The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling

The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.     

Mineralized,obstructive cardiac myxoma with chondroid differentiation in a cocker spaniel

A 12-year-old castrated male cocker spaniel dog was referred for evaluation of signs consistent with right-sided heart failure. Thoracic radiography revealed mineralization in the region of the right atrium. Echocardiography identified a mass partially filling the right atrium and right ventricle and obstructing flow through the right heart. These findings were confirmed at necropsy and histopathologic features were consistent with myxoma with chondroid differentiation.     

Nerve insensitivity resistance to cypermethrin in larvae of the tobacco budworm Heliothis virescens from USA cotton field populations

Spontaneous neuronal activity was recorded from the peripheral nerves of third-instar larvae of strains of Heliothis virescens (F.) obtained directly from cotton fields in the USA. Following a control period the preparations were exposed to increasing concentrations of cis-cypermethrin in a cumulative dose-response assay. A positive response was defined as an increase of at least five-fold in the rate of neuronal activity over that seen during the control period. Up to 35 individuals of each strain were assayed and the responses used to construct a phenotypic profile categorising the individuals from nerve-susceptible to highly nerve-insensitive. An EC₅₀ for the action of cis-cypermethrin was also obtained. There was a positive, significant correlation between non-synergisable resistance to cypermethrin and nerve insensitivity as defined in the neurophysiological assay. It was shown that nerve insensitivity to cypermethrin increased throughout the cotton-growing season.     

Congenital internal hydrocephalus in a quarter horse foal

Since the normal absorption of CSF occurs in the cerebral veins and venous sinuses, any obstruction to the normal flow and absorption of CSF will result in accumulation of CSF central to the site of obstruction. Such accumulation within the cranium is defined as hydrocephalus.A foal was presented with an enlarged and an abnormally-shaped skull, but with normal behavior. The filly's condition deteriorated. Radiographs showed a domeshaped cranial vault with compression of the frontal sinus region. Massive hydrocephalus with little normal cerebral tissue left was diagnosed with ultrasound.Surgery was attempted to relieve the pressure. Eventually the foal was euthanized. Post-mortem confirmed the radiographic and ultrasound diagnosis. Since there was a lack of demonstrable obstruction, the authors suspected the foal had suffered from the Arnold-Chiari syndrome.     

Effects of monoamines formed in the cecum of horses on equine digital blood vessels and platelets

OBJECTIVE: To determine in vitro vasoactive potency of monoamines formed in the cecum and found in the systemic circulation of horses. SAMPLE POPULATION: Segments of digital blood vessels obtained from 6 healthy mixed-breed horses and ponies euthanatized at an abattoir and platelets isolated from 4 healthy ponies. PROCEDURE: Paired rings of digital artery and vein from the same horse were examined, and isometric tension was recorded. Concentration-response curves for tryptamine (TRP), tyramine (TYR), phenylethylamine (PEA), isoamylamine (IAA), and isobutylamine (IBA) were obtained. Vasoconstrictor mechanisms were investigated for TRP and TYR by the use of antagonists. Washed platelets loaded with [3H]-5-hydroxytryptamine (5-HT) were incubated with monoamines; the amount of radioactivity displaced after 30 minutes was estimated. RESULTS: TRP, TYR, and PEA were potent constrictors of arteries and veins, with TRP and TYR being more potent in veins than arteries. Constrictions induced by TYR were inhibited by benextramine (alpha-antagonist) and nisoxetine (neuronal-uptake blocker), whereas TRP responses were inhibited by ketanserin (5-HT receptor antagonist). All 5 amines displaced 5-HT from platelets with the order of potency being TYR > TRP > PEA > IAA > IBA. CONCLUSIONS AND CLINICAL RELEVANCE: Amines from the equine cecum cause digital vasoconstriction. The most potent (TRP and TYR) cause selective venoconstriction. Tyrosine activates predominantly alpha-adrenoceptors through the release of neuronal norepinephrine, whereas TRP activates 5-HT receptors. All amines tested released 5-HT from platelets. Amines formed in the cecum and released into the systemic circulation warrant additional investigation as trigger factors for digital ischemia and subsequent laminitis.     

