Endoscopic laser-ablation for the treatment of orthotopic and ectopic ureteroceles in dogs: 13 cases (2008-2017).

BACKGROUND: Ureteroceles are a rare condition in dogs in which conventional treatments can result in substantial morbidity. Cystoscopic and fluoroscopic-guided laser ablation (CLA) of ureteroceles can successfully relieve obstruction. OBJECTIVES: To describe the technique and outcomes of attempting CLA for treatment of ureteroceles in dogs. ANIMALS: Thirteen client-owned dogs that underwent CLA for treatment of ureteroceles. METHODS: Retrospective multicentered study. Medical records were reviewed in all dogs that underwent CLA for ureterocele(s). A laser was used to extend the opening of the ureteral orifice (UO) unless surgical conversion was necessary. Data collected included signalment, clinicopathologic data, imaging, procedural findings, complications, and short- and long-term outcome. RESULTS: Thirteen dogs with 13 ureteroceles associated with 14 UOs resulting in ureteral obstruction were included. One ureterocele extended bilaterally. Treatment was initiated via retrograde cystoscopy (7 females), percutaneous perineal urethrocystoscopy (4 males), or percutaneous antegrade cystoscopy (2 males). Surgical conversion was necessary in 2 males. Ten of 14 (71%) UOs associated with the ureteroceles were ectopic. Thirteen of 14 had stenotic or imperforate UOs. No postoperative complications were noted. Preoperative incontinence or pollakiuria was present in 9 of 13 and 3 of 13 dogs and resolved in 8 of 9 and 3 of 3 dogs, respectively. Follow-up imaging showed resolution of all ureteroceles and improved ureteral/renal pelvic dilatation. Median follow-up time was 27 months (range, 3-96 months). CONCLUSIONS AND CLINICAL IMPORTANCE: Cystoscopic-guided laser ablation was effective for the treatment of ureteroceles(s) in 11 of 13 dogs

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

Chronic inflammation with mucous metaplasia and airway remodeling are hallmarks of allergic asthma, and these outcomes have been associated with enhanced expression and activation of EGFR signaling. Here, we demonstrate enhanced expression of EGFR ligands such as amphiregulin as well as constitutive EGFR activation in cultured nasal epithelial cells from asthmatic subjects compared with nonasthmatic controls and in lung tissues of mice during house dust mite-induced (HDM-induced) allergic inflammation. EGFR activation was associated with cysteine oxidation within EGFR and the nonreceptor tyrosine kinase Src, and both amphiregulin production and oxidative EGFR activation were diminished by pharmacologic or genetic inhibition of the epithelial NADPH oxidase dual oxidase 1 (DUOX1). DUOX1 deficiency also attenuated several EGFR-dependent features of HDM-induced allergic airway inflammation, including neutrophilic inflammation, type 2 cytokine production (IL-33, IL-13), mucous metaplasia, subepithelial fibrosis, and central airway resistance. Moreover, targeted inhibition of airway DUOX1 in mice with previously established HDM-induced allergic inflammation, by intratracheal administration of DUOX1-targeted siRNA or pharmacological NADPH oxidase inhibitors, reversed most of these outcomes. Our findings indicate an important function for DUOX1 in allergic inflammation related to persistent EGFR activation and suggest that DUOX1 targeting may represent an attractive strategy in asthma management

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

Chronic inflammation with mucous metaplasia and airway remodeling are hallmarks of allergic asthma, and these outcomes have been associated with enhanced expression and activation of EGFR signaling. Here, we demonstrate enhanced expression of EGFR ligands such as amphiregulin as well as constitutive EGFR activation in cultured nasal epithelial cells from asthmatic subjects compared with nonasthmatic controls and in lung tissues of mice during house dust mite-induced (HDM-induced) allergic inflammation. EGFR activation was associated with cysteine oxidation within EGFR and the nonreceptor tyrosine kinase Src, and both amphiregulin production and oxidative EGFR activation were diminished by pharmacologic or genetic inhibition of the epithelial NADPH oxidase dual oxidase 1 (DUOX1). DUOX1 deficiency also attenuated several EGFR-dependent features of HDM-induced allergic airway inflammation, including neutrophilic inflammation, type 2 cytokine production (IL-33, IL-13), mucous metaplasia, subepithelial fibrosis, and central airway resistance. Moreover, targeted inhibition of airway DUOX1 in mice with previously established HDM-induced allergic inflammation, by intratracheal administration of DUOX1-targeted siRNA or pharmacological NADPH oxidase inhibitors, reversed most of these outcomes. Our findings indicate an important function for DUOX1 in allergic inflammation related to persistent EGFR activation and suggest that DUOX1 targeting may represent an attractive strategy in asthma management

