Postoperative outcome of ambulatory dogs with intervertebral disc extrusion causing incontinence and/or tail dysfunction: 18 cases (2010-2020).

OBJECTIVES: To assess the recovery of urinary continence, faecal continence and tail function in ambulatory dogs with caudal lumbar intervertebral disc extrusion and to explore clinical factors that may be associated with recovery. MATERIALS AND METHODS: Medical records from January 2010 to December 2020 were searched to identify ambulatory dogs undergoing surgical treatment for a caudal lumbar intervertebral disc extrusion causing urinary incontinence, faecal incontinence and/or tail dysfunction. Signalment, history, presenting clinical signs, neurological examination findings, diagnostic test results, treatment and outcome were recorded for all dogs. RESULTS: Eighteen dogs with caudal lumbar intervertebral disc extrusion causing tail dysfunction, urinary and/or faecal incontinence were included. Urinary continence was recovered in 12 (86%) of 14 affected dogs, faecal continence recovered in nine (90%) of 10 affected dogs and tail function recovered in 13 (87%) of 15 affected dogs. Loss of tail nociception was recorded in three dogs on presentation; two made a full recovery and one showed mild persistent tail paresis. CLINICAL SIGNIFICANCE: The prognosis for functional recovery of urinary continence, faecal continence and tail function in ambulatory dogs with caudal lumbar intervertebral disc extrusion following surgical treatment is good. Larger studies are needed to identify prognostic factors associated with failure of recovery.

Evaluation of the Idexx ProCyte Dx® for analysis of canine cerebrospinal fluid.

OBJECTIVES: To assess the utility of the Idexx ProCyte Dx® haematology analyser for assessing total nucleated cell count and differential cell counts in canine cerebrospinal fluid. MATERIALS AND METHODS: Seventy-three client-owned dogs undergoing investigations for pyrexia and/or neurological signs were prospectively included. Cerebrospinal fluid samples were assessed using an Idexx ProCyte Dx® analyser and the results were compared to those obtained with the external laboratory reference standard. RESULTS: The Idexx ProCyte Dx® performed with good sensitivity (92.6%) and moderate specificity (67.4%) for total nucleated cell count when compared to the reference standard. Qualitative assessment of the Idexx ProCyte Dx® scatter plots, and quantitative assessment of differential cell counts where available, appeared to correlate well with the external laboratory manual differential cell counts, with a good-to-high agreement in 25 of 26 samples (96.2%). CLINICAL SIGNIFICANCE: The Idexx ProCyte Dx® analyser performed well in determining the total nucleated cell count and differential cell counts in canine cerebrospinal fluid when compared to a reference standard of external laboratory analysis, except for cell counts higher than ~1000/µL. As the Idexx ProCyte Dx® currently only provides a cell count in 10 cells/µL increments, software modification may improve agreement between the two methods. As in human medicine, automated methods may prove useful in the future for cerebrospinal fluid analysis in addition to manual assessment, particularly in an emergency setting.

Isocitrate Dehydrogenase 1 Expression in Canine Gliomas.

Mutation of the isocitrate dehydrogenase 1 (IDH1) gene at codon 132 has been identified in approximately 70% of low-grade (II and III) human gliomas and secondary glioblastomas, with the IDH1 R132H point mutation representing 92.7% of these mutations. In people, the presence of an IDH1 gene mutation is associated with a better prognosis (both progression-free survival time and overall survival time) and a better response to therapy, including chemotherapy and radiation therapy. Furthermore, IDH1 mutations are included in diagnostic panels to improve diagnosis and molecular classification. Canine gliomas resemble their human counterpart both morphologically and immunohistochemically, therefore they are likely to share similar genetic abnormalities. The IDH1 gene is also comparable between man and dogs. If the IDH1 R132H point mutation is demonstrated in canine gliomas, the prognostic significance of this mutation in people may be transferable to the dog. The objective of this study was to investigate canine gliomas for the IDH1 R132H point mutation using immunohistochemistry. Thirty-one formalin-fixed and paraffin wax-embedded canine gliomas were examined for both IDH1 R132H expression and pan-IDH1 (IDH1 wild-type and point mutated IDH1). Glial tumour specimens were recorded to be either positive or negative for expression. Pan-IDH1 expression was identified in all 31 tumours (100%), while the IDH1 R132H point mutation was identified in none of the tumours (0%). Therefore, the IDH1 R132H point mutation was not identified in this population of canine gliomas and may not be a suitable biomarker or treatment target in canine gliomas. Further investigation is required to determine if other point mutations occur in the IDH1 gene of canine gliomas.

