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.

Mammalian motor units: physiological-histochemical correlation in three types in cat gastrocnemius.

The correlation among a variety of physiological properties and the histochemical characteristics of muscle fibers belonging to single motor units in a mixed mammalian muscle is directly demonstrated. The population of motor units making up the cat gastrocnemius was classified into three nonoverlapping groups on the basis of a combination of physiological parameters. The muscle fibers belonging to motor units of each physiological type exhibited a distinctive histochemical profile, such that the three basic histochemical "fiber types" exactly matched the three physiologically defined groups. Within each individual motor unit, the muscle fibers were histochemically uniform.

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.

Crossed buccofacial apraxia.

The cerebral hemisphere contralateral to the preferred hand is generally dominant for learned representational motor acts, including those involving buccofacial muscles. It is generally also language-dominant. This buccofacial apraxia has, with rare exceptions, been associated with left hemispheric lesions in right-handers. We describe two patients with severe buccofacial apraxia caused by large middle cerebral artery territory infarcts in the hemisphere ipsilateral to the preferred hand and nondominant for language. Neither patient had aphasia or major limb apraxia. Computed tomographic scans in the first patient and neuropathologic examination in the second failed to reveal an abnormality of the hemisphere contralateral to the preferred hand. Hence, in some individuals, the hemisphere controlling skilled representational buccofacial movements may not be the one that is dominant either for handedness or for language.

The anatomic basis of delusions after right cerebral infarction.

We studied the nature and causes of delusions after infarction of the right cerebral hemisphere. Delusions involved orientation in time and place, events in the recent past, and the identities of familiar individuals. Some were transient and disorganized, and others were more fixed. No particular site in the right hemisphere was associated with particular delusions. The different delusions may be varied manifestations of a basic disorder of thought and memory. The major determinant of the delusions was cerebral atrophy. Age, location, and size of lesion had no major effect. The superimposition of a new right hemisphere lesion on a diffusely atrophied brain seems to cause delusions that can be expressed verbally because the left hemisphere is relatively preserved.

Visual discrimination after lesion of the posterior corpus callosum.

Visual discrimination was studied in each visual field of a patient with surgical section of the posterior corpus callosum. Light-detection thresholds were increased nearly equally in right and left visual fields, suggesting that normal thresholds require the cooperative activity of both posterior cerebral hemispheres, mediated by the corpus callosum. In contrast, there was superiority in the right visual field in naming, coping, and matching letter, number, and colors, but not unfamiliar shapes. The results are attributed to a differential effect of experience on perception in each visual field. The right-visual-field superiority in learning to perceive arrays on letters, numbers, and colors may result directly from the superiority of the left hemisphere in speech.

Opticosensory ataxia and alien hand syndrome after posterior cerebral artery territory infarction.

A right-handed woman developed left homonymous hemianopia and left hemianesthesia from infarction due to right posterior cerebral artery occlusion. Ataxia of the left arm and leg was severe and was not improved by vision. The patient often interpreted spontaneous movements of the left arm as alien in origin. The ataxia may have been caused by a combination of sensory ataxia, resulting from right thalamic infarction, and crossed-optic ataxia, resulting from posterior disconnection of the hemispheres due to right temporo-occipital infarction. This opticosensory ataxia was associated with a new form of "alien hand" syndrome.

Delayed psychosis after right temporoparietal stroke or trauma: relation to epilepsy.

We observed acute onset of delayed psychosis in 8 patients 1 month to 11 years after right temporoparietooccipital (TPO) stroke or trauma. The psychotic disorder included hallucinations and, in some patients delusions and agitation. All patients had spatioconstructional difficulties. None had an earlier psychiatric disorder. Seven of eight patients had clinical seizures, often in close temporal relationship to the psychosis. The pathophysiology of the psychosis may be related to that of the epilepsy.

Language after bilateral cerebral infarctions: role of the minor hemisphere in speech.

Language was studied in four patients with bilateral cerebral infarctions. Bilateral destruction of the third frontal gyri did not necessarily produce the severely limited language output characteristic of global or severe Broca aphasia; for Broca aphasia to occur, there must be extensive frontoparietal damage in the dominant cerebral hemisphere. Thus, the marked recovery of language after lesions limited to the dominant third frontal gyrus is mediated by adjacent areas of the dominant hemisphere, and not by the nondominant third frontal gyrus. The nondominant hemisphere nevertheless has a limited capacity to produce oral speech after extensive damage to the dominant hemisphere and may play an appreciable, although still subsidiary, role in normal articulation. The central gyri and rolandic operculum may be more essential than the third frontal gyri for well-articulated speech.

