Malignant Cutaneous Peripheral Nerve Sheath Tumour with Rhabdomyosarcomatous Differentiation (Triton Tumour) in a Domestic Cat.

Divergent differentiation is encountered frequently within human malignant peripheral nerve sheath tumours (MPNSTs). The new component is often a rhabdomyosarcoma, but in animals this specific form of divergent differentiation within MPNSTs has only been reported once (in a dog). Incisional wedge biopsy of a locally extensive, ventral abdominal wall mass, which extended from the dermis to the subcutis, from a 12-year-old female domestic shorthaired cat, was performed. The tissue was examined with routine haematoxylin and eosin staining and immunohistochemical methods. A malignant neoplasm with spindle and polygonal cell components and progression towards a rhabdomyosarcomatous phenotype was observed. Both neoplastic cell populations exhibited strong expression of vimentin and there was multifocal expression of S100 and desmin. There was strong cytoplasmic labelling for α-sarcomeric actin and muscle actin and weak labelling for myoglobin within the cells positive for desmin. There was multifocal positive nuclear labelling for myogenin. Glial fibrillary acidic protein, α-smooth muscle actin, microphthalmia-associated transcription factor and melanoma antigen recognized by T cells were not expressed. Microscopical features, aided by immunohistochemistry, identified a MPNST with progression towards a rhabdomyosarcomatous phenotype, a so-called 'triton tumour'. A Schwann cell component could account for the divergent patterns of growth, given the plasticity of the neural crest. Nerve sheath tumours have been reported in the skin and subcutis of cats and are a differential diagnosis of feline cutaneous spindle cell neoplasms.

Clinicopathologic Features and Magnetic Resonance Imaging Findings in 24 Cats With Histopathologically Confirmed Neurologic Feline Infectious Peritonitis.

BACKGROUND: Feline infectious peritonitis (FIP) is the most common infectious central nervous system (CNS) disease in the cat and is invariably fatal. Improved means of antemortem diagnosis is required to facilitate clinical decision making. Information regarding the magnetic resonance imaging (MRI) findings of neurologic FIP currently is limited, resulting in the need for better descriptions to optimize its use as a diagnostic tool. OBJECTIVE: To describe the clinicopathologic features and MRI findings in cases of confirmed neurologic FIP. ANIMALS: Twenty-four client-owned cats with histopathologic confirmation of neurologic FIP. METHODS: Archived records from 5 institutions were retrospectively reviewed to identify cases with confirmed neurologic FIP that had undergone antemortem MRI of the CNS. Signalment, clinicopathologic, MRI, and histopathologic findings were evaluated. RESULTS: Three distinct clinical syndromes were identified: T3-L3 myelopathy (3), central vestibular syndrome (7), and multifocal CNS disease (14). Magnetic resonance imaging abnormalities were detected in all cases, including meningeal contrast enhancement (22), ependymal contrast enhancement (20), ventriculomegaly (20), syringomyelia (17), and foramen magnum herniation (14). Cerebrospinal fluid was analysed in 11 cases; all demonstrated a marked increase in total protein concentration and total nucleated cell count. All 24 cats were euthanized with a median survival time of 14 days (range, 2-115) from onset of clinical signs. Histopathologic analysis identified perivascular pyogranulomatous infiltrates, lymphoplasmacytic infiltrates, or both affecting the leptomeninges (16), choroid plexuses (16), and periventricular parenchyma (13). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnetic resonance imaging is a sensitive means of detecting neurologic FIP, particularly in combination with a compatible signalment, clinical presentation, and CSF analysis.

Retrospective evaluation of COX-2 expression, histological and clinical factors as prognostic indicators in dogs with renal cell carcinomas undergoing nephrectomy.

Limited veterinary literature is available regarding prognostic markers for canine renal cell carcinoma (CRCC). We retrospectively evaluated COX-2 expression, histological and clinical features associated with prognosis of CRCC. Sixty-four cases post-nephrectomy were included, 54 had histopathological assessment and 30 had COX-2 immunostaining performed. Eight dogs (13%) had metastatic disease at initial diagnosis. Twenty-seven dogs (42%) received adjuvant therapy after nephrectomy. On univariate analysis, COX-2 expression, mitotic index (MI), histologic type, vascular invasion, neoplastic invasiveness and metastasis at diagnosis were significantly associated with overall median survival time (MST). COX-2 score (COX-2 score > 3 MST 420 days versus 1176 days if COX-2 score <3; P = 0.011) and MI (MI > 30 MST 120 days versus 540 days for MI < 30; P = 0.003) were the only variables associated with CRCC outcome on multivariate analysis. The addition of MI and COX-2 immunostaining to standard histopathological evaluation would help predicting outcome in CRCC patients.

WITHDRAWN: Clinical Signs, Neuroanatomical Distribution and Histopathological Characterisation of Meningoencephalitis in Wild Red Foxes (Vulpes vulpes) Associated with a Novel fox Circovirus.

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Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder.

