Nasal tumor with widespread cutaneous metastases in a Golden Retriever.

An intact, 8-year-old, male Golden Retriever dog was presented for evaluation of a nasal mass and approximately 30 firm, raised, variably ulcerated dermal and subcutaneous masses. Histopathology of both nasal and multiple skin masses revealed multiple nonencapsulated, infiltrative masses comprising clusters, anastomosing trabeculae, and packets of neoplastic, round to ovoid, hyperchromatic cells with marked nuclear molding. Surrounding the neoplastic cells was a marked stromal response in which many of the spindle-shaped cells expressed muscle-specific actin and had ultrastructural features consistent with myofibroblasts. A literature search indicates that this is the first report in a peer-reviewed journal of cutaneous metastasis of a nasal neuroendocrine tumor in any domestic animal species.

Benefit-risk assessment of vitamin D supplementation.

UNLABELLED: Current intake recommendations of 200 to 600 IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D. INTRODUCTION: This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk. METHODS AND RESULTS: Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000 IU vitamin D per day or mean 25(OH)D between 75 and 110 nmol/l (30-44 ng/ml). Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110 nmol/l). In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000 IU per day or achieved 25(OH)D up to 643 nmol/l. Mean levels of 75 to 110 nmol/l were reached in most RCTs with 1,800 to 4,000 IU vitamin D per day without risk. CONCLUSION: Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population.

Identification and characterization of murine alternatively spliced tissue factor.

Tissue factor (TF) is a transmembrane glycoprotein that initiates coagulation and plays a critical role in regulating hemostasis and thrombosis. We have recently reported a naturally occurring, soluble form of human tissue factor (asTF) generated by alternative splicing. This splice variant has a novel C-terminus with no homology to that of the full-length TF (flTF), lacks a transmembrane domain, and is active in the presence of phospholipids. Mouse models offer unique opportunities to examine the relative importance of flTF and asTF in mediating thrombosis, the response to arterial injury, and ischemic damage. To that end, we have identified and characterized murine asTF (masTF). Like the human splice variant, masTF lacks a transmembrane domain and has a unique C-terminus. We have generated antibodies specific to masTF and murine flTF (mflTF) to examine the expression of both forms of TF. masTF antigen is widely and abundantly expressed, with a pattern similar to that of mflTF, in adult tissues, in experimentally induced thrombi, and during development. These studies demonstrate that masTF contributes to the pool of total TF and may thus play an important role in mediating TF-dependent processes.

Vitamins and minerals: efficacy and safety.

Safety and efficacy are crucial but separate issues for vitamin and mineral supplements. Misinterpretation of "safe and adequate" to mean "safety limit" would impose restrictions on vitamin and mineral intakes that are not needed to ensure safety. Substantial evidence indicates that intakes greater than the recommended dietary allowances (RDAs) of certain vitamins and minerals such as calcium, folic acid, vitamin E, selenium, and chromium reduce the risk of certain diseases for some people. Limitation of intakes to the RDAs would preclude reductions in disease risk from these nutrients. The margin of safety between the usual dietary intake and the intake that would produce adverse effects varies greatly among the different nutrients. Very high intakes of vitamins A and D, niacin, pyridoxine, and selenium have produced adverse effects. Many widely discussed putative adverse effects of vitamin C, vitamin E, and trivalent chromium have little factual basis. There is no evidence of adverse effects from beta-carotene supplements except in current heavy smokers.

Thiamin deficiency effects on rat leukocyte pyruvate decarboxylation rates.

Thiamin status usually is assessed by urinary excretion of thiamin or by exogenous thiamin pyrophosphate (TPP) stimulation of erythrocyte transketolase activity. Because of the possible great utility of a biologically and chemically sensitive alternative method for thiamin status assessment, studies were made of rat leukocyte pyruvate decarboxylation activity in thiamin deficiency. Pyruvate decarboxylation rates were determined by assaying 14CO2 produced by leukocytes from 1-14C-pyruvic acid in vitro. Reaction conditions were 5 mumoles pyruvic acid, 2.2 X 10(4) DPM 1-14C-pyruvic acid, leukocytes from 5 ml whole blood, 50 mumoles NaH2PO4, 5 mumoles MgSO4, and 1 mumole MnSO4 at pH 7.4 in 1 ml reaction volume at 25 C. Four weeks of thiamin deficiency decreased leukocyte pyruvate decarboxylation rates and markedly increased the TPP effect on this reaction. Dual weekly assays in the same rats showed that 21 days of thiamin deficiency significantly increased the TPP effect on leukocyte pyruvate decarboxylation rates. In contrast, the TPP effect on erythrocyte transketolase activity was significantly increased after only 7 days of thiamin deficiency. Erythrocyte transketolase is more sensitive than leukocyte pyruvate decarboxylation rate to early thiamin deficiency in rats.

