Development of the EVIBEC Learning Outcomes Framework to support the delivery of evidence-based practice curricula in health care professional programmes: a codesign approach.

BACKGROUND: All healthcare professional education programmes must adopt a systematic approach towards ensuring graduates achieve the competencies required to be an evidence-based practitioner. While a list of competencies for evidence-based practice exist, health care educators continue to struggle with effectively integrating the necessary competencies into existing curricula. The purpose of this project was to develop an open access cross-discipline, learning outcomes framework to support educators in integrating the teaching, learning and assessment required to ensure all graduates of health care professional programmes can achieve the necessary evidence-based practice competencies. METHODS: An interdisciplinary team of health care professional educators and a librarian completed a review of the health professions literature on the teaching and assessment of evidence-based practice. The literature, coupled with the teams' collective experiences in evidence-based education and research, were used to identify relevant teaching, learning and evidence-based competency frameworks to inform the project design. The guide and toolkit for experience-based co-design developed by the National Health Service Institute for Innovation and Improvement was adopted for this study ( Institute for Innovation and Improvement: Experience Based Design: Guide & Tools In. Leeds: NHS; 2009.). A four-step approach involving three online participatory co-design workshops and a national validation workshop was designed. Students (n = 33), faculty (n = 12), and clinical educators (n = 15) participated in formulating and mapping learning outcomes to evidence-based competencies. RESULTS: Through a rigorous, systematic co-design process the Evidenced-based Education Collaborative (EVIBEC) Learning Outcomes Framework was developed. This framework consists of a series of student-centred learning outcomes, aligned to evidence-based practice competencies, classified according to the 5 As of EBP and mapped to the cognitive levels of Bloom's taxonomy. Associated learning activities for each step of EBP are suggested. CONCLUSIONS: A consensus-based, student-centred learning outcomes framework aligned to a contemporary set of EBP core competencies has been developed. The freely accessible EVIBEC framework may support entry level health care professional EBP education, by informing EBP curriculum development and offering the potential for interdisciplinary approaches to and sharing of valuable teaching and learning resources. Co-design proved an effective method in creating and refining this framework.

Digitally Enhanced Psychological Assessment and Treatment of Paranoia: A Systematic Review.

BACKGROUND: Paranoia is relatively common but can lead to significant distress, impairment and need for care. Digital technologies offer a valuable extension to service provision and are increasingly being integrated into healthcare. This systematic review evaluated feasibility, acceptability, and effectiveness of digitally enhanced psychological assessments and treatments for paranoia across the paranoia continuum (PROSPERO: CRD42023393257). METHODS: Databases PsychINFO, EMBASE, MEDLINE and Web of Science were searched until 12 June 2023; the Effective Public Health Practice Project (EPHPP) quality assessment tool evaluated studies; and a narrative synthesis was conducted. RESULTS: Twenty-seven studies met inclusion criteria (n = 3457, 23 assessment and 4 treatment, 2005-2023, most in Europe). Technologies included virtual reality (VR, n = 23), experience sampling methodology (ESM, n = 2), an app (n = 1) and a combination of VR and ESM (n = 1). Assessments involved monitoring paranoia under various virtual conditions or in everyday life. Treatments were generally integrated with Cognitive Behaviour Therapy (CBT), which involved using VR to test out threat beliefs and drop safety behaviours or using an app to support slowing down paranoid thinking. EPHPP ratings were strong (n = 8), moderate (n = 12) and weak (n = 7). CONCLUSIONS: Digitally enhanced assessments and treatments showed promising acceptability, feasibility and treatment effectiveness. Limitations of studies include small sample sizes, lack of comparison groups and long-term data and limited randomised controlled trials. Results support the potential future integration of VR in the assessment of paranoia and show promise for treatments such as CBT, although further clinical trials are required. Investigation of other technologies is limited.

New developments on the Encyclopedia of DNA Elements (ENCODE) data portal.

The Encyclopedia of DNA Elements (ENCODE) is an ongoing collaborative research project aimed at identifying all the functional elements in the human and mouse genomes. Data generated by the ENCODE consortium are freely accessible at the ENCODE portal (https://www.encodeproject.org/), which is developed and maintained by the ENCODE Data Coordinating Center (DCC). Since the initial portal release in 2013, the ENCODE DCC has updated the portal to make ENCODE data more findable, accessible, interoperable and reusable. Here, we report on recent updates, including new ENCODE data and assays, ENCODE uniform data processing pipelines, new visualization tools, a dataset cart feature, unrestricted public access to ENCODE data on the cloud (Amazon Web Services open data registry, https://registry.opendata.aws/encode-project/) and more comprehensive tutorials and documentation.

