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In collaboration with the American College of Veterinary Pathologists

GM-CSF co-expressing T17 cells instigate pathologic inflammation during autoimmune disorders, but their function in immunity to infections is unclear. Here, we demonstrate the role of GM-CSF

Summary A 7-year-old neutered male domestic shorthair cat was presented with chronic lameness in the right forelimb. A cystic bony lesion was identified in the distal right humerus and amputation was performed. The epiphyseal trabecular bones of the capitulum and trochlea was replaced by a tan to pink, expansile mass that was surrounded by a thin rim of cortical bone. Microscopically, the tumour was composed of a bland, osteoid producing spindle cell population within a well-vascularized fibrous stroma. Radiographical and histological features were consistent with osteoblastoma. Osteoblastoma and the related osteoid osteoma are uncommon, benign osteoblastic tumours that are reported rarely in animals. These tumours should be considered as differential diagnoses for slow growing, cystic bony lesions in cats.

Two adult male dogs (a 7-year-old shorthaired Chihuahua and 14-year-old Shih Tzu) and one adult female dog (a 9-year-old Maltese) presented for evaluation of new-onset seizure activity. Magnetic resonance imaging of the brain demonstrated a large, poorly marginated T2-weighted hyperintense, and strong contrast enhancing extra-axial mass in each case. A surgical biopsy for histopathologic evaluation was elected in all cases, and intraoperative impression smears were successfully obtained. Intraoperative cytology identified a homogenous population of round to polygonal cells with central to eccentric nuclei, coarse chromatin, and variably amphophilic to eosinophilic granular cytoplasm. Cytologic findings led to a suspected diagnosis of granular cell tumor (GCT) in all cases. Histopathologic review identified a densely cellular, unencapsulated neoplastic mass comprised of sheets of large round to polygonal cells with abundant eosinophilic cytoplasm containing numerous eosinophilic intracytoplasmic granules, confirming the diagnosis of GCT in all cases. The cases reported here are unique in that they reveal an accurate intraoperative cytologic diagnosis of a rare canine central nervous system neoplasm. Intraoperative cytology of the intracranial masses could provide clinicians with important and quick diagnostic and prognostic information; therefore, expediting decisions made intraoperatively. Further research is warranted to determine the diagnostic accuracy of intraoperative cytology for neoplasia in veterinary patients.

Objectives To describe the clinical features, magnetic resonance imaging (MRI) findings, and outcome of dogs and cats with central nervous system (CNS) lymphoma that involved the choroid plexus. Materials and methods A bi-institutional retrospective study of MRI of dogs and cats with CNS lymphoma, in which the choroid plexus was affected on MRI. Signalment, clinical, MRI, clinicopathologic and histopathologic findings were recorded and evaluated. Results CNS lymphoma with choroid plexus involvement on the MRI was identified in five dogs and one cat. MRI revealed diffuse enlargement and multifocal nodularity in the choroid plexus in most cases, with the fourth ventricle the most common site affected. Five of the cases had signs of extraneural involvement (including the cat), while the sixth case was not staged. Four of five CSF samples analysed provided a diagnosis of lymphoma. Clinical significance We report MRI findings of CNS lymphoma involving the choroid plexus. These results show the importance of recognising novel imaging patterns and the potential utility of CSF collection in diagnosing CNS lymphoma involving the choroid plexus ante mortem.

Background Cholecystectomy (XGB) is the most common abdominal surgery performed in the United States and is associated with an increased post-surgery incidence of metabolic and gastrointestinal (GI) diseases. Two main risk factors for XGB are sex (female) and age (40–50 yr), corresponding with onset of menopause. Post-menopausal estrogen loss alone facilitates metabolic dysfunction, but the effects of XGB on metabolic and GI health have yet to be investigated in this population. Study objectives were to (1) identify possible short-term effects of XGB and (2) develop a novel murine model of XGB in human menopause via subsequent ovariectomy (OVX) and assess longitudinal effects of OVX on metabolism, GI physiology, and GI microbiota in XGB mice. Methods Female C57BL/6 mice were utilized in two parallel studies (S1&S2). In S1, XGB mice were compared to a non-XGB baseline group after six wk. In S2, mice were XGB at wk0, either sham (SHM) or OVX at wk6, and sacrificed at wk12, wk18, and wk24. Body composition assessment and fresh fecal collections were conducted periodically. Serum and tissues were collected at sacrifice for metabolic and GI health endpoints. Results Compared to baseline, XGB increased hepatic CYP7A1 and decreased HMGCR relative expression, but did not influence BW, fat mass, or hepatic triglycerides after six wk. In S2, XGB/OVX mice had greater BW and fat mass than XGB/SHM. Cecal microbiota alpha diversity metrics were lower in XGB/OVX mice at wk24 compared the XGB/SHM. No consistent longitudinal patterns in fasting serum lipids, fecal microbial diversity, and GI gene expression were observed between S2 groups. Conclusions In addition to developing a novel, clinically-representative model of XGB and subsequent OVX, our results suggest that OVX resulted in the expected phenotype to some extent, but that XGB may modify or mask some responses and requires further investigation.