Evaluation of vitamin A toxicity.

Toxicity has been associated with abuse of vitamin A supplements and with diets extremely high in preformed vitamin A. Consumption of 25,000-50,000 IU/d for periods of several months or more can produce multiple adverse effects. The lowest reported intakes causing toxicity have occurred in persons with liver function compromised by drugs, viral hepatitis, or protein-energy malnutrition. Certain drugs or other chemicals may markedly potentiate vitamin A toxicity in animals. Especially vulnerable groups include children, with adverse effects occurring with intakes as low as 1,500 IU.kg-1.d-1, and pregnant women, with birth defects being associated with maternal intakes as low as approximately 25,000 IU/d. The maternal dose threshold for birth defects cannot be identified from present data. An identifiable fraction of the population surveyed consumes vitamin A supplements at 25,000 IU/d and a few individuals consume much more. beta-Carotene is much less toxic than vitamin A.

Rapid generation of thrombin by atheroma and platelets.

Rapid re-occlusion of an atheromatous vessel after angioplasty may occur through yet incompletely known mechanisms. Atheromatous plaque has been shown to contain tissue factor (TF) activity. When atheroma extracts (atheroma) and platelets are incubated together a powerful prothrombinase is rapidly generated, which neither platelets nor atheroma alone can generate. Large amounts of thrombin were generated in minutes by many atheroma-platelet mixtures. However in these mixtures, generation of factor (F)Xa activity was not enhanced, but was in fact decreased by platelet tissue factor pathway inhibitor (TFPI) activity. Leukocytes had no appreciable effect in these short-term experiments. Although levels of factor VII and FX in atheroma were extremely low, antibodies to each of these factors inhibited prothrombinase formation. So did an antibody to factor V. A FXa inhibitor, DX 9065a, was very effective in preventing prothrombinase generation. These findings may explain the rapid occlusion that has been observed after angioplasty and point to avenues of prevention.

Hepatic toxicity of unmodified and time-release preparations of niacin.

Niacin (nicotinic acid) is used frequently in the treatment of hypercholesteremia. It is available in both unmodified and time-release preparations. The latter were developed in attempts to minimize the skin-flushing reaction that affects virtually all users and may limit acceptance. Adverse effects on the liver from both unmodified and time-release preparations have been recognized for many years. We reviewed the literature on the hepatic toxicity of both types of niacin preparations. Adverse reactions in six patients resulted from the exclusive use of unmodified niacin and in two patients from the exclusive use of time-release preparations. In 10 additional patients, adverse reactions developed after an abrupt change from unmodified to time-release preparations. Many of these patients were ingesting time-release niacin at doses well above the usual therapeutic doses currently recommended. Signs of liver toxicity developed in less than 7 days in four of these 10 patients. In doses that achieve equivalent reductions in serum lipids, hepatic toxicity occurred more frequently with time-release preparations than with unmodified preparations. An awareness of toxicity associated with ingestion of high doses of time-release niacin preparations is important because of their widespread availability and the potential for self-prescribed, unmonitored use.

Safety limits for nutrient intakes: concepts and data requirements.

The possible quantitative methods calculating safety limits for nutrient intakes are related conceptually to those used to calculate safe limits for exposure to environmental chemicals and to the therapeutic index used to assess the relative safety of drugs. The impact of using a fixed SF has been compared with the use of variable SFs. Of the methods identified, the SRM gives lower limits than does the MPM. However, neither of these methods calculates safety limits below the RDA, even for nutrients with narrow margins of safety. The acceptability criteria for toxicity data for use in identifying safety limits are an issue of major importance and must be resolved before calculated limits may be used to support policy or regulatory decisions. An advantage of adopting a standard formula involving systematically varying SFs to calculate safety limits is that the margin of safety below the expected range of toxicity for each nutrient would be systematic, without having the safety limit for any nutrient regress below its RDA. Once the data acceptability criteria were met, the safety limit would be identified objectively. The confidence in and reasonableness of safety limits, regardless of the method used to define them, will be enhanced if the objectives, data criteria, and the quantitative method have been agreed upon ahead of time by groups responsible for nutrition and health policy. Even with such agreement, the confidence in using such procedures to support policy decisions will be improved by the extent and quality of the data base on toxicity and adverse reactions associated with consumption of excessive levels of the nutrients under consideration.