Polyneuropathy in Young Siberian Huskies Caused by Degenerative and Inflammatory Diseases.

Polyneuropathy is defined as the simultaneous dysfunction of several peripheral nerves. In dogs, a number of breeds are predisposed to a variety of immune-mediated and/or degenerative inherited forms of polyneuropathy, with laryngeal paralysis and/or megaesophagus as important clinical features of many of these conditions. This case series describes degenerative and inflammatory polyneuropathies in 7 young Siberian huskies that were categorized based on clinicopathological characteristics as follows: (1) slowly progressive laryngeal paralysis and megaesophagus caused by primary axonal degeneration with large fiber loss (n = 2); (2) slowly progressive polyneuropathy without megaesophagus or laryngeal paralysis caused by primary axonal degeneration with large fiber loss (n = 2); (3) acute inflammatory demyelinating neuropathy causing sensory, motor and autonomic nerve deficits (n = 2); and (4) ganglioradiculitis (sensory neuronopathy; n = 1). Based on the predominantly young age at onset, slow progression, relatedness of affected dogs, and clinical and pathological similarities with inherited neuropathies reported in other dog breeds, a hereditary basis for the degenerative polyneuropathies in Siberian huskies is suspected. However, 5 different mutations in 3 genes known to cause polyneuropathy in other dog breeds (NDRG1, ARHGEF10, or RAB3GAP1) were not detected in the affected Siberian huskies suggesting that more genetic variants remain to be identified. This study highlights the varied underlying lesions of polyneuropathies in young Siberian huskies.

Evaluation of red blood cell distribution width in dogs with various illnesses.

In humans, increased red blood cell distribution width (RDW) values are associated with higher morbidity and mortality in a variety of pathological processes. The main objective of this study was to evaluate RDW in dogs with a diverse range of pathologies. Clinical data from 276 dogs were retrospectively evaluated. Significantly higher RDW values were found in dogs with primary immune-mediated hemolytic anemia (P < 0.0001), immune-mediated thrombocytopenia (P < 0.0004), hyperadrenocorticism (P < 0.0001), hypothyroidism (P = 0.0220), hepatic vascular anomaly (P < 0.0001), pneumonia (P < 0.0001), chronic kidney disease (P = 0.0005), multi-centric lymphoma (P = 0.0002), and myxomatous mitral valve degeneration (P = 0.0032). However, there was extensive overlap with the values from healthy dogs, limiting the diagnostic value of RDW in this setting. Although RDW may have a role as a potential prognostic indicator, further studies would be necessary to address this.

Évaluation de l'indice de distribution des globules rouges chez des chiens avec différentes maladies. Chez les humains, une augmentation des valeurs de l'indice de distribution des globules rouges (RDW) est associée avec une plus grande morbidité et mortalité dans une variété de processus pathologiques. L'objectif principal de la présente étude était d'évaluer la RDW chez des chiens avec une variété de pathologies. Les données cliniques de 276 chiens ont été rétrospectivement évaluées. Des valeurs significativement plus élevées de RDW ont été trouvées chez des chiens avec une anémie hémolytique primaire à médiation immunitaire (P < 0,0001), une thrombocytopénie à médiation immunitaire (P < 0,0004), de l'hyperadrénocorticisme (P < 0,0001), de l'hypothyroïdisme (P < 0,0220), une anomalie vasculaire hépatique (P < 0,0001), une pneumonie (P < 0,0001), une maladie rénale chronique (P = 0,0005), un lymphome multicentrique (P = 0,0002), et une dégénérescence myxomateuse de la valvule mitrale (P = 0,0032). Toutefois, il y avait un chevauchement important avec les valeurs provenant de chiens en santé, limitant ainsi la valeur diagnostique de RDW dans ce contexte. Bien que le RDW peut avoir un rôle d'indicateur potentiel de pronostic, des études supplémentaires seraient nécessaires pour y répondre.(Traduit par Dr Serge Messier).