Background Yeast products and psyllium husk may provide relief from clinical signs of colitis due to their ability to promote gut integrity, modulate gut microbiota, or positively affect immune responses, which have been demonstrated in several species. Objective The objective of this study was to investigate the effects of a Saccharomyces cerevisiae fermentation product (SCFP) and psyllium husk (PH) on cecal and fecal microbiota, colonic gene expression and histopathology, and mesenteric lymph node (MLN) immune cells in a dextran sulfate sodium (DSS)–induced colitis model. Methods Male C57BL/6J mice (n = 54) were assigned to a control, 5% SCFP, or 5% PH diet. After 2 wk of diet adaptation, mice were provided distilled water or 3% (wt:vol) DSS for 5 d ad libitum. Body weight, food and water intakes, and disease activity index (DAI) were recorded daily during the treatment period. Fresh fecal samples were collected before and during treatment for microbial analyses. After treatment, mice were killed, followed by tissue collection. Tissues were stored in proper solutions until further analyses. Data were analyzed using the Mixed Models procedure of SAS 9.4 (SAS Institute). Results Consumption of SCFP increased (P < 0.05) species richness of the gut microbiota and relative abundance of Butyricicoccus in fecal and cecal samples compared with control or PH mice. PH mice had greater (P < 0.05) gene expression of claudin (Cldn) 2, Cldn3, Cldn8, and occludin(Ocln) compared with control mice. DAI, MLN immune cell populations, colonic histopathology, and colonic gene expression were not affected (P > 0.05) by SCFP in DSS mice. DSS mice consuming PH had lower (P < 0.05) DAI compared with control or SCFP mice. Conclusions Results suggest that, despite the modest changes it had on cecal and fecal microbiota, SCFP did not attenuate clinical signs associated with DSS-induced colitis in mice, while PH showed protective effects.

Histopathologic surgical margin assessment in veterinary patients is an imprecise science with assessment limited to a small proportion of the surgical margin due to time and finances. Incomplete excision of canine mast cell tumours (MCTs) alters treatment recommendations and prognosis. Optical coherence tomography (OCT) is a novel imaging modality that has been reported in a single veterinary study for surgical margin assessment. Twenty-five dogs with 34 MCTs were enrolled in a prospective pilot-study to assess the imaging characteristics of canine MCTs with OCT and to evaluate the feasibility and utility of OCT-guided histopathology. All dogs underwent routine surgical excision of MCTs. OCT imaging was used to assess the entire surgical margin prior to placement in formalin. Either normal areas or areas suspected of incomplete MCT excision were inked. Standard histopathologic sectioning and tangential sectioning of inked areas were performed and compared to OCT results. OCT identified MCT near the surgical margin in 10 of 26 specimens (38.4%). Four specimens suspicious for incomplete margins on OCT had incomplete MCT excision that was missed on standard histopathologic sectioning. Six specimens had OCT-guided sections taken as suspicious, which did not show MCT on histopathology. OCT-guided pathology sections were able to detect incompletely excised MCT near the surgical margin with a sensitivity of 90% and specificity of 56.2% in this preliminary study. OCT imaging shows promise for guiding pathologists to areas of interest to improve the diagnostic accuracy of surgical margin assessment in excised canine MCTs.

