Use of rivaroxaban for treatment of cranial vena cava syndrome secondary to transvenous pacemaker lead thrombosis in a dog.

A six-year-old Brussels griffon was presented for cervical swelling three months after implantation of a transvenous pacemaker. Transthoracic echocardiography demonstrated a thrombus associated with the pacemaker lead, partially obstructing right atrial inflow. The laboratory findings were consistent with protein-losing nephropathy. Initial medical therapy consisted of rivaroxaban (0.68 mg/kg orally every 24 hours), clopidogrel (2.5 mg/kg orally every 24 hours), and enalapril (0.5 mg/kg orally every 12 hours). Resolution of cervical and thoracic edema was noted within two weeks of initiating therapy. Recheck echocardiography two months and one year later revealed decreasing thrombus size despite worsening proteinuria. To the authors' knowledge, this is the first documented use of rivaroxaban for successful medical treatment of cranial vena cava syndrome caused by intracardiac pacemaker lead thrombosis in a hypercoagulable patient.

Development of a fibrinolysis assay for canine plasma.

Unbalanced coagulation and fibrinolysis leads to hemorrhage or thrombosis. Thromboelastography has been used to characterize hypo- and hyper-fibrinolysis in dogs, however the technique requires specialized instrumentation and proprietary reagents that limit its availability. The aim of this study was to develop a simple microplate method for assessment of fibrinolysis in canine plasma. Plasma from healthy dogs was mixed in a microwell plate with tissue factor, calcium, phospholipid and tissue plasminogen activator. Light absorbance was measured at regular intervals until return to baseline. Peak optical density (milli-absorption units, mAU), formation velocity (mAU/s), lysis velocity (mAU/s) and area under the curve (mAU.s) were calculated. The influence of potential interferents, variation in fibrinogen and ex vivo addition of heparin and aminocaproic acid on assay performance was determined. Inter-day coefficients of variation were ≤15% for all variables. Bilirubin≤1.88mg/dL and hemoglobin≤0.09mg/dL did not interfere with assay variables. Aminocaproic acid (40µg/mL) and heparin (0.125U/mL) caused almost complete inhibition of fibrinolysis and coagulation, respectively. All variables except lysis velocity (R2=0.08) were associated with fibrinogen concentration (R2>0.8). This assay showed acceptable performance characteristics for measurement of fibrinolysis in normal canine plasma. The assay utilizes small volume citrate plasma samples and readily available instrumentation and reagents, is not influenced by mild to moderate hemolysis or icterus and detects the presence of fibrinolysis inhibitors.

Cell-Free DNA and DNase Activity in Dogs with Immune-Mediated Hemolytic Anemia.

BACKGROUND: Immune-mediated hemolytic anemia (IMHA) in dogs has a high risk of thrombosis and is associated with marked neutrophilia and necrosis. Cell death and release of neutrophil extracellular traps contribute to increased serum concentrations of cell-free DNA, and in human autoimmune disease reduced DNase activity further increases cell-free DNA. Free DNA in blood has prothrombotic properties and could contribute to hypercoagulability in IMHA. HYPOTHESIS: Cell-free DNA is elevated and DNase activity reduced in dogs with IMHA compared to healthy dogs. ANIMALS: Dogs presenting to two referral hospitals with IMHA (n = 28) and healthy controls (n = 20). METHODS: Prospective observational study. Blood was collected and death and thrombotic events occurring in the first 14 days after hospitalization recorded. DNA was extracted from plasma with a commercial kit and quantified by PicoGreen fluorescence. DNase activity of serum was measured by radial diffusion assay. RESULTS: Cell-free DNA was significantly higher in cases (median: 45 ng/mL, range: 10-2334 ng/mL) than controls (26 ng/mL, range 1-151 ng/mL, P = 0.0084). DNase activity was not different between cases and controls (P = 0.36). Four cases died and there were five suspected or confirmed thrombotic events. Cell-free DNA concentration was associated with death (odds ratio for upper quartile versus lower 3 quartiles: 15; 95% confidence interval 1.62-201; P = 0.03) but not thrombosis (P = 0.57). CONCLUSIONS AND CLINICAL IMPORTANCE: Cell-free DNA is elevated in dogs with IMHA and likely reflects increased release rather than impaired degradation of DNA. Cell-free DNA concentration is potentially associated with death and might be a prognostic indicator, but this requires confirmation in a larger population.

Association of Sphingosine-1-phosphate (S1P)/S1P Receptor-1 Pathway with Cell Proliferation and Survival in Canine Hemangiosarcoma.