NO2 inhalation induces maturation of pulmonary CD11c+ cells that promote antigenspecific CD4+ T cell polarization

<p>Abstract</p> <p>Background</p> <p>Nitrogen dioxide (NO₂) is an air pollutant associated with poor respiratory health, asthma exacerbation, and an increased likelihood of inhalational allergies. NO₂is also produced endogenously in the lung during acute inflammatory responses. NO₂can function as an adjuvant, allowing for allergic sensitization to an innocuous inhaled antigen and the generation of an antigen-specific Th2 immune response manifesting in an allergic asthma phenotype. As CD11c⁺antigen presenting cells are considered critical for naïve T cell activation, we investigated the role of CD11c⁺cells in NO₂-promoted allergic sensitization.</p> <p>Methods</p> <p>We systemically depleted CD11c⁺cells from transgenic mice expressing a simian diphtheria toxin (DT) receptor under of control of the CD11c promoter by administration of DT. Mice were then exposed to 15 ppm NO₂followed by aerosolized ovalbumin to promote allergic sensitization to ovalbumin and were studied after subsequent inhaled ovalbumin challenges for manifestation of allergic airway disease. In addition, pulmonary CD11c⁺cells from wildtype mice were studied after exposure to NO₂and ovalbumin for cellular phenotype by flow cytometry and <it>in vitro </it>cytokine production.</p> <p>Results</p> <p>Transient depletion of CD11c⁺cells during sensitization attenuated airway eosinophilia during allergen challenge and reduced Th2 and Th17 cytokine production. Lung CD11c⁺cells from wildtype mice exhibited a significant increase in MHCII, CD40, and OX40L expression 2 hours following NO₂exposure. By 48 hours, CD11c⁺MHCII⁺DCs within the mediastinal lymph node (MLN) expressed maturation markers, including CD80, CD86, and OX40L. CD11c⁺CD11b^-and CD11c⁺CD11b⁺pulmonary cells exposed to NO₂<it>in vivo </it>increased uptake of antigen 2 hours post exposure, with increased ova-Alexa 647⁺CD11c⁺MHCII⁺DCs present in MLN from NO₂-exposed mice by 48 hours. Co-cultures of ova-specific CD4⁺T cells from naïve mice and CD11c⁺pulmonary cells from NO₂-exposed mice produced IL-1, IL-12p70, and IL-6 <it>in vitro </it>and augmented antigen-induced IL-5 production.</p> <p>Conclusions</p> <p>CD11c⁺cells are critical for NO₂-promoted allergic sensitization. NO₂exposure causes pulmonary CD11c⁺cells to acquire a phenotype capable of increased antigen uptake, migration to the draining lymph node, expression of MHCII and co-stimulatory molecules required to activate naïve T cells, and secretion of polarizing cytokines to shape a Th2/Th17 response.</p

Clinical profile and treatment of infantile spasms using vigabatrin and ACTH - a developing country perspective

Background: Infantile spasms represent a serious epileptic syndrome that occurs in the early infantile age. ACTH and Vigabatrin are actively investigated drugs in its treatment. This study describes the comparison of their efficacy in a large series of Patients with infantile spasms from Pakistan. Methods: All Patients with infantile spasms who presented to Aga Khan University Hospital, Karachi, Pakistan from January, 2006 to April, 2008 were included in this study. Inclusion criteria were clinical symptoms of infantile spasms, hypsarrythmia or modified hyparrythmia on electroencephalography, at least six months of follow-up period and receipt of any of the two drugs mentioned above. The type of drug distribution was random according to the availability, cost and ease of administration. Results: Fifty six cases fulfilled the inclusion criteria. 62.5% were males. Mean age at onset of seizures was 5 +/- 1.4 months. Fifty two (92.8%) Patients demonstrated hypsarrythmia on electroencephalography. 64.3% cases were identified as symptomatic while 19.6% were cryptogenic and 16.1% were idiopathic. Eighteen Patients received ACTH while 38 Patients received Vigabatrin as first line therapy. Initial response to first line therapy was similar (50% for ACTH and 55.3% for Vigabatrin). Overall, the symptomatic and idiopathic groups responded better to Vigabatrin. The relapse rate was higher for ACTH as compared to Vigabatrin (55.5% vs. 33.3%) when considering the first line therapy. Four Patients evolved to Lennox-Gastaut variant, all of these Patients had initially received Vigabatrin and then ACTH. Conclusion: Vigabatrin and ACTH showed no significant difference in the initial treatment of infantile spasms. However, Patients receiving ACTH were 1.2 times more likely to relapse as compared to the Patients receiving Vigabatrin when considering monotherapy. We suggest that Vigabatrin should be the initial drug of choice in Patients presenting with infantile spasms. However, larger studies from developing countries are required to validate the therapeutic trends observed in this study