Non-Tuberculous Mycobacteria (NTM) are ubiquitous in nature, present in soil and water, and cause primary leading to disseminated infections in immunocompromised individuals. NTM infections are surging in recent years due to an increase in an immune-suppressed population, medical interventions, and patients with underlying lung diseases. Host regulators of innate immune responses, frontiers for controlling infections and dissemination, are poorly defined during NTM infections. Here, we describe the role of CBLB, an E3-ubiquitin ligase, for innate immune responses and disease progression in a mouse model of NTM infection under compromised T-cell immunity. We found that CBLB thwarted NTM growth and dissemination in a time- and infection route- dependent manner. Mechanistically, we uncovered defects in many innate immune cells in the absence of Cblb, including poor responses of NK cells, inflammatory monocytes, and conventional dendritic cells. Strikingly, Cblb-deficient macrophages were competent to control NTM growth in vitro. Histopathology suggested the lack of early formation of granulomatous inflammation in the absence of CBLB. Collectively, CBLB is essential to mount productive innate immune responses and help prevent the dissemination during an NTM infection under T-cell deficiency.

Pulmonary mycoses are difficult to treat and detrimental to patients. Fungal infections modulate the lung immune response, induce goblet cell hyperplasia and metaplasia, and mucus hypersecretion in the airways. Excessive mucus clogs small airways and reduces pulmonary function by decreasing oxygen exchange, leading to respiratory distress. The forkhead box protein A2 (FOXA2) is a transcription factor that regulates mucus homeostasis in the airways. However, little is known whether pulmonary mycosis modulates FOXA2 function. Herein, we investigated whether Blastomyces dermatitidis and Histoplasma capsulatum-infected canine and feline lungs and airway epithelial cells could serve as higher animal models to examine the relationships between fungal pneumonia and FOXA2-regulated airway mucus homeostasis. The results indicate that fungal infection down-regulated FOXA2 expression in airway epithelial cells, with concomitant overexpression of mucin 5AC (MUC5AC) and mucin 5B (MUC5B) mucins. Mechanistic studies reveal that B. dermatitidis infection, as well as β-glucan exposure, activated the Dectin-1-SYK-epidermal growth factor receptor-AKT/extracellular signal-regulated kinase 1/2 signaling pathway that inhibits the expression of FOXA2, resulting in overexpression of MUC5AC and MUC5B in canine airway cells. Further understanding of the role of FOXA2 in mucus hypersecretion may lead to novel therapeutics against excessive mucus in both human and veterinary patients with pulmonary mycosis.

Background Quantifying hepatic gene expression is important for many pharmacogenetic studies. However, this usually requires biopsy (BX), which is invasive. Objectives The objectives of this study were to determine the feasibility of using minimally invasive fine needle aspirate (FNA) to quantify hepatic gene expression and to assess expression variability between different sampling sites. Methods Biopsy and FNA samples were acquired from central and peripheral locations of the right and left lateral liver lobes of a dog. Relative expression of ABCB1, GSTT1 and CYP3A12 were measured via reverse transcriptase, quantitative PCR. The effect of sampling method, lobe and location within the lobe on gene expression was assessed using a three‐way ANOVA. Results Relative expression of ABCB1 and GSTT1 were not statistically different between sampling methods but CYP3A12 expression was higher in samples collected by BX (p = .013). Lobe sampled affected ABCB1 expression (p = .001) and site within lobe affected ABCB1 (p = .018) and GSTT1 (p = .025) expression. Conclusions FNA appears to be a feasible technique for minimally invasive evaluation of hepatic gene expression but results should not be directly compared to biopsy samples. Sampling location impacts expression of some targets; combination of FNAs from multiple sites may reduce variation., This study documents that liver samples for gene expression quantification can be obtained minimally invasively via fine needle aspirate rather than invasive biopsy. This technique will allow investigators to much more easily and safely obtain samples for future studies.

Background Perianal (hepatoid) gland tumors are common in dogs, and the distinction between the benign and malignant forms is clinically important. Cytology of these tumors typically contains many large hepatoid cells and fewer small basal cells. Objectives The objective of this study was to determine whether the proportion of the smaller basaloid reserve cells in cytologic samples from perianal tumors correlates with malignancy. Methods Eighty-three cases of cytologically diagnosed perianal gland tumors with corresponding histopathologic sections were identified from two separate institutions and included six (7.2%) malignant tumors and 77 (92.8%) benign tumors. The proportion of basal cells from each sample was evaluated. Results No difference between these groups was found, although the study was sufficiently powered to detect an approximately 1.5-fold change in basal cell proportion. Conclusions This report found no evidence that the proportion of basal cells in canine perianal tumor cytology is an indication of the potential for malignancy. We, therefore, do not recommend citing this feature in cytologic reports or when communicating with clinicians.