BACKGROUND: Sphingosine-1-phosphate (S1P) is a key biolipid signaling molecule that regulates cell growth and survival, but it has not been studied in tumors from dogs. HYPOTHESIS/OBJECTIVES: S1P/S1P1 signaling will contribute to the progression of hemangiosarcoma (HSA). ANIMALS: Thirteen spontaneous HSA tissues, 9 HSA cell lines, 8 nonmalignant tissues, including 6 splenic hematomas and 2 livers with vacuolar degeneration, and 1 endothelial cell line derived from a dog with splenic hematoma were used. METHODS: This was a retrospective case series and in vitro study. Samples were obtained as part of medically necessary diagnostic procedures. Microarray, qRT-PCR, immunohistochemistry, and immunoblotting were performed to examine S1P1 expression. S1P concentrations were measured by high-performance liquid chromatography/mass spectrometry. S1P signaling was evaluated by intracellular Ca(2+) mobilization; proliferation and survival were evaluated using the MTS assay and Annexin V staining. RESULTS: Canine HSA cells expressed higher levels of S1P1 mRNA than nonmalignant endothelial cells. S1P1 protein was present in HSA tissues and cell lines. HSA cells appeared to produce low levels of S1P, but they selectively consumed S1P from the culture media. Exogenous S1P induced an increase in intracellular calcium as well as increased proliferation and viability of HSA cells. Prolonged treatment with FTY720, an inhibitor of S1P1 , decreased S1P1 protein expression and induced apoptosis of HSA cells. CONCLUSIONS AND CLINICAL IMPORTANCE: S1P/S1P1 signaling pathway functions to maintain HSA cell viability and proliferation. The data suggest that S1P1 or the S1P pathway in general could be targets for therapeutic intervention for dogs with HSA.

Endoscopic assessment of the duodenum in dogs with inflammatory bowel disease.

BACKGROUND: Endoscopy is performed for direct inspection of the mucosa and acquisition of biopsies in dogs with inflammatory bowel disease (IBD). AIM: To evaluate the interobserver agreement in the endoscopic assessment of duodenal mucosa in dogs with IBD. METHODS: Thirty-five archived endoscopic images of grossly normal (n = 6) and inflamed (n = 29) duodenal mucosa were displayed to 3 expert and 5 trainee endoscopists. Each image was assessed independently by endoscopists for mucosal abnormalities using established indices (of hyperemia, granularity, friability, lymphatic dilatation, and erosions) or interpreted as normal mucosa (trial 1). A repeated trial (trial 2) was performed with the same images presented in random order 1 month later, and accompanied by a visual template. RESULTS: There was slight interobserver agreement in initial mucosal assessment for expert and trainee endoscopists in trial 1 (kappa ≤ 0.02, P > .05). Interobserver agreement improved in trial 2 for both expert and trainee endoscopists (kappa = 0.2, P > .05) for experts and (P < .05) for trainees. There was a significant (P < .01) improvement in trainee endoscopy scores of lesions from trial 1 to trial 2. Regression analysis showed a significant (P < .01) difference between expert versus trainee endoscopy scores in trial 1. Repeat lesion assessment aided by use of a visual template (trial 2) improved the overall scores of trainee endoscopists to near that of expert endoscopists (P = .06). CONCLUSIONS AND CLINICAL IMPORTANCE: Interobserver agreement of IBD mucosal appearance from endoscopic findings benefitted from operator experience.

Ronidazole pharmacokinetics in cats following delivery of a delayed-release guar gum formulation.

Ronidazole (RDZ) is the only known effective treatment for feline diarrhea caused by Tritrichomonas foetus. This study aimed to develop guar gum-coated colon-targeted tablets of RDZ and to determine the pharmacokinetics of this delayed-release formulation in cats. Guar gum-coated tablets were administered orally once to five healthy cats (mean dose 32.3 mg/kg). The tablets were then administered once daily for 5 days to four cats (mean dose 34.5 mg/kg), and absorption studies repeated on day 5. Plasma was collected and analyzed for RDZ concentration, and pharmacokinetic noncompartmental and deconvolution analysis were performed on the data. There was negligible RDZ release until after 6 h, and a delayed peak plasma concentration (mean Cmax 28.9 µg/mL) at approximately 14.5 h, which coincides with colonic arrival in cats. Maximum input rate (mg/kg per hour) occurred between 6 and 16 h. This delayed release of ronidazole from guar gum-coated tablets indicates that release of RDZ may be delayed to deliver the medication to a targeted area of the intestine. Repeated dosing with guar gum tablets to steady-state did not inhibit drug bioavailability or alter the pharmacokinetics. Such targeted RDZ drug delivery may provide improved efficacy and reduce adverse effects in cats.

