Oral cytarabine ocfosfate pharmacokinetics and assessment of leukocyte biomarkers in normal dogs.

BACKGROUND: Cytosine arabinoside (Ara-C) is a nucleoside analog prodrug utilized for immunomodulatory effects mediated by its active metabolite Ara-CTP. Optimal dosing protocols for immunomodulation in dogs have not been defined. Cytarabine ocfosfate (CO) is a lipophilic prodrug of Ara-C that can be administered PO and provides prolonged serum concentrations of Ara-C. OBJECTIVES: Provide pharmacokinetic data for orally administered CO and determine accumulation and functional consequences of Ara-CTP within peripheral blood leukocytes. ANIMALS: Three healthy female hound dogs and 1 healthy male Beagle. METHODS: Prospective study. Dogs received 200 mg/m2 of CO PO q24h for 7 doses. Serum and cerebrospinal fluid (CSF) CO and Ara-C concentrations were measured by liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Complete blood counts, flow cytometry, and leukocyte activation assays were done up to 21 days. Incorporation of Ara-CTP within leukocyte DNA was determined by LC-MS/MS. RESULTS: Maximum serum concentration (Cmax ) for Ara-C was 456.1-724.0 ng/mL (1.88-2.98 µM) and terminal half-life was 23.3 to 29.4 hours. Cerebrospinal fluid: serum Ara-C ratios ranged from 0.54 to 1.2. Peripheral blood lymphocyte concentrations remained within the reference range, but proliferation rates poststimulation were decreased at 6 days. Incorporation of Ara-CTP was not saturated and remained >25% of peak concentration at 13 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Oral CO may produce prolonged serum Ara-C half-lives at concentrations sufficient to induce functional changes in peripheral leukocytes and is associated with prolonged retention of DNA-incorporated Ara-CTP. Application of functional and active metabolite assessment is feasible and may provide more relevant data to determine optimal dosing regimens for Ara-C-based treatments.

Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BACKGROUND: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog. HYPOTHESIS/OBJECTIVE: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies. ANIMALS: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs. METHODS: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database. RESULTS: Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.

Peripheral cranial neuropathies consistent with cavernous sinus syndrome caused by extracranial nasopharyngeal lymphoma in a cat.

Cavernous sinus syndrome is a unique constellation of cranial nerve deficits occurring typically as a result of pathologic infiltration of the cavernous sinus, which is located in the lateral sellar compartment of the calvarium. This case report describes a polyneuropathy consistent with cavernous sinus syndrome as a result of a lesion outside of the cavernous sinus. The cat was presented with right internal and external ophthalmoplegia, loss of right corneal sensation, inspiratory stridor, dysphagia, dysphonia, tongue weakness, and weight loss. Magnetic resonance imaging identified a large nasopharyngeal mass along the base of, but without extension into, the calvarium. The histologic diagnosis was nasopharyngeal lymphoma. Focal extracranial masses should be considered as differential diagnoses for multiple cranial nerve deficits, including the constellation of clinical signs recognized as cavernous sinus syndrome.

Neuropathies crâniales périphériques compatibles avec un syndrome du sinus caverneux causé par un lymphome nasopharyngé extra-crânial chez un chat. Le syndrome du sinus caverneux est une constellation unique de déficits des nerfs crâniens se produisant typiquement comme le résultat d'une infiltration pathologique du sinus caverneux, qui est situé dans le compartiment sellaire latéral du calvarium. Le présent rapport de cas décrit une polyneuropathie compatible avec un syndrome du sinus caverneux résultant d'une lésion à l'extérieur du sinus caverneux. Le chat fut présenté avec une ophtalmoplégie interne et externe droit, perte de sensation au niveau de la cornée droite, stridor inspiratoire, dysphagie, dysphonie, faiblesse de la langue, et perte de poids. Un examen d'imagerie par résonnance magnétique permis d'identifier une large masse nasopharyngée suivant la base du calvarium, mais sans extension à l'intérieur. Le diagnostic histologique en fut un de lymphome nasopharyngé. Les masses focales extra-crâniales devraient être considérées dans le diagnostic différentiel lors de déficits de plusieurs nerfs crâniens, incluant la multitude de signes cliniques reconnus comme le syndrome du sinus caverneux.(Traduit par Dr Serge Messier).

A review of Horner's syndrome in small animals.

Horner's syndrome arises from dysfunction of the oculosympathetic pathway and is characterized by miosis, enophthalmos, protrusion of the third eyelid, and ptosis. It has been recognized in a wide variety of breeds and ages in small animal patients. The oculosympathetic pathway is a 3-neuron pathway. The central/first order neuron arises from the hypothalamus and extends down the spinal cord. The preganglionic/second order neuron arises from the first 3 thoracic spinal cord segments and travels through the thorax and cervical region until it synapses at the cranial cervical ganglion. The postganglionic/third order neuron travels from this ganglion to the orbit. Topical application of cocaine is the gold standard for differentiating Horner's syndrome from other causes of miosis. Topical 1% phenylephrine allows for identification of a post-ganglion Horner's syndrome. Numerous etiologies have been reported for Horner's syndrome, but idiopathic disease is most common. Ancillary diagnostics include otoscopic examination, thoracic radiographs, or advanced imaging. Treatment and prognosis are determined by the etiology.

Examen du syndrome de Horner chez les petits animaux. Le syndrome de Horner provient d'une dysfonction de la voie oculo-sympathique et est caractérisée par la miose, l'enophtalmie, la protrusion de la troisième paupière et la ptose. Elle a été reconnue chez une grande variété de races et d'âges chez les patients petits animaux. La voie oculo-sympathique est une voie à trois neurones. Le neurone central/de premier ordre provient de l'hypothalamus et s'étend vers le bas sur la colonne vertébrale. Le neurone préganglionnaire/de deuxième ordre provient des trois premiers segments thoraciques de la colonne vertébrale et se déplace dans le thorax et la région cervicale jusqu'à la synapse au ganglion cervical crânien. Le neurone postganglionnaire/de troisième ordre se déplace de ce ganglion jusqu'à l'orbite. L'application topique de cocaïne est le test de référence pour la différenciation du syndrome de Horner des autres causes de miose. La phényléphrine topique 1 % permet l'identification d'un syndrome de Horner postganglionnaire. Plusieurs étiologies ont été signalées pour le syndrome de Horner, mais la maladie idiopathique est la plus commune. Les diagnostics auxiliaires incluent l'examen otoscopique, des radiographies thoraciques ou une imagerie avancée. Le traitement et le pronostic sont déterminés par l'étiologie.(Traduit par Isabelle Vallières).

Wild hummingbirds rely on landmarks not geometry when learning an array of flowers.

Rats, birds or fish trained to find a reward in one corner of a small enclosure tend to learn the location of the reward using both nearby visual features and the geometric relationships of corners and walls. Because these studies are conducted under laboratory and thereby unnatural conditions, we sought to determine whether wild, free-living rufous hummingbirds (Selasphorus rufus) learning a single reward location within a rectangular array of flowers would similarly employ both nearby visual landmarks and the geometric relationships of the array. Once subjects had learned the location of the reward, we used test probes in which one or two experimental landmarks were moved or removed in order to reveal how the birds remembered the reward location. The hummingbirds showed no evidence that they used the geometry of the rectangular array of flowers to remember the reward. Rather, they used our experimental landmarks, and possibly nearby, natural landmarks, to orient and navigate to the reward. We believe this to be the first test of the use of rectangular geometry by wild animals, and we recommend further studies be conducted in ecologically relevant conditions in order to help determine how and when animals form complex geometric representations of their local environments.