Rapid, effective and user-friendly immunophenotyping of canine lymphoma using a personal flow cytometer.

BACKGROUND: Widespread use of flow cytometry for immunophenotyping in clinical veterinary medicine is limited by cost and requirement for considerable laboratory space, staff time, and expertise. The Guava EasyCyte Plus (Guava Technologies, Hayward, CA, US) is the first, personal, bench-top flow cytometer designed to address these limitations. OBJECTIVE: The aim of this study was to adapt the immunohistochemical protocol used for immunophenotyping of canine lymphoma to the personal flow cytometer for rapid, effective and user-friendly application to the diagnosis and prognosis of canine lymphoma and to demonstrate its practicality for widespread veterinary application. Performance of the personal flow cytometer for immunophenotyping T and B lymphocytes in blood and lymph nodes from normal dogs and dogs with lymphoproliferative disease, was assessed using only two monoclonal antibodies (against CD3 and CD21), and by comparison with analysis using two conventional flow cytometers. METHODS: 26 dogs with lymphoproliferative disease (23 with lymphoma, 3 with lymphocytic leukaemia) were studied along with 15 controls (2 non-lymphoma lymph nodes and 13 non-leukemic bloods. Lymphocytes were immunostained with fluorescent-labeled, monoclonal antibodies against CD3 and CD21. To assess the effectiveness of the personal flow cytometer in discrimination between T and B cell immunophenotypes, T and B cell counts for half the samples (14 blood and 11 lymph node) were also determined using the same method and conventional flow cytometers (FACSCalibur, Cyan Dako). To assess the effectiveness of the personal flow cytometer in discriminating between leukocyte types, lymphocyte differential counts were determined for 21 blood samples and compared with those from automated hematology analyzers (CELL-DYN 3500, n=11 and ADVIA 2120, n=10). Quality and sub-cellular distribution of immunostaining was assessed using fluorescence microscopy. RESULTS: The protocol for immunophenotyping took 2 to 3 hours to complete from the point of receipt of sample to reporting of immunophenotype. The personal flow cytometer differential lymphocyte counts correlated highly (n=20; r=0.97, p<0.0001) with those of automated haematology analyzers. The personal flow cytometer counts consistently, but mildly, underestimated the percentages of lymphocytes in the samples (mean bias of -5.3%.). The personal flow cytometer immunophenotype counts were indistinguishable from those of conventional flow cytometers for both peripheral blood samples (n=13; r=0.95; p<0.0001; bias of -1.1%) and lymph node aspirates (n=11,r=0.98; p<0.001; bias of 1%). All but one leukemic and one lymphomatous lymph node sample, out of 26 samples of dogs with lymphoproliferative disease analyzed, could be immunophenotyped as either B or T cells. CONCLUSIONS: We conclude that use of only 2 monoclonal antibodies is sufficient for immunophenotyping most cases of canine lymphoma by flow cytometry and enables rapid immunophenotyping. The personal flow cytometer may be as effectively used for immunophenotyping canine lymphoma as conventional flow cytometers. However, the personal flow cytometer is more accessible and user-friendly, and requires lower sample volumes.

Ultrasonographic measurement of gallbladder wall thickness in fasted dogs without signs of hepatobiliary disease.

BACKGROUND: Ultrasound-determined gallbladder wall thickness is widely used to aid in the diagnosis of gallbladder disease, but no reference values supported by published measurement data are available in dogs. HYPOTHESIS/OBJECTIVE: Establish normal thickness of the gallbladder wall in dogs. ANIMALS: Fifty-three dogs presented to a referral hospital and required abdominal ultrasound examination for reasons unrelated to primary hepatobiliary disease. METHODS: Cross-sectional observational study recruiting dogs requiring abdominal ultrasound examination. A standard sequence of gallbladder wall images was recorded for later review. Inclusion criteria were normal ultrasonographic hepatobiliary, pancreatic, and small intestinal findings. Exclusion was determined by 2 European College of Veterinary Internal Medicine (ECVIM)-certified veterinary internists blinded to gallbladder wall thickness data. Dogs were excluded if they had inadequate medical records, a previous history of hepatobiliary, gastrointestinal, or pancreatic disease likely to impact the biliary system (eg, chronic vomiting, nausea, jaundice, diarrhea), unexplained increases in liver enzyme activities, hypoalbuminemia, or ascites. Gallbladder wall thickness was determined by 2 European College of Veterinary Diagnostic Imaging (ECVDI)-certified veterinary radiologists working together to generate a consensus for each dog. The final output was the maximum normal wall thickness for this population of dogs. RESULTS: The upper limit for gallbladder wall thickness in 53 fasted (8 hours) dogs <40 kg was 1.30 mm (90% confidence interval, 1.19-1.41). CONCLUSIONS AND CLINICAL IMPORTANCE: Normal gallbladder wall thickness in dogs is lower than previously reported. Additional studies are required to determine potential effects of body weight and the optimal cut-off to distinguish between healthy and diseased gallbladders.

