly improved the application of risk assessment to the evaluation of nutrient safety for humans, but a UL is only set where the data establish a hazard resulting from high intakes. Absence of a UL for those nutrients with no established hazard has been misinterpreted by regulators and resulted in overly restrictive policies. To prevent such misinterpretation, the observed safe level (OSL) was developed and defined as "the highest intake with convincing evidence of safety, even if there are no established adverse effects at any level." More recently, a FAO/WHO report gave a similar definition for the highest observed intake (HOI). Another disadvantage of the UL method is the application of arbitrary uncertainty factors (UF). An alternative to the traditional adjustment for uncertainty involves arranging the data in decreasing order of daily intake, followed by evaluation of each trial for quantity and quality of data. Studies are selected downward until no adverse effects are observed in a trial of sufficient quality to justify no further correction for uncertainty (i.e. selection of data that qualify for UF = 1). Thus, the no observed adverse effect level or OSL selected requires no further adjustment for uncertainty. For supplemental intakes of some vitamins, many bioactive substances, and most amino acids, no adverse effects that are clearly related to high intakes have been established, but where the dataset is sufficiently robust, application of the OSL-HOI technique can provide risk assessment values.

Are low tolerable upper intake levels for vitamin A undermining effective food fortification efforts?

Vitamin A deficiency (VAD) is a major health problem, particularly in low-resource countries, putting an estimated 125-130 million preschool-aged children at increased risk of morbidity and mortality from infectious diseases. Vitamin A supplementation reduces VAD and increases child survival; it is complemented by fortifying foods with vitamin A. Concern over increased risk of bone fracture associated with vitamin A intakes below the tolerable upper intake level (UL) among populations in affluent countries conflicts with the need to increase intakes in less developed countries, where populations are at greater risk of VAD and intakes are unlikely to reach the UL as diets include fewer foods containing retinol while vitamin A from carotenoids poses no risk of overdose. With the implementation of recently developed risk management tools, vitamin A can be used safely in food fortification, including point-of-use fortification in the context of supplementation among specific target groups in low-resource countries.