Angularis oris axial pattern buccal flap for reconstruction of recurrent fistulae of the palate

OBJECTIVE: To describe the use of an axial pattern flap based on the angularis oris artery and vein for reconstruction of palate defects. STUDY DESIGN: Clinical case report ANIMALS: Two dogs with recurrent oronasal fistulae. METHODS: Oronasal fistulae previously treated by buccal mucosal random pattern flaps that subsequently dehisced were repaired using an angularis oris-based buccal tissue axial pattern flap. This flap was developed by full thickness incision of the cheek tissue, excluding the skin, about the angularis oris vascular pedicle resulting in a vascularized flap covered by oral mucosa on one side. RESULTS: In one dog, the repair was intact and healed 6 months after surgery. In the second dog with a fistula that resulted because of radiation necrosis, approximately 95% of the defect healed with a small (<1.0 cm(2)) area of dehiscence. Repair of this persistent fistula with a random pattern buccal flap failed and this small fistula remained with minimal clinical signs. CONCLUSION: An axial pattern flap based on the angularis oris artery and vein can be used to repair difficult or recurrent palate defects. CLINICAL RELEVANCE: Angularis oris axial pattern flaps provide an additional effective option for repair of defects in the hard and soft palate to the distal gingival margin of the canine tooth or beyond, depending on skull conformation. Advantages of this flap include its highly vascular and robust character, high degree of mobility and a surface of tough buccal mucosa.     

Effects of the calcium channel antagonist amlodipine in cats with surgically induced hypertensive renal insufficiency

OBJECTIVE: To determine whether amlodipine besylate decreases systemic arterial blood pressure (BP) and reduces the prevalence of complications in cats with induced hypertensive renal insufficiency. ANIMALS: 20 cats with partial nephrectomy. PROCEDURE: Following reduction in renal mass, 10 cats were administered 0.25 mg of amlodipine/kg, PO, q 24 h (group A). Ten cats served as a control group (group C). Systolic BP (SBP), diastolic BP (DBP), and mean BP (MBP), physical activity, and pulse rate were measured continuously for 36 days by use of radiotelemetric devices. RESULTS: Compared with values for clinically normal cats, SBP, DBP, and MBP were significantly increased in cats of group C. Cats in group A had significant reductions in SBP, DBP, and MBP, compared with values for cats in group C. Albuminuria but not urine protein-to-creatinine ratio was significantly correlated (R2 = 0.317) with SBP in hypertensive cats. Prevalence of ocular lesions attributable to systemic hypertension in group C (7 cats) was greater than that observed in group A (2). Two cats in group C were euthanatized on day 16 because of nuerologic complications attributed to systemic hypertension. One normotensive cat in group A was euthanatized because of purulent enteritis of unknown cause on day 27. CONCLUSIONS AND CLINICAL RELEVANCE: Amlodipine had an antihypertensive effect in cats with coexistent systemic hypertension and renal insufficiency. Its use may improve the prognosis for cats with systemic hypertension by decreasing the risk of ocular injury or neurologic complications induced by high BP.     

Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation

OBJECTIVE: To determine prevalence of systolic hypertension and associated risk factors in cats with chronic renal failure evaluated in first-opinion practice. DESIGN: Prospective study. ANIMALS: 103 cats with chronic renal failure. PROCEDURE: Systolic arterial blood pressure (SABP) was measured with a noninvasive Doppler technique, and cats that had SABP > 175 mm Hg on 2 occasions or that had SABP > 175 mm Hg and compatible ocular lesions were classified as hypertensive. Information from the history (previous treatment for hyperthyroidism, age), physical examination (sex, body weight), routine plasma biochemical analyses (creatinine, cholesterol, potassium, sodium, chloride, and calcium concentrations), and thyroid status were evaluated as potential risk factors for systolic hypertension. Variables associated with systolic hypertension were evaluated by use of logistic regression. RESULTS: 20 (19.4%; 95% confidence interval, 13 to 28%) cats had systolic hypertension. Plasma potassium concentration was significantly and inversely associated with systolic hypertension. CONCLUSIONS AND CLINICAL RELEVANCE: Prevalence of systolic hypertension, although clinically important, was lower than that reported previously. The cause of the inverse association between systolic hypertension and plasma potassium concentration is not yet known.     

Use of intraluminal nitinol stents in the treatment of tracheal collapse in a dog

Tracheal collapse is a common problem that is typically observed in middle-aged and older small-breed dogs. It is a structural, obstructive airway disease with a dynamic component that can affect the intra- and extrathoracic portions of the trachea and mainstem bronchi. Many methods of treatment have been suggested, including medical management and provision of extraluminal and intraluminal support. All techniques used to treat intrathoracic and mainstem bronchial collapse have been associated with major complications or limitations. This report describes the implantation of intraluminal nitinol stents to successfully treat intrathoracic as well as extrathoracic tracheal collapse in a dog. The stents are composed of material that has characteristics similar to those of the trachea; nitinol stents may provide a method of supporting intrathoracic tracheal and mainstem bronchial collapse in dogs.