Immune checkpoint inhibitors: new strategies to checkmate cancer.

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or programmed cell death protein 1 (PD-1) receptors have demonstrated remarkable efficacy in subsets of patients with malignant disease. This emerging treatment modality holds great promise for future cancer treatment and has engaged pharmaceutical research interests in tumour immunology. While ICIs can induce rapid and durable responses in some patients, identifying predictive factors for effective clinical responses has proved challenging. This review summarizes the mechanisms of action of ICIs and outlines important preclinical work that contributed to their development. We explore clinical data that has led to disease-specific drug licensing, and highlight key clinical trials that have revealed ICI efficacy across a range of malignancies. We describe how ICIs have been used as part of combination therapies, and explore their future prospects in this area. We conclude by discussing the incorporation of these new immunotherapeutics into precision approaches to cancer therapy.

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.

Epidermal Growth Factor Receptor and Ki-67 Expression in Canine Gliomas.

Novel therapies, including molecular targeted therapies, are being developed for the treatment of human gliomas. To use such therapies for canine gliomas, more complete characterization of molecular targets is required. Epidermal growth factor receptor (EGFR) is one such therapeutic target used in human glioma trials, and the Ki-67 labeling index (LI) is a marker of proliferation and a prognostic indicator. The objectives of this cross-sectional study were to evaluate the expression of EGFR and Ki-67 in canine gliomas and to determine if immunopositivity is associated with tumor type and histologic grade. Thirty-one formalin-fixed, paraffin-embedded canine gliomas were evaluated for EGFR and Ki-67 expression by immunohistochemistry. EGFR immunopositivity was evaluated using a semi-quantitative score and the Ki-67 LI calculated based on the percentage of positive cells. EGFR and Ki-67 expression were identified in 16 of 31 (52%) and 28 of 31 (90%) tumors, respectively. EGFR expression was significantly greater in high-grade tumors compared with low-grade tumors (P = .04) and was significantly greater in gliomatosis cerebri compared with oligodendroglioma (P = .002), astrocytoma (P = .01), and oligoastrocytoma (P = .04). The Ki-67 LI was significantly greater in high-grade tumors compared with low grade tumors (P = .02); the median Ki-67 LI was 2.3% (range, 0%-17.6%) for low-grade tumors and 9.3% (range, 1.7%-41.0%) for high-grade tumors. A significant moderate correlation was identified between EGFR immunopositivity and Ki-67 LI (r = 0.47, P = .007). Overall, EGFR may be a suitable therapeutic target for some canine gliomas, particularly gliomatosis cerebri.

Lissencephaly in an adult Australian Kelpie.

CASE REPORT: A 6-year-old neutered male Australian Kelpie presented with a 2-year history of seizures. Neurological examination was consistent with a generalised prosencephalic lesion. Serum biochemical testing was performed in addition to magnetic resonance imaging of the brain and cerebrospinal fluid analysis. Magnetic resonance imaging revealed a reduction in the number of sulci and gyri in addition to cortical thickening, resulting in a diagnosis of lissencephaly. The dog was treated with anticonvulsants and follow-up information obtained from the referring veterinarian 11 months after diagnosis indicated that the dog had good seizure control. CONCLUSION: This is the first report of lissencephaly in the Australian Kelpie and would suggest that some dogs with the condition can be managed with long-term anticonvulsant medication.