Depression is associated with elevated rates of cardiovascular morbidity and mortality. This elevation seems to be due to a significantly increased risk of coronary artery disease and myocardial infarction and, once the ischemic heart disease is established, sudden cardiac death. Recent data suggest that the increased rates of cardiovascular disease in patients with depression may be the result of one or more still-unrecognized underlying physiological factors that predispose a patient to both depression and cardiovascular disease. Two possibly related factors that may have a causal relation with both depressive disorders and cardiovascular disease are an omega-3 fatty acid deficiency and elevated homocysteine levels. We present the available data connecting cardiovascular disease, depression, omega-3 fatty acids, and homocysteine. In addition, we suggest research strategies and some preliminary treatment recommendations that may reduce the increased risk of cardiovascular mortality in patients with major depressive disorder.

Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro.

Preliminary clinical data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and arachidonic acid (AA) were incubated with the catalytic domain of protein kinase C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity. Thus, PKC represents a potential site of action of omega-3 fatty acids in their effects on the treatment of bipolar disorder.

The McLean-Harvard first-episode project: 6-month symptomatic and functional outcome in affective and nonaffective psychosis.

BACKGROUND: The McLean-Harvard First-Episode Project recruited affective and nonaffective patients at their first lifetime psychiatric hospitalization. METHODS: Baseline evaluation and 6-month follow-up in 257 cases yielded recovery outcomes defined by syndromal (absence of DSM-IV criteria for a current episode) and functional (vocational and residential status at least at baseline levels) status. Time to recovery was assessed by survival analysis, and risk factors by multivariate logistic regression. RESULTS: Syndromal recovery was attained by 77% of cases over an average of 84 days. By diagnostic group, syndromal recovery rates ranked (p = .001) major affective disorders (81%) > nonaffective acute psychoses (74%) > schizoaffective disorders (70%) > schizophrenia (36%). Functional recovery was significantly associated to syndromal recovery, diagnosis, shorter hospitalization normalized to year, and older age at onset. Average hospital stay declined across the study period, but recovery did not vary with year of entry. CONCLUSIONS: Syndromal recovery was achieved by nearly one half of patients within 3 months of a first lifetime hospitalization for a psychotic illness, but functional recovery was not achieved by 6 months in nearly two thirds of patients who had attained syndromal recovery.

Neuroimaging in bipolar disorder: what have we learned?

New technologies are offering increasingly powerful means to obtain structural, chemical, and functional images of the brain during life, often without the use of ionizing radiation. Bipolar disorder, with its clear physiologic features, would appear to be a prime candidate for the application of current brain imaging; however, only a modest number of studies have been reported to date, and most studies have small sample sizes and heterogeneous subject groups. Nonetheless, there are a few consistent findings among these studies, including the following: 1) Structural imaging studies suggest an increased number of white matter hyperintensities in patients with bipolar disorder. These may be lesions unique to bipolar disorder and its treatment, or related to cardiovascular risk factors, which are more common in bipolar patients. Decreased cerebellar size and anomalies of cerebellar blood volume have also been reported. Increased sulcal prominence and enlargement of the lateral and third ventricles are less consistently observed findings. 2) Spectroscopic imaging suggests abnormalities of metabolism of choline-containing compounds in symptomatically ill bipolar patients and, possibly, treatment-induced changes in choline- and myoinositol-containing compounds. Each of these groups of metabolites serves as a component of membrane phospholipids and cellular second-messenger cycles. 3) Metabolic and blood flow studies provide evidence for decreased activity of the prefrontal cortex (PFC) in bipolar patients during depression. It is not clear if these changes are restricted to particular subregions of the PFC, nor if they are reversed with mania. No single pathophysiologic mechanism yet explains these findings, although all might be due to regional alterations in cellular activity and metabolism or changes in cell membrane composition and turnover. The development of imaging technologies has far outpaced their use in bipolar disorder. The promise of future studies is great, with more powerful magnetic resonance scanners, additional ligands for positron emission tomography and single photon emission computed tomography imaging, and improved image generation and processing already available.

Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features.

OBJECTIVE: Psychotic affective disorders are the most prevalent idiopathic psychoses, but their outcome from onset has rarely been studied. In this study, the authors determined the rate and latency of syndromal recovery and rates of functional recovery after first lifetime hospitalization in patients with first-episode psychotic affective disorders. METHOD: From first lifetime hospitalization in 1989-1996, 219 patients with a DSM-IV psychotic affective illness were assessed at intervals over 24 months. Time to syndromal recovery (no longer meeting DSM-IV episode criteria) was assessed by survival analysis, and functional recovery (regaining baseline vocational and residential status) was rated. Factors associated with recovery were identified by bivariate and multivariate methods. RESULTS: By 3, 6, 12, and 24 months after first hospitalization, syndromal recovery was attained by 65.1%, 83.7%, 91.1%, and 97.5%, respectively, of subjects. Time to syndromal recovery (6.1 weeks to 50% of subjects recovered) was shorter for patients who had bipolar disorder, were married, were age 30 or older at onset, lacked comorbidity, required relatively brief hospitalization, and received fewer medicines. Functional recovery by 6 (30.4%) and 24 months (37. 6% of patients) was 2.6-2.7 times less likely than syndromal recovery; 63.1% of those recovering syndromally did not recover functionally by 2 years. Functional recovery was associated with older age at onset and shorter hospitalization. Annual recovery rates remained stable as mean hospital length of stay decreased 3. 6-fold over the 8-year study period. CONCLUSIONS: Syndromal recovery was attained by most psychotic affective disorder patients soon after hospitalization, but only one-third recovered functionally by 24 months. The findings suggest that these very common psychotic illnesses can carry a grave functional prognosis from the initial episode and first hospitalization.

