Neurogenic factor-induced Langerhans cell activation in diabetic mice with mechanical allodynia

Abstract Background Langerhans cells (LCs) are antigen-presenting dendritic cells located in the skin. It has been reported that LC activation is associated with painful diabetic neuropathy (PDN); however, the mechanism of LC activation is still unclear. Methods The db/db mouse, a rodent model of PDN, was used to study the roles of LCs in the development of PDN in type 2 diabetes. Hind foot pads from db/db and control db/+ mice from 5 to 24 weeks of age (encompassing the period of mechanical allodynia development and its abatement) were collected and processed for immunohistochemistry studies. LCs were identified with immunohistochemistry using an antibody against CD207 (Langerin). The intraepidermal nerve fibers and subepidermal nerve plexus were identified by immunohistochemistry of protein gene product 9.5 (PGP 9.5) and tropomyosin-receptor kinase (Trk) A, the high affinity nerve growth factor receptor. Results CD207-positive LCs increased in the db/db mouse during the period of mechanical allodynia, from 8 to 10 weeks of age, in both the epidermis and subepidermal plexus. At 16 weeks of age, when mechanical allodynia diminishes, LC populations were reduced in the epidermis and subepidermal plexus. Epidermal LCs (ELCs) were positive for Trk A. Subepidermal LCs (SLCs) were positive for CD68, suggesting that they are immature LCs. Additionally, these SLCs were positive for the receptor of advanced glycation end products (RAGE) and were in direct contact with TNF-α-positive nerve fibers in the subepidermal nerve plexus during the period of mechanical allodynia. Intrathecal administration of SB203580, a p38 kinase inhibitor, significantly reduced mechanical allodynia, TNF-α expression in the subepidermal plexus, and increased both ELC and SLC populations during the period of mechanical allodynia. Conclusions Our data support the hypothesis that increased LC populations in PDN are activated by p38-dependent neurogenic factors and may be involved in the pathogenesis of PDN.http://deepblue.lib.umich.edu/bitstream/2027.42/135942/1/12974_2013_Article_838.pd

Toward the development of a virtual spray test-rig using the Smoothed Particle Hydrodynamics method

In this work we present the numerical simulation of air-assisted liquid atomization at high pressure us- ing the Smoothed Particle Hydrodynamics (SPH) method. Different post-processing tools are applied to facilitate the comparison with experimental observations. This allows to quantitatively validate the nu- merical method against the experiment, in terms of (i) frequency of the Kelvin–Helmholtz instability that develops on the jet surface, and (ii) statistical distribution of the jet intact length. The qualitative com- parison also shows a good prediction of the jet global instability and of the fragmented liquid lumps, with regards to length and time scales. In addition, the post-processing tools also give access to the local parameters of the generated spray in the vicinity of the nozzle, which are not easily accessible in a real experiments. Using these tools, 1D profiles and 2D maps of the liquid phase properties such as the vol- ume fraction, the droplet concentration, the Sauter Mean Diameter (SMD) and the droplet sphericity are presented. Because of the Lagrangian nature of the SPH method, it is also possible to monitor the whole atomization cascade as a causal tree, from the primary instabilities to the spray characteristics. This tree contains various information such as the fragmentation spectrum and the breakup activity, which are of great interest for researchers and engineers. Hence, the capability of the Smoothed Particle Hydrody- namics (SPH) method for simulating air-assisted atomization at high ambient pressure is demonstrated as well as its applicability to realistic configurations. This is a first step towards the development of a complete virtual spray test-rig

Neurogenic factor-induced Langerhans cell activation in diabetic mice with mechanical allodynia