Concurrent idiopathic vestibular syndrome and facial nerve paralysis in a cat.

CASE REPORT: A 4-year-old male neutered Domestic Medium-hair cat was referred for right head tilt and ataxia of 2 weeks duration. On examination it was determined that the cat had right facial nerve paralysis and peripheral vestibular signs. Haematology and serum biochemical testing were performed in addition to magnetic resonance imaging of the brain and ears, and cerebrospinal fluid analysis. An underlying condition was not identified. A diagnosis of idiopathic vestibular syndrome and concurrent idiopathic right facial nerve paralysis was consequently made. The cat was re-evaluated over the following weeks and was determined to have complete resolution of clinical signs within 7 weeks. CONCLUSION: Vestibular dysfunction and concurrent facial nerve paralysis have previously been reported in the cat, but not of an idiopathic nature.

Suppression, subversion and escape: the role of regulatory T cells in cancer progression.

Regulatory T cells (T(regs) ) are crucial in mediating immune homeostasis and promoting the establishment and maintenance of peripheral tolerance. However, in the context of cancer their role is more complex, and they are thought to contribute to the progress of many tumours. As cancer cells express both self- and tumour-associated antigens, T(regs) are key to dampening effector cell responses, and therefore represent one of the main obstacles to effective anti-tumour responses. Suppression mechanisms employed by T(regs) are thought to contribute significantly to the failure of current therapies that rely on induction or potentiation of anti-tumour responses. This review will focus on the current evidence supporting the central role of T(regs) in establishing tumour-specific tolerance and promoting cancer escape. We outline the mechanisms underlying their suppressive function and discuss the potential routes of T(regs) accumulation within the tumour, including enhanced recruitment, in-situ or local proliferation, and de-novo differentiation. In addition, we review some of the cancer treatment strategies that act, at least in part, to eliminate or interfere with the function of T(regs) . The role of T(regs) is being recognized increasingly in cancer, and controlling the function of these suppressive cells in the tumour microenvironment without compromising peripheral tolerance represents a significant challenge for cancer therapies.

Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies.

Cancer is one of the most important pathological conditions facing mankind in the 21st century, and is likely to become the most important cause of death as improvements continue in health, diet and life expectancy. The immune response is responsible for controlling nascent cancer through immunosurveillance. If tumours escape this control, they can develop into clinical cancer. Although surgery and chemo- or radiotherapy have improved survival rates significantly, there is a drive to reharness immune responses to treat disease. As T cells are one of the key immune cells in controlling cancer, research is under way to enhance their function and improve tumour targeting. This can be achieved by transduction with tumour-specific T cell receptor (TCR) or chimaeric antigen receptors (CAR) to generate redirected T cells. Virus-specific cells can also be transduced with TCR or CAR to create bi-functional T cells with specificity for both virus and tumour. In this review we outline the development and optimization of redirected and bi-functional T cells, and outline the results from current clinical trials using these cells. From this we discuss the challenges involved in generating effective anti-tumour responses while avoiding concomitant damage to normal tissues and organs.

Hepatic myelolipoma incarcerated in a peritoneopericardial diaphragmatic hernia in a cat.

Hepatic myelolipoma incarcerated in a peritoneopericardial diaphragmatic hernia was diagnosed in an 11-year-old, desexed female Persian cat. The cat was initially referred for investigation of tachypnoea and dyspnoea. Peritoneopericardial diaphragmatic hernia is a common incidental finding in cats and is usually asymptomatic. Myelolipoma is an extremely rare benign tumour, composed of extramedullary haematopoietic cells and adipose tissue. Myelolipomas are hypothesised to result from metaplastic alteration, rather than a neoplastic process, although this theory cannot be substantiated. The present case is only the fourth report of such an unusual occurrence in cats and displays significant differences to previous reports. Hepatic entrapment and burgeoning of the mass within the pericardial sac resulted in cardiac tamponade and overt signs of right-sided cardiac failure. Surgical intervention was successful and despite concerns regarding the cat's clinical presentation and the gross appearance of the lesion(s), a good long-term outcome is anticipated.