Choline, myo-inositol and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex.

OBJECTIVES: Alterations in choline and myo-inositol metabolism have been noted in bipolar disorder, and the therapeutic efficacy of lithium in mania may be related to these effects. We wished to determine the relationship between anterior cingulate cortex choline and myo-inositol levels, assessed using proton magnetic resonance spectroscopic imaging (MRSI), and mood state in subjects with bipolar disorder. METHODS: Serial assessments of anterior cingulate cortex choline and myo-inositol metabolism were performed in nine subjects with bipolar disorder, taking either lithium or valproate, and 14 controls. Each bipolar subject was examined between one and four times (3.1 +/- 1.3). On the occasion of each examination, standardized ratings of both depression and mania were recorded. RESULTS: In the left cingulate cortex, the bipolar subjects' depression ratings correlated positively with MRSI measures of Cho/Cr-PCr. In the right cingulate cortex, the Cho/Cr-PCr ratio was significantly higher in subjects with bipolar disorder compared with control subjects. In addition, bipolar subjects not taking antidepressants had a significantly higher right cingulate cortex Cho/Cr-PCr ratio compared with patients taking antidepressants or controls. No clinical or drug-related changes were observed for the Ino/Cr-PCr ratio. CONCLUSIONS: The results of this study suggest that bipolar disorder is associated with alterations in the metabolism of cytosolic, choline-containing compounds in the anterior cingulate cortex. As this resonance arises primarily from phosphocholine and glycerophosphocholine, both of which are metabolites of phosphatidylcholine, these results are consistent with impaired intraneuronal signaling mechanisms.

Omega-3 fatty acids and bipolar disorder: a review.

The important role of the omega-3 fatty acids in the pathophysiology and treatment of bipolar disorder is now supported by a substantial body of indirect and direct evidence. This paper will describe the clinical and pharmacological features of bipolar disorder, review the available data regarding omega-3 fatty acids in bipolar disorder and provide recommendations for future research.

Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.

BACKGROUND: Omega3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega3 fatty acid group performed better than the placebo group. CONCLUSION: Omega3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

The effect of lithium on calcium-induced changes in adrenocorticotrophin levels.

The calcium receptor (CaR) plays a central role in calcium (Ca) sensing by the parathyroid gland and other organs, including the brain. Chronic lithium (Li) therapy causes a significant alteration in Ca-sensing by the CaR-expressing parathyroid chief cells through an unknown mechanism, shifting the PTH set-point (the level of Ca that half-maximally suppresses PTH secretion) to the right. Ca is known to stimulate ACTH levels in normal subjects, and baseline ACTH levels are increased in patients with bipolar disorder. Because the stimulation of ACTH secretion by Ca likely involves the CaR, the aim of this study was to investigate the effects of Li on Ca-induced changes in ACTH levels, using Ca and citrate infusions in seven Li-treated patients and seven controls. During the Ca infusion, increments in serum-ionized Ca concentration (Ca(i)) were accompanied by increments in ACTH levels that were significantly greater in the Li-treated group, P = 0.014, by ANOVA. Also, cortisol levels increased significantly in the Li-treated, but not the control group, during the Ca infusion, P < 0.0001. There was a statistically significant shift in the midpoint of the Ca(i)/ACTH curve, to the right, in the Li-treated group, compared with the controls (P = 0.042), that was largely caused by an effect of Li on Ca(i). However, for comparable levels of Ca(i), there were no significant differences in the levels of ACTH between the two groups. Therefore, within the physiological range of Ca, there was no effect of Li on Ca(i)-induced change in ACTH levels.

Mood stabilizer combinations: a review of safety and efficacy.

OBJECTIVE: Polypharmacy is common in the treatment of refractory bipolar disorder. The purpose of this article is to review the safety and efficacy of mood stabilizers in combinations. METHOD: A manual and computer (MEDLINE) search was performed for combinations of the most commonly used mood-stabilizing agents. RESULTS: The authors review safety and efficacy data on the more frequently encountered combinations of established and putative mood stabilizers. CONCLUSIONS: There have been few controlled studies of the use of combinations of mood stabilizers. The interactions of such combinations are sometimes complex, often very useful, and potentially dangerous. One general rule that may reduce the risks of toxic drug interactions is to add medication to the patient's current regimen in modest doses and increase the dose slowly. The safest and most efficacious mood stabilizer combinations appear to be the mixtures of anticonvulsants and lithium, particularly valproate plus lithium. Once the mechanisms of the mood stabilizers are identified, it is possible that a more rational approach to combination therapy will emerge, based on synergism at the sites of action.