Evaluation of risk factors for mortality in dogs with lung lobe torsion: A retrospective study of 66 dogs (2000-2015).

The objectives of this retrospective case series study were to describe a group of 66 dogs with lung lobe torsion (LLT) and to investigate the incidence of complications and risk factors for mortality and overall outcome in this population. Sixty-six dogs with LLT from 3 independent academic institutions were investigated. Information on signalment, history, clinical findings, and interventions was obtained. Associations with mortality outcome were examined via logistic regression. Dogs with a depressed mentation at presentation were 21 times more likely to die than dogs with normal mentation [P = 0.008, 95% confidence interval (CI) = 1.949 to 579.904]. The overall odds of mortality were increased by 18% for each unit change in Acute Patient Physiologic and Laboratory Evaluation (APPLEfast) score (P = 0.04, 95% CI = 0.998 to 1.44). No other clinical abnormalities correlated with outcome.

Évaluation des facteurs de risque pour la mortalité chez les chiens souffrant d'une torsion du lobe pulmonaire : étude rétrospective de 66 chiens (2000­2015). Les objectifs de cette étude rétrospective d'une série de cas consistaient à décrire un groupe de 66 chiens ayant une torsion du lobe pulmonaire (TLP) et d'investiguer l'incidence de complications et les facteurs de risque pour la mortalité et les résultats généraux chez cette population. Soixante-six chiens atteints de TLP provenant de trois établissements universitaires indépendants ont été étudiés. Des données ont été obtenues sur le signalement, les résultats cliniques et les interventions. Les associations avec les résultats de mortalité ont été examinées via la régression logistique. Il était 21 fois plus probable que les chiens ayant un état mental déprimé à la présentation meurent que les chiens ayant un état mental normal (P = 0,008, intervalle de confiance [IC] de 95 % = de 1,949 à 579,904). Les probabilités globales de mortalité augmentaient de 18 % pour chaque unité de changement selon la note Acute Patient Physiologic and Laboratory Evaluation (APPLEfast) (P = 0,04, IC de 95 % = de 0,998 à 1,44). Aucune autre anomalie clinique n'offrait de corrélation avec les résultats.(Traduit par Isabelle Vallières).

Internal hemipelvectomy for treatment of obstipation secondary to pelvic malunion in 3 cats.

Pelvic fractures are a common injury in cats, and both surgical and conservative management approaches have been described. One of the major complications of pelvic fractures managed conservatively is narrowing of the pelvic canal. Severe pelvic canal narrowing can result in constipation and subsequent megacolon. The purpose of this case series is to describe the long-term outcome for 3 cats with obstipation treated with internal hemipelvectomy because of megacolon secondary to pelvic canal narrowing after conservative management. All cats had a good functional outcome of the affected limb. Two cats required ongoing medical management for recurrent constipation. Overall, internal hemipelvectomy offers good long-term limb function; however, its success in relieving clinical signs of constipation requires additional research.

Hémipelvectomie interne pour le traitement de la constipation opiniâtre secondaire à un cal vicieux pelvien chez 3 chats. Les fractures pelviennes sont une blessure commune chez les chats et les approches chirurgicales et prudentes ont toutes deux été décrites. L'une des complications majeures des fractures pelviennes gérées de manière prudente consiste à raccourcir le canal pelvien. Un rétrécissement sévère du canal pelvien peut se traduire par la constipation et un mégacôlon subséquent. Le but de cette série de cas consiste à décrire le résultat à long terme pour 3 chats souffrant de constipation opiniâtre traitée par une hémipelvectomie interne en raison d'un mégacôlon secondaire au rétrécissement du canal pelvien après une gestion prudente. Tous les chats ont obtenu de bons résultats fonctionnels du membre affecté. Deux chats ont nécessité une gestion médicale permanente pour une constipation opiniâtre. En général, l'hémipelvectomie interne offre une bonne fonction du membre, mais son succès dans le soulagement des signes cliniques de la constipation exige de la recherche additionnelle.(Traduit par Isabelle Vallières).

Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective.

The introduction of biologics, especially tumour necrosis factor (TNF) inhibitors, has revolutionized the management of chronic inflammatory diseases. However, at least one third of patients with these diseases, receiving TNF inhibitors either do not respond to treatment, or lose initial responsiveness. For a significant proportion, improvement of clinical response is achieved after switching to another anti-TNF drug, suggesting a basis for failure unrelated to the therapeutic target itself. A likely explanation for this is immunogenicity, as all biologics are potentially immunogenic, and the resulting anti-drug antibodies (ADAb) can theoretically decrease the efficacy of biologics and/or induce adverse events. Indeed, in these chronic inflammatory diseases, many studies have now established correlations between ADAb formation, low serum drug levels, and the failure or loss of response to anti-TNF antibodies. This article will review key findings related to ADAb, and propose a model wherein monitoring of drug levels and ADAb may be a predictive tool leading to a better choice of biologics. Such an approach could improve chronic inflammatory disease management toward a personalized and more cost-effective approach.