Immature monocytes from G-CSF-mobilized peripheral blood stem cell collections carry surface-bound IL-10 and have the potential to modulate alloreactivity.

Production of the anti-inflammatory cytokine IL-10 by monocytes has been implicated as a probable negative regulator of graft-versus-host disease (GvHD) in patients undergoing allogeneic stem cell transplants (SCT). Monocytes from G-CSF-mobilized peripheral blood stem cell (gmPBSC) collections have been reported to produce more IL-10 than unmobilized monocytes in response to proinflammatory factors such as LPS. Why this should occur is unclear. In this study, monocyte phenotype and IL-10 localization and release were investigated in PB mononuclear cells (MNC) from 27 healthy donors mobilized for allogeneic SCT and from 13 patients with hematological malignancies mobilized for autologous SCT. All isolates contained elevated total percentages of monocytes in comparison with unmobilized PB, a high proportion of which displayed an immature phenotype. Stimulation of gmPB MNC with an inflammatory stimulus [fixed Staphylococcus aureus cells (SAC)] induced rapid up-regulation of CD14, indicating conversion to mature status. Localization studies indicated that IL-10 was predominantly present, bound on the surface of CD64(+)/CD14(low/neg) immature monocytes. Inflammatory stimuli (LPS, polyinosinic:polycytidylic acid, or SAC) induced release of variable quantities of IL-10 from the cell surface. MNC, separated into surface IL-10-positive or -negative fractions, differed in their ability to stimulate alloreactivity in MLR, and IL-10(+) MNC induced significantly lower levels of proliferation than IL-10(-) MNC. Thus, the subset of immature monocytes carrying surface-bound IL-10 in gmPB has the potential to modulate alloreactivity and GvHD after allogeneic SCT through cell-to-cell contact and released IL-10.

Targeting the silent minority: emerging immunotherapeutic strategies for eradication of malignant stem cells in chronic myeloid leukaemia.

Standard allogeneic stem cell transplantation (alloSCT) has provided a cure for chronic myeloid leukaemia (CML) over the last 25 years, but is only an option for a minority of patients. It was hoped that the introduction of imatinib mesylate (IM), a specific tyrosine kinase inhibitor that targets the Bcr-Abl oncogene product, would provide long-term remission or even cure for those patients without a donor, but studies have shown that IM does not eliminate leukaemic stem cells in CML patients. To overcome this problem of molecular persistence, research is underway to combine reduced intensity stem cell transplant or non-donor-dependent immunotherapies with IM with the aim of increasing cure rate, reducing toxicity and improving quality of life. The alternative approach is to combine IM or second-generation agents with other novel drugs that interrupt key signalling pathways activated by Bcr-Abl. This article will focus on the latest immunotherapy and molecularly targeted therapeutic options in CML and how they may be combined to improve the outcome for CML patients in the future.

Role of quantitative mineralogical analysis in the investigation of sites contaminated by chromite ore processing residue.

