The cytologic and histologic diagnosis of ureteral fibroepithelial polyp in a dog.

A 6-year-old, intact male, brindled, 30-Lb English Bulldog presented to the Purdue University Veterinary Teaching Hospital with a recurrent history of hematuria, periuria, and lethargy that responded temporarily to antibiotic therapy. The work-up included a complete blood count, serum biochemical profile, complete urinalysis, diagnostic imaging (abdominal radiographs and ultrasound with contrast urography), and exploratory laparotomy. The diagnostic imaging findings and subsequent exploratory revealed a unilateral, intraluminal, right-sided, 3-cm ureteral mass extending from the proximal ureter into the renal pelvis. Subsequently, a unilateral right-sided ureteronephrectomy followed by biopsy with cytopathology/cytology (impression smears) and histopathology of the ureteral mass was performed. The cytopathologic interpretation was benign mesenchymal proliferation with mildly atypical urothelial cells. The association of this mass with vascular tissue and a benign nuclear appearance on cytology is similar to reports of fibroepithelial polyps (FEPs) and myxomatous tumors. Histopathology diagnosed the mass as an FEP. Cytopathology proved useful in the presumptive diagnosis of this benign urothelial polyp. To the authors' knowledge, this is the first report using cytopathology to depict and characterize FEPs in veterinary and human medical literature.

Influence of bilateral cochlear implants on vocal control.

Receiving a cochlear implant (CI) can improve fundamental frequency (F0) control for deaf individuals, resulting in increased vocal pitch control. However, it is unclear whether using bilateral CIs, which often result in mismatched pitch perception between ears, will counter this benefit. To investigate this, 23 bilateral CI users were asked to produce a sustained vocalization using one CI, the other CI, both CIs, or neither. Additionally, a set of eight normal hearing participants completed the sustained vocalization task as a control group. The results indicated that F0 control is worse with both CIs compared to using the ear that yields the lowest vocal variability. The results also indicated that there was a large range of F0 variability even for the relatively stable portion of the vocalization, spanning from 6 to 46 cents. These results suggest that bilateral CIs can detrimentally affect vocal control.

Conception and Synthesis of Oxabicyclic Nucleoside Phosphonates as Internucleotidic Phosphate Surrogates in Antisense Oligonucleotide Constructs.

The stereocontrolled synthesis of a novel oxabicyclic nucleoside phosphonate comprising a perhydrofuropyran core unit was achieved. It was incorporated in an oligonucleotide sequence as a 5'-3' phosphonate-phosphate insert, and the stability properties of the resulting duplex were measured. The oxabicyclic nucleoside framework was designed so as to restrict rotation around angles γ, δ, and ε of a natural nucleoside.

Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy.

OBJECTIVES: Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. METHODS: In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]). RESULTS: Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ±â€Š2.22, P < 0.0001; ΔSOWS = 12.48 ±â€Š11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ±â€Š2.39, P < 0.0001; ΔSOWS = 12.21 ±â€Š10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. CONCLUSION: We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

Comparison of semi-automated scar quantification techniques using high-resolution, 3-dimensional late-gadolinium-enhancement magnetic resonance imaging.

The quantification and modeling of myocardial scar is of expanding interest for image-guided therapy, particularly in the field of arrhythmia management. Migration towards high-resolution, three-dimensional (3D) MRI techniques for spatial mapping of myocardial scar provides superior spatial registration. However, to date no systematic comparison of available approaches to 3D scar quantification have been performed. In this study we compare the reproducibility of six 3D scar segmentation algorithms for determination of left ventricular scar volume. Additionally, comparison to two-dimensional (2D) scar quantification and 3D manual segmentation is performed. Thirty-five consecutive patients with ischemic cardiomyopathy were recruited and underwent conventional 2D late gadolinium enhancement (LGE) and 3D isotropic LGE imaging (voxel size 1.3 mm(3)) using a 3 T scanner. 3D LGE datasets were analyzed using six semi-automated segmentation techniques, including the signal threshold versus reference mean (STRM) technique at >2, >3, >5 and >6 standard deviations (SD) above reference myocardium, the full width at half maximum (FWHM) technique, and an optimization-based technique called hierarchical max flow (HMF). The mean ejection fraction was 32.1 ± 12.7 %. Reproducibility was greatest for HMF and FWHM techniques with intra-class correlation coefficient values ≥0.95. 3D scar quantification and modeling is clinically feasible in patients with ischemic cardiomyopathy. While several approaches show acceptable reproducibility, HMF appears superior due to maintenance of accuracy towards manual segmentations.

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer's-like cognitive decline.

Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of amyloid ß protein (Aß), particularly neurotoxic Aß(1-42). Angiotensin-converting enzyme (ACE) can degrade Aß(1-42), and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE(10/10) mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APP(SWE)/PS1(ΔE9) mouse model of AD (AD⁺). Evaluation of brain tissue from these AD⁺ACE(10/10) mice at 7 and 13 months revealed that levels of both soluble and insoluble brain Aß(1-42) were reduced compared with those in AD⁺ mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Aß levels in AD⁺ACE(10/10) mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD⁺ACE(10/10) mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Aß plaques. At 11 and 12 months of age, the AD⁺ACE(10/WT) and AD⁺ACE(10/10) mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.

Structure Activity Relationships of α-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals.

We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs) modified with α-L-locked nucleic acid (LNA) and related modifications targeting phosphatase and tensin homologue (PTEN) messenger RNA in mice. α-L-LNA represents the α-anomer of enantio-LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT) levels indicative of hepatotoxicity, gapmer ASOs modified with α-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the α-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing α-L-LNA nucleotides in the 3'- and 5'-flanks with R-5'-Me-α-L-LNA but not R-6'-Me- or 3'-Me-α-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5'-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5'-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.Molecular Therapy - Nucleic Acids (2012) 1, e47; doi:10.1038/mtna.2012.34; published online 18 September 2012.

Myxoma viral serpin, Serp-1, inhibits human monocyte adhesion through regulation of actin-binding protein filamin B.

Serp-1 is a secreted myxoma viral serine protease inhibitor (serpin) with proven, highly effective, anti-inflammatory defensive activity during host cell infection, as well as potent immunomodulatory activity in a wide range of animal disease models. Serp-1 binds urokinase-type plasminogen activator (uPA) and the tissue-type PA, plasmin, and factor Xa, requiring uPA receptor (uPAR) for anti-inflammatory activity. To define Serp-1-mediated effects on inflammatory cell activation, we examined the association of Serp-1 with monocytes and T cells, effects on cellular migration, and the role of uPAR-linked integrins and actin-binding proteins in Serp-1 cellular responses. Our results show that Serp-1 associates directly with activated monocytes and T lymphocytes, in part through interaction with uPAR (P<0.001). Serp-1, but not mammalian serpin PA inhibitor-1 (PAI-1), attenuated cellular adhesion to the extracellular matrix. Serp-1 and PAI-1 reduced human monocyte and T cell adhesion (P<0.001) and migration across endothelial monolayers in vitro (P<0.001) and into mouse ascites in vivo (P<0.001). Serp-1 and an inactive Serp-1 mutant Serp-1(SAA) bound equally to human monocytes and T cells, but a highly proinflammatory mutant, Serp-1(Ala(6)), bound less well to monocytes. Serp-1 treatment of monocytes increased expression of filamin B actin-binding protein and reduced CD18 (beta-integrin) expression (P<0.001) in a uPAR-dependent response. Filamin colocalized and co-immunoprecipitated with uPAR, and short interference RNA knock-down of filamin blocked Serp-1 inhibition of monocyte adhesion. We report here that the highly potent, anti-inflammatory activity of Serp-1 is mediated through modification of uPAR-linked beta-integrin and filamin in monocytes, identifying this interaction as a central regulatory axis for inflammation.

A comparison of epidural buprenorphine with epidural morphine for postoperative analgesia following stifle surgery in dogs.

Objective To compare the efficacy of epidural buprenorphine with epidural morphine for post-operative pain relief in dogs undergoing cranial cruciate ligament rupture repair. Study design A randomized, double blind clinical trial. Animals Twenty client-owned dogs with cranial cruciate ligament rupture. Methods Dogs were randomly assigned to receive either epidural buprenorphine (4 µg kg-1) or epidural morphine (0.1 mg kg-1) in a total volume of 0.2 mL kg-1. Epidural injections were performed immediately after induction of anesthesia. End-tidal halothane and CO2 were recorded every 15 minutes from the time of epidural administration of drug to extubation. A numerical rating pain score system was used by a blinded observer to evaluate analgesia beginning at extubation and continuing at specific intervals for 24 hours after surgery. Heart rate, respiratory rate, and blood pressure were recorded noninvasively at the same times. If pain score indicated moderate discomfort, rescue morphine at 1.0 mg kg-1 was administered intramuscularly. Results There were no significant differences between groups with respect to pain score, heart rate, respiratory rate, indirect blood pressure, end-tidal halothane or end-tidal CO2 at any time point. Fifty percent of dogs in the buprenorphine group and 50% of dogs in the morphine group required rescue analgesic medication. Time of systemic rescue morphine administration did not differ significantly between the two groups. There were no clinically observable side-effects from epidural administration of either drug in any of the dogs of this study. Conclusions Epidural buprenorphine is as effective as epidural morphine for the relief of postoperative hindlimb orthopedic pain in dogs. Clinical relevance Buprenorphine appears to be an effective opioid for epidural use in healthy dogs. Buprenorphine may offer certain advantages over morphine for epidural use, such as lower abuse potential and, in some clinics, reduced cost and less wastage of drug.