The comparative performance of a custom Canine NanoString® panel on FFPE and snap frozen liver biopsies.

Formalin-Fixed Paraffin Embedded (FFPE) biopsies would provide a critical mass of cases to allow investigation of canine liver disease, however their use is often limited by challenges typically associated with transcriptomic analysis. This study evaluates the capability of NanoString® to measure the expression of a broad panel of genes in FFPE liver samples. RNA was isolated from matched histopathologically normal liver samples using FFPE (n = 6) and snap frozen in liquid nitrogen (n = 6) and measured using a custom NanoString® panel. Out of the 40 targets on the panel, 27 and 23 targets were above threshold for non-diseased snap frozen and FFPE tissue respectively. The binding density and total counts were significantly reduced in the FFPE samples relative to the snap frozen samples (p = 0.005, p = 0.01, respectively), confirming a reduction in sensitivity. The concordance between the snap frozen and FFPE samples was high, with correlations (R) ranging between 0.88 and 0.99 between the paired samples. An additional 14 immune-related targets, undetectable the non-diseased FFPE liver, were above threshold when the technique was applied to a series of diseased samples, further supporting their inclusion on this panel. This use of NanoString® based analysis opens up huge opportunity for retrospective evaluation of gene signatures in larger caseloads through harnessing the capacity of archived FFPE samples This information used alongside clinical and histological data will not only afford a way to explore disease etiopathogenesis, it may also offer insight into sub-types of liver disease in dogs, which cannot be discerned using more traditional diagnostic methods.

Comparison of survival after surgical or medical treatment in dogs with a congenital portosystemic shunt.

OBJECTIVE: To compare survival of dogs with a congenital portosystemic shunt (CPSS) that received medical or surgical treatment. DESIGN: Prospective cohort study. ANIMALS: 126 client-owned dogs with a single CPSS. PROCEDURES: Dogs were examined at 1 of 3 referral clinics, and a single CPSS was diagnosed in each. Dogs received medical or surgical treatment without regard to signalment, clinical signs, or results of hematologic or biochemical analysis. Survival data were analyzed via a Cox regression model. RESULTS: During a median follow-up period of 579 days, 18 of 126 dogs died as a result of CPSS. Dogs treated via surgical intervention survived significantly longer than did those treated medically. Hazard ratio for medical versus surgical treatment of CPSS (for the treatment-only model) was 2.9 (95% confidence interval, 1.1 to 7.2). Age at CPSS diagnosis did not affect survival. CONCLUSIONS AND CLINICAL RELEVANCE: Both medical and surgical treatment can be used to achieve long-term survival of dogs with CPSS, although results of statistical analysis supported the widely held belief that surgery is preferable to medical treatment. However, the study population consisted of dogs at referral clinics, which suggested that efficacy of medical treatment may have been underestimated. Although surgical intervention was associated with a better chance of long-term survival, medical management provided an acceptable first-line option. Age at examination did not affect survival, which implied that early surgical intervention was not essential. Dogs with CPSS that do not achieve acceptable resolution with medical treatment can subsequently be treated surgically.

The ENCODE Portal as an Epigenomics Resource.