Left visual spatial neglect is both environment-centered and body-centered.

To determine whether the left space that is neglected after right hemisphere lesions is body centered or environment centered, we asked patients with right hemisphere stroke and normal controls to report the contents of spatial arrays of objects or words, either while seated or while reclining on their side. The reclining posture eliminated the alignment of the vertical axis of the body with the vertical axis of the environment. Patients made fewer reports to the body left, but also fewer reports to the environment left, independent of body position. This suggest that a cerebral hemisphere directs attention not only relative to the body midline axis, but also relative to an environmental reference frame.

Crossed Wernicke's aphasia.

Severe Wernicke's aphasia occurred suddenly in a right-handed man and persisted with little improvement until he died 54 days later. Postmortem examination showed an infarct in the posterior temporoparietal region of the right hemisphere. This case demonstrates two new features of crossed dextral aphasia. First, language skills may be fully lateralized to the right hemisphere in right-handed patients. Second, when crossed lateralization occurs, the usual localization of aphasic syndromes is common, suggesting that the intrahemispheric organization mediating language activities is the same in the right hemisphere of the crossed dextral and the left hemisphere of the typical right-handed individual.

Acquired learning disability for reading after left temporal lobe damage in childhood.

A 6-year-old boy developed hemorrhage in the left temporal lobe and subsequently underwent left temporal lobectomy. Afterwards, he was completely unable to learn to read or write. Psychological tests showed impairment in verbal learning and memory, with right ear and right visual field superiority in verbal perception. A Wada test showed no aphasia after right carotid injection. We conclude that damage to the speech-dominant temporal lobe resulted in the inability to learn to read or write. Despite the lesion, speech remained strongly lateralized to the left hemisphere, accounting for the right-sided advantage in verbal perception. Some patients with developmental dyslexia may have dysfunction of a strongly dominant left hemisphere rather than a delay or incompleteness of language lateralization.

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.

Two visual systems in mental imagery: dissociation of "what" and "where" in imagery disorders due to bilateral posterior cerebral lesions.

We studied two patients with impaired visual perception and imagery caused by bilateral posterior cerebral lesions. The first had prosopagnosia and achromatopsia, and the imagery disorder involved the description of objects from memory, especially faces and animals, and colors of objects. The second had visual disorientation; the imagery problem involved the description of spatial relations from memory. Impairments of visual imagery, like disorders of visual perception, can be dissociated. Object and color imagery may be dissociated from imagery for spatial relations. A given imagery deficit tends to be associated with the corresponding type of perceptual deficit.

Dementia after surgery for cerebellar stroke: an unrecognized complication of acute hydrocephalus?

Three patients became demented after surgery for cerebellar hemorrhage or infarction with acute hydrocephalus. All were inattentive, perseverative, and disoriented. They had difficulty with memory, and trouble solving arithmetic problems or copying geometric figures. None showed aphasia, apraxia, or agnosia, although one had word-finding difficulty. One improved substantially in 6 months; one improved slightly in 1 year, and one did not change. None had persistent hydrocephalus. Acute hydrocephalus may have damaged the periventricular white matter to cause the dementia.

Crossed aphasia in a dextral: a clinicopathological study.

Severe Broca aphasia and left hemiplegia without right limb apraxia occurred suddenly in a right-handed man with no personal or family history of left-handedness. Postmortem examination showed infarction of the right hemisphere, limited almost entirely to the precentral gyrus. In this patient, cerebral dominance for speech lay in the right hemisphere, but dominance for limb praxis lay in the left. This case provides evidence that cerebral dominance for speech and handedness in dextrals may be dissociated. It also suggests that lesions of the precentral gyrus are of major importance in producing Broca aphasia.

Inaccurate reaching associated with a superior parietal lobe tumor.

A man with a tumor in the right superior parietal lobule had difficulty reaching for visualized objects. There were no significant deficits in visual sensation, visual attention, somatosensory function, elementary motility, praxis, or visuospatial performance. If allowed to visually fixate the target before reaching, he misreached only with his left arm and only when he was not allowed to observe the reaching limb. If he was required to maintain central visual fixation while reaching into his peripheral visual fields, his left arm misreached into both visual hemifields but his right arm misreached only into the left visual hemifield. These results demonstrate abnormalities, referable to both the contralateral arm and the contralateral visual field, that can neither be reduced to elementary disturbances of visual or somatosensory function nor to an elementary disturbance of motility. This pattern of misreaching has not been previously reported in human subjects or in experimental animals, but this may be attributable to differences of methodology. The misreaching observed in this patient may correspond to loss of posterior parietal neurons serving a supramodal integrative function.