Mortality events in eastern box turtles (

A medulloblastoma was surgically debulked from a 6 year old American Staffordshire Terrier, who then received a modified lomustine (CCNU), vincristine, procarbazine, and prednisolone (LOPP) protocol. The dog improved significantly and continued to do well until deterioration and euthanasia 5 months following surgery. This is the first known published case report of surgical cytoreductive surgery of a medulloblastoma in a dog with documented response to surgery and chemotherapy. Medulloblastoma is a primitive neuroectodermal tumor that is the most common malignant central nervous system (CNS) tumor in children, though it is less common in adults. This case illustrates the value of considering human literature when creating treatment plans for uncommon brain tumors in veterinary patients. Medulloblastoma should be a differential for cerebellar tumors in young to middle aged dogs, and surgery and chemotherapy should be considered.

A 9-week-old male puppy was submitted for necropsy examination after a reported history of developing acute melaena and vomiting blood before death. Grossly, the animal had multiple skull fractures, mostly affecting the occipital region and cranial floor, associated with extensive regions of subcutaneous, periosteal and subdural haemorrhages, as well as petechial haemorrhages within the right middle and caudal lung lobes. Histopathology of the brain revealed multifocal acute meningeal and parenchymal haemorrhage with laceration of the cerebellar folia. In the lung, multiple small- and medium-calibre branches of pulmonary arteries were occluded by aggregates of brain tissue, which exhibited weak immunoreactivity for glial fibrillary acidic protein and strong labelling for neuron specific enolase on immunohistochemistry. These findings were consistent with brain tissue pulmonary embolism, an infrequent phenomenon following severe head trauma. To the best of the authors' knowledge, this is the first reported case of canine brain tissue pulmonary embolism.

Objective To evaluate the pharmacokinetics (PK) of platinum (Pt) and safety of carboplatin-impregnated calcium sulfate hemihydrate (C-I CSH) beads after implantation in healthy cats. Study design In vivo experimental study. Animals Six healthy adult cats. Methods Three C-I CSH beads were implanted in muscle pockets over the right and left hemithoraces of each cat (~3.9 mg/kg of Pt; 60.4 mg/m2 of calculated carboplatin). Hematology and blood chemistry were tested at baseline and 3, 7, 14, and 21 days postimplantation. Serum was analyzed for Pt at specific times from 1 hour to 21 days. Tissue was obtained for histopathology and analysis of Pt at 3, 7, 14, and 21 days at standardized distances from implantation sites. Results Platinum was detected in tissues at all times and distances (range, 0.1-4.19 μg/g). Serum Pt increased up to 2.6 hours (3.25 μg/mL) then decreased sharply. Samples containing muscle had higher Pt compared with samples without muscle (P = .004). Mild hypercalcemia was noted in four cats, and mild inflammatory reaction was noted on histopathology of all samples. Conclusion Platinum was released from C-I CSH beads differentially into surrounding tissues over 21 days. Systemic absorption of Pt was minimal, but mild hypercalcemia occurred. Clinical significance Implantation was well tolerated by healthy adult cats. Securing beads within muscle may limit Pt diffusion to targeted tissue. Although Pt concentrations did not achieve levels reported to be cytotoxic for feline sarcoma cells in culture, results provide evidence to support evaluation of efficacy in the tumor microenvironment of cats with locally invasive cancers.

OBJECTIVE To determine the ability of functional side-to-side small intestinal anastomoses (FSS-SIA) created with an electrothermal bipolar vessel sealing (EBVS) device to resist leakage. STUDY DESIGN Experimental, ex vivo. SAMPLE POPULATION Jejunal segments (n = 130) from 10 healthy canine cadavers. METHODS Four types of anastomoses were created (two segments/construct and 15 constructs/group): EBVS (group A), EBVS + transverse stapling (group B), stapled (group C), and EBVS + suture augmentation (group D). Initial leakage pressure (ILP), initial leakage location (ILL), and maximal intraluminal pressure were compared between groups, and five group A constructs were analyzed histologically. RESULTS Initial leakage pressure was greater in group D than in groups A, B, and C (P

