Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

The evaluation of a healthcare passport to improve quality of care and communication for people living with dementia (EQuIP): a protocol paper for a qualitative, longitudinal study

Background\ud \ud There is an urgent need for the development of simple communication tools that convey the strengths, assets, and healthcare needs of people living with dementia. A Healthcare Passport may improve communication with range of health and social support services, enhancing quality and continuity of care, and to permit a consideration of the challenges and how these might be managed effectively and compassionately. This study aims to evaluate the acceptability and use of this type of intervention for people living with dementia and their carers.\ud \ud \ud Methods/Design\ud \ud This is a qualitative longitudinal study informed by a critical realist review. The participants will be individuals identified as having mild-moderate dementia and informal carers. The in-depth interviews will occur at three points over the course of 18 months as they use the passport. This will be supplemented by analysis of the content of the passports and information from health and social care providers on the daily practicalities of using the passport in a range of healthcare settings.\ud \ud \ud Discussion\ud \ud By using a critical realist review and a qualitative, longitudinal approach, the study allows for the assessment of a complex intervention in a manner which goes beyond evaluating the basic efficacy of the passport, but looking more deeply at how it worked, for whom, and in what context. It has the potential to develop new data on how interventions improve communication across a range of service providers, while encouraging health and social care professionals to respect and encourage the development of self-management and retention of personhood throughout the progression of life-limiting illnesses

Specifying the design for customer learning in the mixed reality experience

Peer reviewe

The Increase in Balloon Size to Over 15 mm Does Not Affect the Development of Pancreatitis After Endoscopic Papillary Large Balloon Dilatation for Bile Duct Stone Removal

BACKGROUND: Endoscopic papillary large balloon dilatation (EPLBD) after endoscopic sphincterotomy (EST) has recently become widely used for common bile duct (CBD) stone removal, but many clinicians remain concerned about post-procedural pancreatitis with increasing the balloon size to over 15 mm. AIMS: We aimed to evaluate the safety and efficacy of EPLBD with a relatively large balloon (15-20 mm) after EST and to evaluate the factors related to post-EPLBD pancreatitis. METHODS: A retrospective review was undertaken of the endoscopic database of 101 patients with CBD stones who underwent EPLBD using a larger balloon size of over 15 mm (15-20 mm). Clinical parameters, endoscopic data, and outcomes were analyzed. RESULTS: The mean age of the subjects was 69 years. All patients had a dilated CBD of over 11 mm (mean = 22.6 mm). The mean size of balloon used in EPLBD was 17.1 ± 1.9 mm (range 15-20 mm). Mechanical lithotripsy was required in seven patients (6.9%). The rate of complete stone removal in the first session was 92.1%. Post-procedural pancreatitis developed in five cases (5.4%), but none were graded as severe. The smaller dilatation of the CBD, longer cannulation time, and longer time for stone removal were associated with post-procedural pancreatitis, but larger size of balloon did not affect the development of post-EPLBD pancreatitis. CONCLUSIONS: EPLBD with a large balloon of over 15 mm with EST is an effective and safe procedure with a very low probability of severe post-procedural pancreatitis. Post-EPLBD pancreatitis was not associated with larger balloon size, but was associated with longer procedure time and smaller dilatation of the CBD.ope

B7-H1-Deficiency Enhances the Potential of Tolerogenic Dendritic Cells by Activating CD1d-Restricted Type II NKT Cells

Background: Dendritic cells (DC) can act tolerogenic at a semi-mature stage by induction of protective CD4+ T cell and NKT cell responses. Methodology/Principal Findings: Here we studied the role of the co-inhibitory molecule B7-H1 (PD-L1, CD274) on semimature DC that were generated from bone marrow (BM) cells of B7-H12/2 mice and applied to the model of Experimental Autoimmune Encephalomyelitis (EAE). Injections of B7-H1-deficient DC showed increased EAE protection as compared to wild type (WT)-DC. Injections of B7-H12/2 TNF-DC induced higher release of peptide-specific IL-10 and IL-13 after restimulation in vitro together with elevated serum cytokines IL-4 and IL-13 produced by NKT cells, and reduced IL-17 and IFN-c production in the CNS. Experiments in CD1d2/2 and Ja2812/2 mice as well as with type I and II NKT cell lines indicated that only type II NKT cells but not type I NKT cells (invariant NKT cells) could be stimulated by an endogenous CD1d-ligand on DC and were responsible for the increased serum cytokine production in the absence of B7-H1. Conclusions/Significance: Together, our data indicate that BM-DC express an endogenous CD1d ligand and B7-H1 to ihibit type II but not type I NKT cells. In the absence of B7-H1 on these DC their tolerogenic potential to stimulate tolerogenic CD4+ and NKT cell responses is enhanced