A range of techniques, normally associated with mineralogical studies of soils and sediments, has been used to characterise the solid materials found on sites contaminated with chromite ore processing residue (COPR). The results show that a wide range of minerals are present, many of which are found extensively in high-temperature synthetic systems such as cements and clinkers and their low temperature hydration products. Thus, the minerals in COPR can be divided into three main categories: unreacted feedstock ore (chromite); high temperature phases produced during chromium extraction (brownmillerite, periclase and larnite); and finally, minerals formed under ambient weathering conditions on the disposal sites (brucite, calcite, aragonite, ettringite, hydrocalumite, hydrogarnet). Apart from chromite, chromium occurs in brownmillerite, ettringite, hydrocalumite and hydrogarnet. Detailed study of the chemistry and stoichiometry of chromium-bearing phases in conjunction with phase abundance provides a quantitative description of the solid state speciation of Cr(III) and Cr(VI) in and amongst these minerals and in the COPR as a whole. Of the total chromium present in the samples most, approximately 60-70% is present as Cr(III) in chromite, whilst brownmillerite also represents a significant reservoir of Cr(III) which is approximately 15% of the total. The remaining chromium, between 20 and 25%, is present as Cr(VI) and resides mainly in hydrogarnet, and to a slightly lesser extent in hydrocalumite. In the latter, it is present principally in an exchangeable anionic form. Chromium (VI) is also present in ettringite, but quantitatively ettringite is a much less important reservoir of Cr(VI), accounting for approximately 3% of total chromium in one sample, but less than 1% in the other two. This description provides insight into the processes likely to control the retention and release of Cr(VI) from COPR-contaminated sites. Such information is of particular value in chemical modelling of the system, in risk assessment and in the development of methods of informed remediation.

A double blind trial of moclobemide versus amitriptyline in the treatment of depressive disorders.

The antidepressant efficacy and side-effect profile of amitriptyline were compared to those of moclobemide, a reversible monoamine oxidase inhibitor with selectivity for the type A isozyme. Forty nine patients with DSM-III major depression were randomly assigned to receive either amitriptyline or moclobemide. Thirty seven patients (amitriptyline n = 16, moclobemide n = 21) completed the six week protocol, which was conducted under double blind conditions. The results indicated a comparable antidepressant time course and efficacy for the two treatments. Amitriptyline produced significantly more sedation and antimuscarinic side-effects. Moclobemide appears to be a well tolerated antidepressant without the liability to produce significant postural hypotension and without the need for a tyramine-poor diet.

Atypical mitochondrial DNA from the deep-sea scallop Placopecten magellanicus.

The mitochondrial DNA of most metazoan animals is highly conserved in size, averaging about 17 kilobase paris (kbp). The mitochondrial DNA from the deep-sea scallop Placopecten magellanicus, in contrast, has been found to be approximately 34 kbp long. It is also highly variable in size from individual to individual and is unusual in the extent of its size variation. Mitochondrial DNAs from individuals collected at the same site differ by as much as 7 kbp. The size variation is due largely to differences in the number of copies of a tandemly repeated 1.2-kbp element.

Kinetics for glutamine-synthetase inhibition by phosphinothricin and measurement of other enzyme activities in situ in isolated asparagus cells using a freeze-thaw technique.

Kinetics for the inhibition of glutamine synthetase (EC 6.3.1.2) in situ by the herbicidal glutamate analogue, phosphinothricin, have been generated, and produce an inhibitor dissociation constant (Ki) of 6.5 µM. This has been achieved through the development of a rapid technique for the isolation of mesophyll cells from the cladophylls of young asparagus (Asparagus sprengeri) plants to provide starting material for the direct measurement of enzyme activities in situ. A modification of the technique developed by Rhodes and Stewart (Planta 118, 133-144 (1974) for the direct determination of enzyme activities in higher-plant tissues has been applied to these asparagus cells. Treatment of the cells by a single freezing in liquid nitrogen for a very short period (10 s), followed by thawing, alters the permeability of cell and organelle membranes allowing enzymes to become accessible to many small molecules, and yet remain concentrated and active within the cell. The activities of enzymes known to be located specifically in the organelles as well as the cytoplasm can be measured in asparagus cells treated in this way. Comparisons have been made between the activity and inhibition of glutamine synthetase in situ, and the enzyme isolated and partially purified from asparagus cells by fast protein liquid chromatography. Similarities in Km and Ki values obtained between these two emphasize the efficacy of the freeze-thaw technique. There is only a single glutamine-synthetase isoenzyme in asparagus mesophyll cells, which copurifies with the one normally associated with the chloroplast (GS2).