Non-Tuberculous Mycobacteria (NTM) are ubiquitous and cause chronic lung infections to fatal disseminated diseases in immunocompromised individuals. The incidence and prevalence of NTM infections are increasing globally, mainly due to the surging numbers of immunocompromised patients. The diagnosis is often misleading, and the emergence of multi-drug resistant NTM has deprived the treatment options. Innate immune responses, dictated by immune regulators, shape the clinical outcomes of NTM infections. Here, we describe the role of an E3 ubiquitin ligase, CBLB, for innate immunity against an NTM infection. We found that the absence of CBLB, under T-cell deficiency, enhanced the bacterial burden and dissemination following both intravenous and intratracheal infections. Strikingly, CBLB fostered an early induction of granulomatous inflammation, which thwarts the dissemination. CBLB-deficiency caused a significant reduction of NK cell numbers, but not their intrinsic functions. Further, we found that CBLB was required to augment the numbers of inflammatory monocytes and conventional dendritic cells, the latter, additionally, for their activation. Thus, our findings suggest that CBLB plays an essential role in eliciting protective innate immune responses to control the growth and dissemination of NTM during T-cell deficiency.

Mortality events in eastern box turtles (Terrapene carolina carolina) threaten conservation efforts across the species range. These events are often under-diagnosed and, when observed, pre...

Numerous infectious agents are responsible for causing primary or secondary respiratory disease in dogs. These agents can cause upper or lower respiratory infections commonly observed in veterinary practices. Clinical signs might vary from mild dyspnea, sneezing, and coughing to severe pneumonia with systemic manifestations. Depending on the etiologic agent, the gross and microscopic changes observed during these infections can be rather unspecific or have highly characteristic patterns. While histopathology and cytology are not always required for diagnosis of respiratory infections, they are often useful for establishing a definitive diagnosis and identifying specific etiologic agents. Research regarding epidemiology, pathogenesis, diagnostics, and clinical manifestations related to these infectious pathogens provides valuable information that has improved treatments and management of the diseases they cause. This review discusses the epidemiology, general clinical characteristics, and pathologic lesions for some of the important viral, bacterial, fungal, and parasitic etiologies of canine respiratory disease.

We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns. Our results showed HDAC6 inhibition decreased SLE disease by inhibiting immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production and increasing splenic Treg cells. Inhibition of HDAC6 increased the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation.

Gut microbiota dysbiosis has been observed in a number of autoimmune diseases. However, the role of the gut microbiota in systemic lupus erythematosus (SLE), a prototypical autoimmune disease characterized by persistent inflammation in multiple organs of the body, remains elusive. Here we report the dynamics of the gut microbiota in a murine lupus model, NZB/W F1, as well as intestinal dysbiosis in a small group of SLE patients with active disease. The composition of the gut microbiota changed markedly before and after the onset of lupus disease in NZB/W F1 mice, with greater diversity and increased representation of several bacterial species as lupus progressed from the predisease stage to the diseased stage. However, we did not control for age and the cage effect. Using dexamethasone as an intervention to treat SLE-like signs, we also found that a greater abundance of a group of lactobacilli (for which a species assignment could not be made) in the gut microbiota might be correlated with more severe disease in NZB/W F1 mice. Results of the human study suggest that, compared to control subjects without immune-mediated diseases, SLE patients with active lupus disease possessed an altered gut microbiota that differed in several particular bacterial species (within the genera Odoribacter and Blautia and an unnamed genus in the family Rikenellaceae ) and was less diverse, with increased representation of Gram-negative bacteria. The Firmicutes / Bacteroidetes ratios did not differ between the SLE microbiota and the non-SLE microbiota in our human cohort. IMPORTANCE SLE is a complex autoimmune disease with no known cure. Dysbiosis of the gut microbiota has been reported for both mice and humans with SLE. In this emerging field, however, more studies are required to delineate the roles of the gut microbiota in different lupus-prone mouse models and people with diverse manifestations of SLE. Here, we report changes in the gut microbiota in NZB/W F1 lupus-prone mice and a group of SLE patients with active disease.

Summary We have demonstrated previously that histone deacetylase (HDAC6) expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) New Zealand Black (NZB)/White F1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for 5 weeks. As the mice aged, we determined autoantibody production and cytokine levels by enzyme-linked immunosorbent assay (ELISA) and renal function by measuring proteinuria. At the termination of the study, we performed a comprehensive analysis on B cells, T cells and innate immune cells using flow cytometry and examined renal tissue for immune-mediated pathogenesis using immunohistochemistry and immunofluorescence. Our results showed a reduced germinal centre B cell response, decreased T follicular helper cells and diminished interferon (IFN)-γ production from T helper cells in splenic tissue. Additionally, we found the IFN-α-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. Taken together, these studies show selective HDAC6 inhibition decreased several parameters of disease pathogenesis in lupus-prone mice. The decrease was due in part to inhibition of B cell development and response.