Abstract Background Langerhans cells (LCs) are antigen-presenting dendritic cells located in the skin. It has been reported that LC activation is associated with painful diabetic neuropathy (PDN); however, the mechanism of LC activation is still unclear. Methods The db/db mouse, a rodent model of PDN, was used to study the roles of LCs in the development of PDN in type 2 diabetes. Hind foot pads from db/db and control db/+ mice from 5 to 24 weeks of age (encompassing the period of mechanical allodynia development and its abatement) were collected and processed for immunohistochemistry studies. LCs were identified with immunohistochemistry using an antibody against CD207 (Langerin). The intraepidermal nerve fibers and subepidermal nerve plexus were identified by immunohistochemistry of protein gene product 9.5 (PGP 9.5) and tropomyosin-receptor kinase (Trk) A, the high affinity nerve growth factor receptor. Results CD207-positive LCs increased in the db/db mouse during the period of mechanical allodynia, from 8 to 10 weeks of age, in both the epidermis and subepidermal plexus. At 16 weeks of age, when mechanical allodynia diminishes, LC populations were reduced in the epidermis and subepidermal plexus. Epidermal LCs (ELCs) were positive for Trk A. Subepidermal LCs (SLCs) were positive for CD68, suggesting that they are immature LCs. Additionally, these SLCs were positive for the receptor of advanced glycation end products (RAGE) and were in direct contact with TNF-α-positive nerve fibers in the subepidermal nerve plexus during the period of mechanical allodynia. Intrathecal administration of SB203580, a p38 kinase inhibitor, significantly reduced mechanical allodynia, TNF-α expression in the subepidermal plexus, and increased both ELC and SLC populations during the period of mechanical allodynia. Conclusions Our data support the hypothesis that increased LC populations in PDN are activated by p38-dependent neurogenic factors and may be involved in the pathogenesis of PDN.http://deepblue.lib.umich.edu/bitstream/2027.42/112392/1/12974_2013_Article_838.pd

Hyper-IgG4 disease: report and characterisation of a new disease

BACKGROUND: We highlight a chronic inflammatory disease we call 'hyper-IgG4 disease', which has many synonyms depending on the organ involved, the country of origin and the year of the report. It is characterized histologically by a lymphoplasmacytic inflammation with IgG4-positive cells and exuberant fibrosis, which leaves dense fibrosis on resolution. A typical example is idiopathic retroperitoneal fibrosis, but the initial report in 2001 was of sclerosing pancreatitis. METHODS: We report an index case with fever and severe systemic disease. We have also reviewed the histology of 11 further patients with idiopathic retroperitoneal fibrosis for evidence of IgG4-expressing plasma cells, and examined a wide range of other inflammatory conditions and fibrotic diseases as organ-specific controls. We have reviewed the published literature for disease associations with idiopathic, systemic fibrosing conditions and the synonyms: pseudotumour, myofibroblastic tumour, plasma cell granuloma, systemic fibrosis, xanthofibrogranulomatosis, and multifocal fibrosclerosis. RESULTS: Histology from all 12 patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils, and sometimes eosinophilic aggregates, with venulitis and obliterative arteritis. The majority of lymphocytes were T cells that expressed CD8 and CD4, with scattered B-cell-rich small lymphoid follicles. In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls. In two cases, biopsies before and after steroid treatment were available, and only scattered plasma cells were seen after treatment, none of them expressing IgG4. Review of the literature shows that although pathology commonly appears confined to one organ, patients can have systemic symptoms and fever. In the active period, there is an acute phase response with a high serum concentration of IgG, and during this phase, there is a rapid clinical response to glucocorticoid steroid treatment. CONCLUSION: We believe that hyper-IgG4 disease is an important condition to recognise, as the diagnosis can be readily verified and the outcome with treatment is very good

Nuclear localisation of Aurora-A: its regulation and significance for Aurora-A functions in cancer.

The Aurora-A kinase regulates cell division, by controlling centrosome biology and spindle assembly. Cancer cells often display elevated levels of the kinase, due to amplification of the gene locus, increased transcription or post-translational modifications. Several inhibitors of Aurora-A activity have been developed as anti-cancer agents and are under evaluation in clinical trials. Although the well-known mitotic roles of Aurora-A point at chromosomal instability, a hallmark of cancer, as a major link between Aurora-A overexpression and disease, recent evidence highlights the existence of non-mitotic functions of potential relevance. Here we focus on a nuclear-localised fraction of Aurora-A with oncogenic roles. Interestingly, this pool would identify not only non-mitotic, but also kinase-independent functions of the kinase. We review existing data in the literature and databases, examining potential links between Aurora-A stabilisation and localisation, and discuss them in the perspective of a more effective targeting of Aurora-A in cancer therapy