The pathophysiology of lumbar puncture headache.

The pathophysiology of lumbar puncture headache (LPH) is still unclear. There is evidence that leakage of cerebrospinal fluid (CSF) leads to CSF hypotension, which causes dilation of intracranial veins, resulting in LPH. However, CSF leaks at the skull base are not associated with orthostatic headache; there is poor correlation between recumbent CSF pressure and LPH; and there has been no satisfactory explanation of how venous dilation causes orthostatic headache. We propose the hypothesis that LPH is caused by an abnormal distribution of craniospinal elasticity. Increased compliance at the lumbar end of the spinal CSF space, resulting both from anatomic joining of the subarachnoid to the epidural space and from reduced CSF filling pressure, causes the hydrostatic indifferent point to move caudally, creating additional intracranial hypotension and venous dilation in the erect position. We are, thus, able to explain the orthostatic character of LPH, the fact that spinal but not cranial sites of leakage produce orthostatic headache and the imperfect correlations both between recumbent CSF pressure and LPH and between reduced CSF volume and LPH. The near absence of LPH in the very young and in the elderly relates to the relative stiffness of the epidural space at these ages. Epidural injections of blood or saline give immediate relief by reducing epidural distensibility.

Ventricular size in pseudotumor cerebri and the theory of impaired CSF absorption.

The purpose of this theoretical study is to determine whether the absence of ventricular enlargement in pseudotumor cerebri (PTC) is consistent with the theory that PTC is caused by reduced absorption of cerebrospinal fluid (CSF), either from increased outflow resistance at the arachnoid villi or from obstruction of the dural venous sinuses. We model the brain as a thick spherical shell of parenchyma, enclosing a CSF-filled ventricular system, and surrounded by a thin cerebral subarachnoid space (CSAS). We treat the parenchyma as a porous solid matrix, filled with interstitial fluid and blood vessels. We subject the model to a uniform increase in CSF pressure (CSFP) and solve the equations of poroelasticity for the resulting displacements of parenchymal tissue. The effect of a rise in CSFP on ventricular size depends on the response of the cerebral blood vessels and the degree to which the pia is tethered to the dura. If the cerebral vessels decrease in caliber with increasing CSFP, a rise in CSFP causes the ventricles to contract and the CSAS to expand if the pial surface is free to move inward, but causes slight ventricular enlargement if the pia is tethered to the dura. If, instead, the vessels dilate, the ventricles contract and the CSAS becomes effaced. Small, normal, or slightly enlarged ventricles in PTC are consistent with the theory of reduced CSF absorption.

The pathogenesis of normal pressure hydrocephalus: a theoretical analysis.

Hydrocephalus is an abnormal accumulation of cerebrospinal fluid (CSF) in the cerebral ventricles, usually caused by impaired absorption of the fluid into the bloodstream. Despite obstructed absorption and continued secretion of CSF into the ventricles at a near normal rate, the ventricular CSF pressure (VCSFP) is often normal. We attempt to understand how hydrocephalus can exist with normal VCSFP by exploring the role of the brain parenchyma in absorbing CSF in hydrocephalus. We test three theories: (1) the ventricular wall is impermeable to CSF; (2) ventricular CSF seeps into the parenchyma, from which it is efficiently absorbed; and (3) ventricular CSF seeps into the parenchyma but is absorbed inefficiently. We model the brain as a thick spherical shell consisting of a porous, elastic, solid matrix, containing interstitial fluid and blood. We modify the equations of poroelasticity, which describe flow of fluid through porous solids, to allow for parenchymal absorption. For each of the three theories we calculate the steady state changes in VCSFP and in parenchymal fluid pressure caused by an incremental defect in CSF absorption. We also calculate the-steady state changes in fluid content, tissue volume, tissue displacement, and stresses caused by a small increment of VCSFP. We conclude that only the second theory-seepage of CSF with efficient parenchymal absorption-accounts for the clinical features of normal pressure hydrocephalus. These features include sustained ventricular dilatation despite normal VCSFP, increased periventricular fluid content, and localized periventricular white matter damage.

Spontaneous pulsation of the retinal veins.