The Encyclopedia of DNA Elements (ENCODE) web portal hosts genomic data generated by the ENCODE Consortium, Genomics of Gene Regulation, The NIH Roadmap Epigenomics Consortium, and the modENCODE and modERN projects. The goal of the ENCODE project is to build a comprehensive map of the functional elements of the human and mouse genomes. Currently, the portal database stores over 500 TB of raw and processed data from over 15,000 experiments spanning assays that measure gene expression, DNA accessibility, DNA and RNA binding, DNA methylation, and 3D chromatin structure across numerous cell lines, tissue types, and differentiation states with selected genetic and molecular perturbations. The ENCODE portal provides unrestricted access to the aforementioned data and relevant metadata as a service to the scientific community. The metadata model captures the details of the experiments, raw and processed data files, and processing pipelines in human and machine-readable form and enables the user to search for specific data either using a web browser or programmatically via REST API. Furthermore, ENCODE data can be freely visualized or downloaded for additional analyses. © 2019 The Authors. Basic Protocol: Query the portal Support Protocol 1: Batch downloading Support Protocol 2: Using the cart to download files Support Protocol 3: Visualize data Alternate Protocol: Query building and programmatic access.

Author Correction: Energy use and life cycle greenhouse gas emissions of drones for commercial package delivery.

In the original version of this Article, the first sentence of the sixth paragraph of the "Comparing emissions" section, the Results originally incorrectly read as 'In the base case, delivery of a small (0.5 kg) package with the small quadrotor drone has lower impacts than delivery by diesel truck, ranging from a 59% reduction in GHGs in California, to a 17% reduction in Missouri'. The correct version states '54%' instead of '59%' and '23%' instead of '17%'.The fourth sentence of the same paragraph originally incorrectly read as 'In the base case, delivery of a medium-sized (8 kg) package has 17% lower GHGs than delivery by truck in California, is about equivalent to delivery trucks for the U.S. average electricity mix, but has 77% higher GHGs than truck delivery in Missouri, which has a carbon-intensive electricity grid'. The correct version states 'In the base case, delivery of a medium-sized (8 kg) package has 9% lower GHGs than delivery by truck in California, is about 24% higher than delivery trucks for the U.S. average electricity mix, and has 50% higher GHGs than truck delivery in Missouri, which has a carbon-intensive electricity grid.The last sentence of the seventh paragraph of the same section originally incorrectly read as 'Because of the importance of electricity used to power the octocopter, charging with low-carbon electricity of 200 g GHG/kWh can reduce delivered package GHGs by 34% compared to diesel trucks'. The correct version states '37%' instead of '34%'.These errors have been corrected in both the PDF and HTML versions of the Article.

Energy use and life cycle greenhouse gas emissions of drones for commercial package delivery.

The use of automated, unmanned aerial vehicles (drones) to deliver commercial packages is poised to become a new industry, significantly shifting energy use in the freight sector. Here we find the current practical range of multi-copters to be about 4 km with current battery technology, requiring a new network of urban warehouses or waystations as support. We show that, although drones consume less energy per package-km than delivery trucks, the additional warehouse energy required and the longer distances traveled by drones per package greatly increase the life-cycle impacts. Still, in most cases examined, the impacts of package delivery by small drone are lower than ground-based delivery. Results suggest that, if carefully deployed, drone-based delivery could reduce greenhouse gas emissions and energy use in the freight sector. To realize the environmental benefits of drone delivery, regulators and firms should focus on minimizing extra warehousing and limiting the size of drones.

IL-10 is essential for disease protection following intranasal peptide administration in the C57BL/6 model of EAE.

We have shown previously that intranasal administration of encephalitogenic peptides in soluble form to H-2u and H-2s mice affords protection from experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that this method of disease protection can be induced in C57BL/6 mice by administration of the soluble peptide 35-55 from myelin oligodendrocyte glycoprotein. This protective effect was demonstrated by the evaluation of both clinical EAE scores and central nervous system histopathology; the latter showing minimal inflammatory infiltrates in treated mice. The employment of an IL-10-/- congenic strain allowed an appraisal of the involvement of IL-10 in this process. The lack of disease protection in these mice clearly demonstrates the non-redundant role of IL-10 in this process.

Cerebrospinal fluid from a 6-year-old dog with severe neck pain.