Endogenous PTH Deficiency Impairs Fracture Healing and Impedes the Fracture-Healing Efficacy of Exogenous PTH(1-34)

Although the capacity of exogenous PTH1-34 to enhance the rate of bone repair is well established in animal models, our understanding of the mechanism(s) whereby PTH induces an anabolic response during skeletal repair remains limited. Furthermore it is unknown whether endogenous PTH is required for fracture healing and how the absence of endogenous PTH would influence the fracture-healing capacity of exogenous PTH.Closed mid-diaphyseal femur fractures were created and stabilized with an intramedullary pin in 8-week-old wild-type and Pth null (Pth(-/-)) mice. Mice received daily injections of vehicle or of PTH1-34 (80 µg/kg) for 1-4 weeks post-fracture, and callus tissue properties were analyzed at 1, 2 and 4 weeks post-fracture. Cartilaginous callus areas were reduced at 1 week post-fracture, but were increased at 2 weeks post-fracture in vehicle-treated and PTH-treated Pth(-/-) mice compared to vehicle-treated and PTH-treated wild-type mice respectively. The mineralized callus areas, bony callus areas, osteoblast number and activity, osteoclast number and surface in callus tissues were all reduced in vehicle-treated and PTH-treated Pth(-/-) mice compared to vehicle-treated and PTH-treated wild-type mice, but were increased in PTH-treated wild-type and Pth(-/-) mice compared to vehicle-treated wild-type and Pth(-/-) mice.Absence of endogenous PTH1-84 impedes bone fracture healing. Exogenous PTH1-34 can act in the absence of endogenous PTH but callus formation, including accelerated endochondral bone formation and callus remodeling as well as mechanical strength of the bone are greater when endogenous PTH is present. Results of this study suggest a complementary role for endogenous PTH1-84 and exogenous PTH1-34 in accelerating fracture healing

Type II NKT Cells Stimulate Diet-Induced Obesity by Mediating Adipose Tissue Inflammation, Steatohepatitis and Insulin Resistance

The progression of obesity is accompanied by a chronic inflammatory process that involves both innate and acquired immunity. Natural killer T (NKT) cells recognize lipid antigens and are also distributed in adipose tissue. To examine the involvement of NKT cells in the development of obesity, C57BL/6 mice (wild type; WT), and two NKT-cell-deficient strains, Jα18−/− mice that lack the type I subset and CD1d−/− mice that lack both the type I and II subsets, were fed a high fat diet (HFD). CD1d−/− mice gained the least body weight with the least weight in perigonadal and brown adipose tissue as well as in the liver, compared to WT or Jα18−/− mice fed an HFD. Histologically, CD1d−/− mice had significantly smaller adipocytes and developed significantly milder hepatosteatosis than WT or Jα18−/− mice. The number of NK1.1+TCRβ+ cells in adipose tissue increased when WT mice were fed an HFD and were mostly invariant Vα14Jα18-negative. CD11b+ macrophages (Mφ) were another major subset of cells in adipose tissue infiltrates, and they were divided into F4/80high and F4/80low cells. The F4/80low-Mφ subset in adipose tissue was increased in CD1d−/− mice, and this population likely played an anti-inflammatory role. Glucose intolerance and insulin resistance in CD1d−/− mice were not aggravated as in WT or Jα18−/− mice fed an HFD, likely due to a lower grade of inflammation and adiposity. Collectively, our findings provide evidence that type II NKT cells initiate inflammation in the liver and adipose tissue and exacerbate the course of obesity that leads to insulin resistance