A nonrandomised pilot study to examine the feasibility and acceptability of reflexology in patients undergoing hospital-based haemodialysis (solitude study).

BACKGROUND: Patients with end-stage kidney disease, receiving haemodialysis can experience complications-hypotension, headache, muscle cramp, chest pain, nausea and vomiting. Patients who experience all or some of these symptoms will often report reduced health-related quality of life (HRQOL) and poor sleep quality, which may lead to increased morbidity and mortality. OBJECTIVE: The objective of this pilot study is to evaluate the feasibility of a larger randomised controlled trial to determine the effect of foot reflexology on a cohort of patients undergoing hospital-based haemodialysis. DESIGN: A nonrandomised pilot study using a multimethod approach. PARTICIPANTS: Twenty patients undergoing hospital-based haemodialysis treatment. MEASUREMENTS: HRQOL and quality of sleep were measured using the SF-12 Health Survey and the Pittsburgh Sleep Quality Index (PSQI). Semi-structured interviews were completed with 10 patients, exploring their experiences, opinions and perceptions of the intervention. RESULTS: There was an increase in the mean scores examining the total physical health and mental health components of the SF-12. All corresponding p values were statistically significant following the intervention. The mean total sleep score postintervention signified positive changes in sleep quality, with the corresponding p values being statistically significant. The study established the feasibility of the intervention and the benefits for patients undergoing haemodialysis. CONCLUSION: This pilot study demonstrated the possibility of recruiting and retaining patients undergoing haemodialysis to a reflexology study. The study did not impact the haemodialysis routine and was positively received. The intervention showed statistically significant improvements in patients' HRQOL and sleep quality.

Defective homing is associated with altered Cdc42 activity in cells from patients with Fanconi anemia group A.

Previous studies showed that Fanconi anemia (FA) murine stem cells have defective reconstitution after bone marrow (BM) transplantation. The mechanism underlying this defect is not known. Here, we report defective homing of FA patient BM progenitors transplanted into mouse models. Using cells from patients carrying mutations in FA complementation group A (FA-A), we show that when transplanted into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) recipient mice, FA-A BM cells exhibited impaired homing activity. FA-A cells also showed defects in both cell-cell and cell-matrix adhesion. Complementation of FA-A deficiency by reexpression of FANCA readily restored adhesion of FA-A cells. A significant decrease in the activity of the Rho GTPase Cdc42 was found associated with these defective functions in patient-derived cells, and expression of a constitutively active Cdc42 mutant was able to rescue the adhesion defect of FA-A cells. These results provide the first evidence that FA proteins influence human BM progenitor homing and adhesion via the small GTPase Cdc42-regulated signaling pathway.

Using Inquiry-Based Learning to Enhance Immunology Laboratory Skills.

A challenge in teaching immunology in the undergraduate laboratory is to encompass the many varied skills that need to be applied when performing an investigative study of such a complex area. It requires background knowledge, data analysis skills, critical thinking, and design capacities to include relevant controls and applications of particular techniques to answer a research question. It also requires strong technical skills. One such approach is to use inquiry-based learning which allows students a more proactive and integrative role in their learning. In one of our final year immunology units we have incorporated an inquiry-based exercise that runs across four 5-hour sessions. Students are given two cornerstone immunology techniques (ELISA and a flow cytometry-based cytokine bead array), which they use to formulate a study investigating inflammation. Stage one is to design the experiment with some guidance from teaching staff, stage two is to perform the experiment, and then finally students are required to analyze the data, apply appropriate statistics, and write a report outlining their findings. This approach provides students ownership of the process and allows them the opportunity to investigate a real-world problem rather than just attempting to obtain the expected "correct answer." Feedback from both students and staff has been positive with strong engagement and high quality reports produced.

Gene therapy strategies towards immune tolerance to treat the autoimmune diseases.