A 6-year-old, intact female, Labrador Retriever/Terrier cross was presented to the University Veterinary Hospital, University College Dublin with a 3-week history of therapy-resistant cervical pain and intermittent fever. Physical examination findings included marked cervical pain resulting in neck extension and vocalization. Examination of the CSF revealed mild pleocytosis (total nucleated cells = 0.009 x 10(9)/L, reference interval <0.005 x 10(9)/L). Cytocentrifuged preparations of the CSF were of low cellularity, containing predominantly macrophages and occasional small lymphocytes. Several small- to medium-sized fragments of a slightly granular, amorphous, eosinophilic substance were observed. The majority of mononuclear cells were located within this material, in small groups of 3-13 cells. The amorphous foamy material stained positive with Luxol fast blue, suggestive of myelin-like material. The dog was euthanized and postmortem examination revealed intervertebral disk protrusion between C2 and C3. Hematoxylin- and Luxol fast blue-stained histopathologic sections of brain and spinal cord revealed only mild hemorrhage. The extracellular material in the CSF of this dog may have been caused by myelin degeneration or leakage of phospholipids from damaged cells. Because no histologic evidence of demyelination was observed with the disk extrusion, the myelin-like material in this case was thought to be the product of phospholipid breakdown from damaged cellular membranes. Three cases of dogs with spinal cord disease and myelin-like material in the CSF have been reported previously. The clinical significance of this finding is still unknown.

Granulomatous meningoencephalomyelitis in dogs: A review.

: Granulomatous meningoencephalomyelitis (GME) is an inflammatory disease of the central nervous system in dogs that is characterised by focal or disseminated granulomatous lesions within the brain and/or spinal cord, non-suppurative meningitis and perivascular mononuclear cuffing. The aetiology of the disease remains unknown, although an immune-mediated cause is suspected. This article reviewed the typical history, clinical signs and pathology of the condition along with current opinions on pathogenesis. The potential differential diagnoses for the disease were discussed along with current treatment options.

Natural and induced regulatory T cells.

Mucosal antigen delivery can induce tolerance, as shown by suppression of subsequent responses to antigen. Our previous work showed that both intranasal and oral routes of antigen delivery were effective but indicated that the intranasal route might be more reliable. Intranasal peptide administration induced cells that could mediate bystander suppression of responses to associated antigenic epitopes. Here, we discuss further investigation into the nature of intranasal, peptide-induced tolerance. Cells from mice treated with intranasal peptide became anergic and shut down secretion of cytokines such as IL-2, but still secreted IL-10. This latter cytokine was required for suppression of immune responses in vivo even though suppression of responses in vitro was IL-10 independent. Intranasal peptide induced a subset of CD25(-), CTLA-4(+) regulatory cells that suppressed naive cell function in vitro and in vivo. We provide evidence that these cells arise from CD25(-) precursors and differentiate independently from natural CD25(+) regulatory cells. IL-10-secreting regulatory cells are also found in the peripheral blood of humans and can be induced by soluble peptide administration. This route of tolerance induction offers promise as a means of antigen-specific immunotherapy of allergic and autoimmune conditions in humans.

Calcospherite-like bodies and caseous necrosis in tracheal mucus from a dog with tuberculosis.

A 3-year-old Wirehaired Fox Terrier was presented to the University Veterinary Hospital, University College Dublin, for evaluation of chronic cough of 8-months duration. Bronchoscopy showed a severely dilated collapsed left principal bronchus filled with highly viscous white mucus. Cytologically, globular lipid-like material and round concentrically laminated crystalline structures were evident within the proteinaceous mucus. These findings resembled the calcospherites and granular caseous debris often observed in human tuberculous patients. A Ziehl-Neelsen-stained cytocentrifuged preparation of material obtained by bronchoalveolar lavage revealed a few acid-fast rods within macrophages, suggestive of tuberculosis. At necropsy, granulomas with caseous necrosis were present in the lung parenchyma, bronchial and mediastinal lymph nodes, liver, pancreas, and mesentery. Granulomas were adherent to both kidney capsules and to the diaphragm. Histologically, there was evidence of mild calcification within caseous granulomas, which was confirmed by von Kossa's stain. Using Ziehl-Neelsen stain, acid-fast rods were identified within granulomas; bacterial culture was positive for Mycobacterium bovis. The cytologic findings in this case have not been reported previously in dogs and demonstrate a possible correlation between tuberculosis and calcospherite-like bodies with caseous, globular material in bronchial mucus, similar to that described in human patients.

Long-term survival and quality of life in dogs with clinical signs associated with a congenital portosystemic shunt after surgical or medical treatment.