Secondary prevention of heart disease – knowledge among cardiologists and Ω-3 (Omega-3) fatty acid prescribing behaviors in Karachi, Pakistan

<p>Abstract</p> <p>Background</p> <p>The use of omega-3 fatty acids is a currently proven strategy for secondary prevention of heart disease. The prescription practices for this important nutraceutical is not currently known. It is imperative to assess the knowledge of cardiologists regarding the benefits of omega-3 fatty acids and to determine the frequency of its prescription. The aim of the study was to determine the practices and associations of dietary fish prescribing among cardiologists of Karachi and to assess their knowledge of fish oil supplementation and attitudes toward dietary practices.</p> <p>Methods</p> <p>A cross sectional survey was conducted during the period of January to March, 2008. A self report questionnaire was employed. All practicing cardiologists of Karachi were included in the study. Multiple logistic regression analysis was performed to determine the independent factors associated with high fish prescribers.</p> <p>Results</p> <p>The sample comprised of a total of 163 cardiologists practicing in Karachi, Pakistan. Most (73.6%) of the cardiologists fell in the age range of 28 – 45 years and were male (90.8%). High fish prescribers only comprised 36.2% of the respondents. After adjusting for age and gender, multivariate analysis revealed that only the variable of knowledge about fish oil's role in reducing sudden cardiac death was independently associated with high fish prescribers OR = 6.38 [95% CI 2.58–15.78].</p> <p>Conclusion</p> <p>The level of knowledge about the benefits of omega-3 fatty acids is high and the cardiologists harbor a favorable attitude towards dispensing dietary fish advice. However, the prescription practices are less than optimal and not concordant with recommendations of organisations such as the American Heart Association and National Heart Foundation of Australia. The knowledge of prevention of sudden cardiac death in CVD patients has been identified as an important predictor of high fish prescription. This particular life-saving property of omega-3 fatty acids should be the focus of any implemented educational strategy targeted to improve secondary CVD prevention via omega-3 fatty acid supplementation.</p

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Serum Amyloid A Induces NLRP-3-Mediated IL-1β Secretion in Neutrophils

Background/Aims: Serum amyloid A (SAA) is an acute phase reactant with significant immunological activities, including effects on cytokine synthesis and neutrophil chemotaxis. Neutrophils can also release cytokines with proinflammatory properties. IL-1β is a key proinflammatory cytokine, the secretion of which is controlled by inflammasome. We investigated the proinflammatory effects of SAA in vitro in relation to the NLRP3 inflammasome in neutrophils. Methodology/Principal Findings: Human neutrophils isolated form healthy subjects were stimulated with serum amyloid A (SAA). The cellular supernatants were analyzed by western blot using anti-IL-1β or anti-caspase-1 antibodies. IL-1β or Nod-like receptor family, pyrin domain containing 3 (NLRP3) mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method. SAA stimulation induced pro-IL-1β mRNA expression in neutrophils. Furthermore, SAA engaged the caspase-1-activating inflammasome, resulting in the production of active IL-1β. SAA-induced pro-IL-1β expression was marginally suppressed by the Syk specific inhibitor, R406, and SAA-induced pro-IL-1β processing in neutrophils was prevented by R406. Furthermore, SAA-induced NLRP3 mRNA expression was completely blocked by R406. Analysis of intracellular signaling revealed that SAA stimulation activated the tyrosine kinase Syk and mitogen-activated protein kinase (MAPK). Conclusions/Significance: These results demonstrate that the innate neutrophil immune response against SAA involves a two-step activation process: an initial signal promoting expression of pro-IL-1β and a second signal involving Syk-dependent activation of the NLRP3 inflammasome and caspase-1, allowing processing of pro-IL-1β and secretion of mature IL-1β

Search for the pair production of light top squarks in the e(+/-)mu(-/+) final state in proton-proton collisions at root s=13 TeV

A search for the production of a pair of top squarks at the LHC is presented. This search targets a region of parameter space where the kinematics of top squark pair production and top quark pair production are very similar, because of the mass difference between the top squark and the neutralino being close to the top quark mass. The search is performed with 35.9 fb(-1) of proton-proton collisions at a centre-of-mass energy of root s = 13 TeV, collected by the CMS detector in 2016, using events containing one electron-muon pair with opposite charge. The search is based on a precise estimate of the top quark pair background, and the use of the M-T2 variable, which combines the transverse mass of each lepton and the missing transverse momentum. No excess of events is found over the standard model predictions. Exclusion limits are placed at 95% confidence level on the production of top squarks up to masses of 208 GeV for models with a mass difference between the top squark and the lightest neutralino close to that of the top quark.Peer reviewe