Autoimmune diseases such as type 1 diabetes and multiple sclerosis pose a significant health burden on our society. As a whole, autoimmune diseases affect approximately 6% of the population and are the third largest disease burden after heart disease and cancer. Such pathologic manifestations arise by way of damaging reactions of B-cell derived antibodies and/or T-cells to self-antigens and are triggered by genetic and environmental factors. Currently there is no known cure, with treatment restricted to toxic, long-term immunosuppressive regimes, replacement therapy and in intractable cases, transplantation of autologous or allogeneic haematopoietic stem cells. In experimental models of autoimmunity, gene therapeutic approaches have demonstrated promise in treating the autoimmune diseases. These include delivery of anti-inflammatory cytokines and exploitation of regulatory T cells. However, none of these approaches provide lasting, long-term benefit. We hypothesise that therapeutically transduced haematopoietic stem cells followed by transplantation is an alternative strategy to establish permanent immune tolerance that can not only prevent autoimmunity but also cure these diseases. Our approach is focused on directing autoimmune disease-specific autoantigen expression in the thymus by genetic manipulation of haematopoietic stem cells to establish molecular chimeras. Our hypothesis originates from experimental studies with a mouse model of experimental autoimmune gastritis (EAG) and more recently with the non-obese diabetic (NOD) mouse model for type 1 diabetes (T1D).

Mechanisms of gastric mucosal cell loss in autoimmune gastritis.

The causes of target cell death in organ-specific autoimmune diseases are not precisely known. In the case of EAG, parietal cell death depends on Th1 CD4 T cells and Fas/Fas-ligand, either through interaction between infiltrating CD4 T cells with gastric parietal cells that have upregulated Fas expression or through homotypic interactions between the parietal cells. TNF-alpha does not appear to have a role in this process. The accompanying loss of zymogenic cells is likely a consequence of the interruption of the normal developmental pathway in the gastric mucosa that follows the destruction of parietal cells in the gastric mucosa.

Reversing the autoimmune condition: experience with experimental autoimmune gastritis.

Autoimmune diseases remain a significant health problem in our society, despite the best efforts to understand and treat these conditions. Current clinical treatments are aimed at alleviating the consequences of these diseases, with limited prospects for cure. Our studies with the experimental model of autoimmune gastritis have led us to explore potential curative strategies that can reverse the autoimmune condition. Using mouse models, we have shown that expression of the known gastric autoantigen in the thymus results in immunological tolerance and resistance to the induction of autoimmune gastritis. Also, induced tolerance in donor mice can be transferred to syngeneic recipient mice by bone marrow cells. Strategies based on these observations could lead to reversal of established disease. Transfer of ensuing knowledge to the cure of serious human autoimmune diseases is our ultimate goal.

Haematopoietic stem cell gene therapy to treat autoimmune disease.

Autoimmune diseases affect approximately 6% of the population and are characterised by a pathogenic immune response that targets self-antigens. Well known diseases of this nature include type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. Treatment is often restricted to replacement therapy or immunosuppressive regimes and to date there are no cures. The strategy of utilising autologous or allogeneic haematopoietic stem cell transplantation to treat autoimmunity and induce immunological tolerance has been trailed with various levels of success. A major issue is disease relapse as the autoimmune response is reinitiated. Cells of the immune system originate from bone marrow and have a central role in the induction of immunological tolerance. The ability to isolate and genetically manipulate bone marrow haematopoietic stem cells therefore makes these cells a suitable vehicle for driving ectopic expression of defined autoantigens and induction of immunological tolerance.

Tolerance established in autoimmune disease by mating or bone marrow transplantation that target autoantigen to thymus.

Autoimmune diseases are a significant cause of death and morbidity, affecting up to 5% of the population. At present, there is no cure. Autologous bone marrow transplantation has been promoted as a treatment for achieving disease reversal and long-term remission. However, clinical trials in progress in Europe and North America report a significant risk of relapse. Here, we have addressed whether we can establish tolerance in an active autoimmune disease model by thymic expression of autoantigen. We show that tolerance and disease resistance can indeed be established in transgenic mice that spontaneously develop granulocyte macrophage colony stimulating factor-induced autoimmune gastritis, by mating them with disease-resistant transgenic mice that target autoantigen to the thymus. T cells from these double-transgenic mice are non-responsive to gastric antigen in vitro and fail to initiate disease following transfer to naive recipients. Further, we show that transplantation with bone marrow from disease-resistant transgenic mice renders recipient mice with gastritis tolerant to autoantigen as shown by a dramatic fall in autoantibody levels and T cell non-responsiveness to antigen in vitro. We suggest that genetically modified bone marrow targeting autoantigen to the thymus may be used to establish tolerance and prevent relapse of autoimmune disease following autologous bone marrow transplantation.

Stem cells engineered to express self-antigen to treat autoimmunity.

Autoimmune diseases are incurable. We propose a combination curative strategy using haematopoietic stem cells and gene therapy. The strategy should establish molecular chimerism with culprit antigen expressed by donor antigen-presenting cells in the thymus, resulting in immunological tolerance. Our strategy is based on the intrathymic tolerance and disease resistance established by transgenic expression of antigen in the thymus under control of an MHC class II promoter. We propose that transplantation with genetically engineered stem cells provides an advance over current autologous bone marrow transplantation, in that it should remove the significant risk of disease relapse.