OBJECTIVE: To compare long-term survival and quality of life data in dogs with clinical signs associated with a congenital portosystemic shunt (CPSS) that underwent medical or surgical treatment. DESIGN: Prospective cohort study. ANIMALS: 124 client-owned dogs with CPSS. PROCEDURES: Dogs received medical or surgical treatment without regard to signalment, clinical signs, or clinicopathologic results. Survival data were analyzed with a Cox regression model. Quality of life information, obtained from owner questionnaires, included frequency of CPSS-associated clinical signs (from which a clinical score was derived), whether owners considered their dog normal, and (for surgically treated dogs) any ongoing medical treatment for CPSS. A Mann-Whitney U test was used to compare mean clinical score data between surgically and medically managed dogs during predetermined follow-up intervals. RESULTS: 97 dogs underwent surgical treatment; 27 were managed medically. Median follow-up time for all dogs was 1,936 days. Forty-five dogs (24 medically managed and 21 surgically managed) died or were euthanized during the follow-up period. Survival rate was significantly improved in dogs that underwent surgical treatment (hazard ratio, 8.11; 95% CI, 4.20 to 15.66) than in those treated medically for CPSS. Neither age at diagnosis nor shunt type affected survival rate. Frequency of clinical signs was lower in surgically versus medically managed dogs for all follow-up intervals, with a significant difference between groups at 4 to 7 years after study entry. CONCLUSIONS AND CLINICAL RELEVANCE: Surgical treatment of CPSS in dogs resulted in significantly improved survival rate and lower frequency of ongoing clinical signs, compared with medical management. Age at diagnosis did not affect survival rate and should not influence treatment choice.

Antigen-induced IL-10+ regulatory T cells are independent of CD25+ regulatory cells for their growth, differentiation, and function.

Recent studies have emphasized the importance of T cells with regulatory/suppressor properties in controlling autoimmune diseases. A number of different types of regulatory T cells have been described with the best characterized being the CD25(+) population. In addition, it has been shown that regulatory T cells can be induced by specific Ag administration. In this study, we investigate the relationship between peptide-induced, CD4(+) regulatory T cells and naturally occurring CD4(+)CD25(+) cells derived from the Tg4 TCR-transgenic mouse. Peptide-induced cells were FoxP3(-) and responded to Ag by secreting IL-10, whereas CD25(+) cells failed to secrete this cytokine. Both cell types were able to suppress the proliferation of naive lymphocytes in vitro although with distinct activation sensitivities. Depletion of CD25(+) cells did not affect the suppressive properties of peptide-induced regulators. Furthermore, peptide-induced regulatory/suppressor T cells could be generated in RAG(-/-), TCR-transgenic mice that do not spontaneously generate CD25(+) regulatory cells. These results demonstrate that these natural and induced regulatory cells fall into distinct subsets.

IL-2 overcomes the unresponsiveness but fails to reverse the regulatory function of antigen-induced T regulatory cells.

Intranasal administration of peptide Ac1-9[4Y], based on the N-terminal epitope of myelin basic protein, can induce CD4(+) T cell tolerance, and suppress experimental autoimmune encephalomyelitis induction. The peptide-induced regulatory T (PI-T(Reg)) cells failed to produce IL-2, but expressed IL-10 in response to Ag and could suppress naive T cell responses in vitro. Analysis of Jak-STAT signaling pathways revealed that the activation of Jak1, STAT3, and STAT5 were induced in tolerant T cells after Ag stimulation in vivo. In addition, the expression of suppressor of cytokine signaling 3 was induced in tolerant T cells, suggesting that cytokines regulate the tolerant state of the PI-T(Reg) cells. Stimulation of PI-T(Reg) cells in vitro with IL-10 induced Jak1 and STAT3 activation, but not STAT5, suggesting that IL-10 is important, but not the only cytokine involved in the development of T cell tolerance. Although IL-2 expression was deficient, stimulation with IL-2 in vitro induced Jak1 and STAT5 activation in PI-T(Reg) cells, restored their proliferative response to antigenic stimulation, and abrogated PI-T(Reg)-mediated suppression in vitro. However, the addition of IL-2 could not suppress IL-10 expression, and the IL-2 gene remained inactive. After withdrawal of IL-2, the PI-T(Reg) cells regained their nonproliferative state and suppressive ability. These results underline the ability of the immune system to maintain tolerance to autoantigens, but at the same time having the ability to overcome the suppressive phenotype of tolerant T cells by cytokines, such as IL-2, during the protective immune response to infection.