The classical theory of spontaneous pulsation of the retinal veins is that during systole intraocular pressure exceeds venous pressure, causing the veins to collapse. We show that this theory is internally inconsistent and not in accord with experimental data. It is inconsistent in assuming both (a) that oscillations of intraocular pressure (IOP) occur because the veins cannot immediately discharge the systolic arterial inflow and (b) that retinal venous pressure (RVP) can fluctuate independently of IOP during the cardiac cycle. It is not in accord with experimental data, which shows that RVP always exceeds IOP and that fluctuations in the latter are instantly transmitted to the former. We present an alternative theory that does not have these problems. We assume the following. (1) Inflow to the retinal venous tree from the capillaries is constant, the pulsatile arterial flow having been completely damped by the arterioles and capillaries. (2) Outflow from the central retinal vein (CRV) varies during the cardiac cycle because oscillations of IOP, transmitted to the intraocular CRV, are of greater amplitude than oscillations in cerebrospinal fluid pressure, transmitted to the extraocular CRV. By showing that the radial blood flow distending the veins obeys a diffusion equation and by employing an "equivalent cylinder" analysis of the branched venous tree to simplify the boundary conditions, we demonstrate that, with the above assumptions and the additional assumption of low amplitude of radial flow, the CRV will pulsate, and the pulsations will remain confined to a small segment near the exit point. The proposed theory can explain disappearance of pulsation with intracranial hypertension, intensification of pulsation in glaucoma, and variability in the linear extent and amplitude of pulsation among normal individuals. The theory may also be applied to other venous pulsations, such as the respiratory pulsation of the terminal portions of large veins entering the thorax or the cardiac cycle pulsation of the superior vena cava.

Pathogenesis of cervical spondylotic myelopathy.

OBJECTIVE: To determine whether either of two mechanical theories predicts the topographic pattern of neuropathology in cervical spondylotic myelopathy (CSM). The compression theory states that the spinal cord is compressed between a spondylotic bar anteriorly and the ligamenta flava posteriorly. The dentate tension theory states that the spinal cord is pulled laterally by the dentate ligaments, which are tensed by an anterior spondylotic bar. METHODS: The spinal cord cross section, at the level of a spondylotic bar, is modelled as a circular disc subject to forces applied at its circumference. These forces differ for the two theories. From the pattern of forces at the circumference the distribution of shear stresses in the interior of the disc-that is, over the transverse section of the spinal cord-is calculated. With the assumption that highly stressed areas are most subject to damage, the stress pattern predicted by each theory can be compared to the topographic neuropathology of CSM. RESULTS: The predicted stress pattern of the dentate tension theory corresponds to the reported neuropathology, whereas the predicted stress pattern of the compression theory does not. CONCLUSIONS: The results strongly favour the theory that CSM is caused by tensile stresses transmitted to the spinal cord from the dura via the dentate ligaments. A spondylotic bar can increase dentate tension by displacing the spinal cord dorsally, while the dural attachments of the dentate, anchored by the dural root sleeves and dural ligaments, are displaced less. The spondylotic bar may also increase dentate tension by interfering locally with dural stretch during neck flexion, the resultant increase in dural stress being transmitted to the spinal cord via the dentate ligaments. Flexion of the neck increases dural tension and should be avoided in the conservative treatment of CSM. Both anterior and posterior extradural surgical operations can diminish dentate tension, which may explain their usefulness in CSM. The generality of these results must be tempered by the simplifying assumptions required for the mathematical model.

The visual variant of Alzheimer's disease: a clinicopathologic case study.

A 59-year-old man developed problems with reading and driving. When first examined, he had great difficulty locating and identifying items by sight. Visual acuity was normal, but contrast sensitivity for low spatial frequencies was severely impaired. The peripheral visual fields were moderately constricted with depressed flicker fusion frequencies, more on the right. Color identification was preserved. The difficulties in identifying and locating objects by sight were aggravated by increasing the complexity and multiplicity of the items in the field of vision and by changing the ambient illumination. Intellect and memory were relatively intact, except for difficulty with calculations. Over a 12-year course the visual defects steadily worsened, and eventually memory and language skills failed. Social manners, perseverance, and affect remained normal. Postmortem examination showed cortical atrophy, predominantly posterior, with abundant neurofibrillary tangles and senile plaques. The density of the tangles was correlated with the severity of the atrophy, being highest in the occipitoparietal areas and lowest in the frontal lobes. Alzheimer's disease can preferentially affect the posterior cerebral hemispheres and cause a dementia presenting with, and dominated by, visual disturbances.

The pathogenesis of anosognosia for hemiplegia.