Oestrogenic potency of genistin and daidzin in mice.

The oestrogenic activity of genistin and daidzin was investigated in the B6D2F1 strain of mouse. Diethylstilboestrol and genistein were used as positive controls. The oestrogenic response to 1.5 mg genistin was equivalent to that of 1 mg genistein, giving a 1:1 molar relationship in oestrogenic activity between genistin and genistein. The oestrogenic response to 3.8 mg daidzin was equivalent to that of 1 mg genistein. Analysis of the blood obtained from the mice in this experiment failed to reveal any free genistein or daidzein in the plasma.

Effects of dietary soya bean trypsin inhibitor concentrate on initiation and growth of putative preneoplastic lesions in the pancreas of the rat.

Two studies evaluated the effects of soya bean trypsin inhibitor concentrate (STIC) on early stages of pancreatic carcinogenesis in Wistar rats. In experiment 1, the effects of a 3-month administration of diets containing 3.7% STIC were compared with the effects of administration of diets containing 20% corn oil, in rats pretreated with a single azaserine injection sufficient to initiate putative preneoplastic atypical acinar cell foci. Experiment 2 investigated the capacity of STIC to initiate pancreatic carcinogenesis. Diets containing 3.7% STIC were fed for 4 wk, then diets containing either 5 or 20% corn oil were fed for 3 months. Pancreases were quantitatively evaluated for foci. All groups of azaserine-initiated rats had large numbers of atypical acinar cell foci per cm3 of pancreas. Of these, the group fed 3.7% STIC had pancreatic foci that occupied a significantly greater (P less than 0.01) percentage volume of pancreas than did groups fed 20% corn oil or control diets, which contained 5% corn oil and no added trypsin inhibitor. Very few or no foci were observed in all other groups of either experiment 1 or 2. STIC had a much greater effect on the growth of azaserine-induced lesions than did corn oil. STIC alone did not appear to initiate pancreatic lesions.

Nutrient-drug interactions.

The full range of drug-nutrient interactions is discussed, with emphasis on metabolic mechanisms. The effects of nutrition on drug oxidation and drug conjugations are discussed separately. Chemical interactions of drugs and nutrients in the stomach and intestine are evaluated.

Residue trypsin inhibitor: data needs for risk assessment.

Trypsin inhibitor (TI) occurs naturally in many foods from plants, notably soybean protein products. Heat treatment inactivates TI and improves nutritional quality, but residual TI activity of 5 to 20% remains after typical commercial treatments. Chronic feeding of TI or products that contain TI can inhibit trypsin and chymotrypsin, stimulate their secretion, cause hypertrophy and hyperplasia of the pancreas, and lead to adenomas and carcinomas of the exocrine pancreas. In the rat, TI promotes pancreatic carcinogenesis initiated by azaserine. Data needed for possible risk assessment on TI would include 2-year bioassays from animals treated with TI and fed diets carefully controlled for type and amount of fat (which also promotes pancreatic carcinogenesis). The effects of TI on protein nutrition would have to be considered when identifying the maximum tolerated dose. Major reductions in human dietary TI exposure may not be feasible because of the multiple sources of TI, the substantial promotion by other factors such as fat, and the adverse effects of excessive heat on food products. For risk assessment of TI in a particular food, other promotors and the feasibility of decreasing TI intake must be considered.

Effect of anaesthesia of the palmar digital nerves on proximal interphalangeal joint pain in the horse.

REASONS FOR PERFORMING STUDY: Anaesthesia of the palmar digital nerves is claimed to attenuate lameness in some horses that are lame because of pain in the proximal interphalangeal (PIP) joint. OBJECTIVE: To determine the response of horses with pain in the PIP joint to anaesthesia of the palmar digital nerves. METHODS: Horses were video recorded trotting before and after induction of pain in the PIP joint and 10 mins after anaesthesia of the palmar digital nerves. The palmar digital nerves were anaesthetised 3 times at different sites, and the video recorded gaits were scored subjectively. RESULTS: The median lameness score of gaits after administration of 2% mepivacaine 1 cm proximal to the cartilages of the foot was not significantly different from the median lameness score before anaesthesia of the palmar digital nerves (P > or = 0.05), although that of 1 of 6 horses improved markedly. The median lameness score was significantly (P < or = 0.05) improved after mepivacaine was administered 2 and 3 cm proximal to the cartilages of the foot. CONCLUSIONS: The PIP joint is unlikely to be anaesthetised when the palmar digital nerves are anaesthetised at the proximal margin of the cartilages of the foot. POTENTIAL RELEVANCE: Pain within the PIP joint cannot be excluded as a cause of lameness when lameness is attenuated by anaesthesia of the palmar digital nerves at any site proximal to the proximal margin of the cartilages of the foot.