Two dogs with a history of being found dead within environments exposed to extremely cold weather were examined postmortem. In both cases, brown to red to black, round to irregularly shaped foci ranging from 0.5–15 mm in diameter were identified within the mucosa of the stomach. These foci are grossly and microscopically consistent with Wischnewsky spots that are reported in humans. These spots in the mucosa of the stomach are considered important findings in cases of hypothermia-related deaths in humans and are for the first time reported in the dog.

To date, there are 18 histone deacetylase (HDAC) enzymes, divided into four classes, which alter protein function by removing acetyl groups from lysine residues. Prior studies report that non-selective HDAC inhibitors decrease disease in lupus mouse models. Concern for adverse side effects of non-selective HDAC inhibition supports investigation of selective-HDAC inhibition. We hypothesized that a selective HDAC-6 inhibitor (HDAC6i) will alleviate disease in a mouse model of lupus by increasing acetylation of alpha-tubulin. Intraperitoneal injections of the selective HDAC6i ACY-1083 (0.3 mg/kg, 1 mg/kg, or 3 mg/kg), vehicle control, or dexamethasone were administered to 21-week-old, female NZB/W mice, 5 days a week, for 13 weeks. Disease progression was evaluated by proteinuria, serum levels of anti-dsDNA antibody, cytokines and immunoglobulins, and post mortem evaluation of nephritis and T cell populations in the spleen. HDAC6i treatment decreased proteinuria, glomerular histopathology, IgG, and C3 scores when compared to vehicle-treated mice. Within glomeruli of HDAC6i-treated mice, there was increased acetylation of alpha-tubulin and decreased NF-κB. Additionally, HDAC6i decreased serum IL-12/IL-23 and Th17 cells in the spleen. Taken together, these results suggest HDAC-6 inhibition may decrease lupus nephritis in NZB/W mice via mechanisms involving acetylation of alpha-tubulin and decreased NF-κB in glomeruli as well as inhibition of Th17 cells.

Prior studies have shown that pan-HDAC inhibition can decrease disease in lupus mice; however, the mechanisms(s) remain to be elucidated. MRL/MpJ-Faslpr (MRL/lpr) mice develop a lupus-like disease characterized by anti-dsDNA production, lymphoproliferation, and immune complex-mediated glomerulonephritis. Early- and late-disease (12 and 20weeks-of-age respectively) female MRL/lpr mice were compared to age-matched, healthy C57BL/6 mice for HDAC expression and activity in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells. We found that HDAC6 was significantly overexpressed in B cells, splenic T cells and glomerular cells, whereas HDAC9 expression was significantly increased in splenic T cells, BM B cells and glomerular cells. Due to the overexpression of HDAC6, we tested whether treatment with a selective HDAC6 inhibitor (ACY-738) or a pan-HDAC inhibitor (TsA) would decrease HDAC activity. ACY-738 significantly reduced cytoplasmic HDAC activity whereas TsA significantly decreased both nuclear and cytoplasmic HDAC activity. In vitro studies in mesangial cells showed that ACY-738 increased α-tubulin and Hsp90 acetylation resulting in decreased nuclear activation of NF-κB. Treatment of pre-B cells with ACY-738 decreased the Bcl-2:Bax ratio leading to a pro-apoptotic environment. These results suggest that increased HDAC6 expression and activity contribute to SLE pathogenesis, and isoform-selective HDAC inhibitors may prove beneficial in the treatment of SLE by acetylating key signaling and transcription factors in inflammation and cell activation.

This report describes the gross, histological, and immunohistochemical features of medullary thyroid carcinoma (MTC) with pulmonary metastases in a young dog. Sheets of pleomorphic cells supported by fibrous stroma characterized the primary mass, while metastatic nodules had a neuroendocrine pattern. Despite differing histologic features, all masses showed marked immunoreactivity against calcitonin and multiple neuroendocrine markers consistent with MTC. Although MTC is a well-recognized entity, it may be difficult to distinguish this mass from other thyroid neoplasms, necessitating immunohistochemical characterization.