We compared patients with unawareness of hemiplegia lasting more than 1 month after right hemisphere stroke with other patients with right hemisphere stroke who became aware of hemiplegia within a few days after onset. Patients with persistent unawareness invariably had severe left hemisensory loss and usually had severe left spatial neglect. They were almost always apathetic; their thought lacked direction, clarity, and flexibility, and they had at least moderate impairment of intellect and memory. Their right hemisphere strokes were large and always affected the central gyri or their thalamic connections and capsular pathways. In addition, there was evidence of at least mild left hemisphere damage, most commonly caused by age-associated atrophy. The pathogenesis of anosognosia for hemiplegia may involve failure to discover paralysis because proprioceptive mechanisms that ordinarily inform an individual about the position and movement of limbs are damaged, and the patient, because of additional cognitive defects, lacks the capacity to make the necessary observations and inferences to diagnose the paralysis. We discuss the implications of this "discovery" theory and contrast it with other explanations of anosognosia.

Reappearance of the visual percept after intentional blinking in a patient with Balint's syndrome.

We present a patient with Balint's syndrome who complained of fading of the scenes under visual fixation. When he intentionally blinked, the faded visual percept reappeared. The disappearance of the visual percept may be explained as the result of either unstable visual fixation or of saturation of the visual pathways. The role of blinking in reviving the visual percept may be explained accordingly as causing a refixation of the target under visual fixation or as resetting the visual pathways for visual processing.

Unawareness of visual and sensorimotor defects: a hypothesis.

A theory is proposed to account for unawareness of blindness, hemianopsia, and hemiplegia, and for phantom limb after amputation. It is assumed that interruption of a sensory pathway at any level--from peripheral nerve to primary sensory cortex--is not associated with any immediate sensory experience that uniquely specifies the defect. Instead the sensory loss must be discovered by a process of self-observation and inference. Discovery is easy for defects that create major functional disability, such as total blindness. Hence unawareness of total blindness occurs only in association with severe intellectual impairment, precluding the required self-observation and inference. In contrast, hemianopsia is difficult to discover because several mechanisms automatically compensate the defect effectively. Thus unawareness of hemianopsia is common, even in intellectually normal individuals. Insensate fields are often the source of suggested (false) percepts, because no information from such a field specifies the absence of a sensory stimulus. The most powerful source of suggestion is sensory activity in uninvolved portions of the affected sensory field. Thus hemianopsics may perceive complete geometric forms when only incomplete forms are shown and the missing portion falls in the hemianopsic fields. Such perceptual completion also occurs in hemianesthetic hemiplegics, creating the illusion that there are normally functioning limbs on the affected side. This perceptual completion increases the difficulty of discovery of hemianesthetic hemiplegia, but the disability is still sufficiently obvious that some additional cognitive impairment is invariably present in patients with lasting unawareness of hemiplegia. Phantom limb after amputation is the product of perceptual completion without associated cognitive impairment. The patient with phantom limb is thus aware of the illusory quality of his phantom. Some insight into the neural basis of perceptual completion and of unawareness of sensory loss may derive from considering sensory systems and associative cortex as parallel-distributed processing mechanisms.

Peduncular hallucinosis associated with isolated infarction of the substantia nigra pars reticulata.

We report the clinicopathological study of an 83-year-old man who abruptly developed complex visual hallucinations, disordered sleep, and mild cognitive impairment that persisted until his death 6 months later. Postmortem neuropathological examination including serial sections through the diencephalon, midbrain, and pons disclosed isolated bilateral infarcts confined to the medial substantia nigra pars reticulata. The findings suggest that destruction of the pars reticulata may be the essential feature to the development of peduncular hallucinosis.

Impaired verbal reasoning and constructional apraxia in subjects with right hemisphere damage.

In addition to causing visuospatial deficits, damage to the right cerebral hemisphere also impairs other cognitive abilities, including those requiring higher-order aspects of language. The present study used a standardized test battery to examine the relationship between visuospatial abilities and comprehension of narrative material in subjects having unilateral right hemisphere damage (RHD). In a series of 41 consecutively admitted RHD subjects, impairments in abstracting information from narrative passages were as prevalent and as severe in magnitude as constructional apraxia. Moreover, the extent of the visuospatial and linguistic impairments were highly correlated. Although age, educational levels, and degree of premorbid brain atrophy were all found to influence performance, analysis of a select subgroup of the population established that the covariation of visuospatial and verbal impairments is related to right hemisphere damage per se. Clinically, these findings may be of significance for understanding the pervasive cognitive impairments that are often evidenced by RHD patients.