Brain stem auditory-evoked response abnormalities in 14 dogs with confirmed central nervous system lesions.

Abnormal brain stem auditory-evoked responses (BAER) were recorded on 14 dogs with brain lesions confirmed by necropsy (n = 13) or magnetic resonance imaging and surgical biopsy (n = 1). Lesions included brain stem or cerebellar tumors (6 dogs), brain stem trauma (1 dog), forebrain tumors (3 dogs), hydrocephalus (2 dogs), granulomatous meningoencephalitis (1 dog), and meningoencephalitis (1 dog). Five affected dogs were comatose at the time of recording. BAER abnormalities could be classified as (1) absence of some or all of waves I to V, (2) increased latencies, with wave V being most frequently affected, or (3) a reduction in the amplitude ratio of waves V/I.

Coccygeal muscle injury in English Pointers (limber tail).

A condition colloquially referred to as "limber tail" and "cold tail" is familiar to people working with hunting dogs, primarily Pointers and Labrador Retrievers. The typical case consists of an adult dog that suddenly develops a flaccid tail. The tail either hangs down from the tail base or is held out horizontally for several inches from the tail base and then hangs straight down or at some degree below horizontal. Initially, the hair on the dorsal aspect of the proximal tail may be raised and dogs may resent palpation of the area 3-4 inches (8-10 cm) from the tail base. Most dogs recover spontaneously within a few days to weeks. Anecdotal reports suggest that anti-inflammatory drugs administered within 24 hours after onset hasten recovery. Less than one half of affected dogs experience a recurrence. Affected Pointers almost always have a history of prolonged cage transport, a hard workout the previous day, or exposure to cold or wet weather Most owners and trainers familiar with the condition do not seek veterinary assistance. In cases where people are not familiar with this disease, other conditions such as a fracture, spinal cord disease, impacted anal glands, or prostatic disease have been incorrectly diagnosed. We examined 4 affected Pointers and found evidence of coccygeal muscle damage, which included mild elevation of creatine kinase early after onset of clinical signs, needle electromyographic examination showing abnormal spontaneous discharges restricted to the coccygeal muscles several days after onset, and histopathologic evidence of muscle fiber damage. Specific muscle groups, namely the laterally positioned intertransversarius ventralis caudalis muscles, were affected most severely. Abnormal findings on thermography and scintigraphy further supported the diagnosis.

Hip dysplasia with bilateral ischiatic nerve entrapment in a dog.

Dysfunction of both ischiatic nerves was detected in a 5-year-old spayed Labrador Retriever with radiographic evidence of severe bilateral hip dysplasia. Marked hyperflexion of the hip and stifle was evident when the dog walked. Results of electromyography confirmed the ischiatic nerve involvement. At staged operations, both ischiatic nerves were found to be compressed between the sacrotuberous ligament and proliferative tissue around the hip. One year after surgery, electromyographic and physical findings were essentially normal.

Metastatic thyroid solid-follicular carcinoma in the cervical portion of the spine of a dog.

A metastatic thyroid solid-follicular carcinoma in the cervical portion of the spine was responsible for severe tetraparesis in a dog. Myelography revealed an extradural compressive lesion dorsal and to the right of the midline of C3. Histologic examination was used to diagnose the mass as a solid-follicular thyroid carcinoma. The primary tumor was not evident on cervical palpation or radiography. A dorsal laminectomy centered over C3 was performed, and all visible tumor was removed from the spine. The owner declined any further treatment for the dog.

Principles and concepts of computed tomography.

The final CT image is actually made of a grid of tiny squares called pixels. The scale of grays assigned to each pixel represents the attenuation of x-rays by the structures in the tomographic slice. Manipulation of the gray scale allows optimal visualization of all the tissues within the slice. This control over the gray scale and the absence of structure superimposition are the advantages of CT over conventional x-ray techniques. The steps used to acquire the final CT image are collection of data from the patient (recording of transmitted x-ray intensities from many angles), computer processing of data (mathematical calculation of attenuation of each structure in the tomographic slice), image display (assigning of appropriate gray scale to CT image to evaluate all structures), and data storage (recording series of tomographic images on x-ray film and archiving image data for later review). Common image artifacts that must be identified and interpreted as such include aliasing, ring artifacts, beam hardening effect, metal, motion, partial volume averaging, and streaking from out-of-field objects.