Dog and cat bite-associated infections in children

Millions of people throughout the world are bitten by animals each year. About 90 % of the bites are caused by dogs and cats, and infections are the most common complications. As children are the most frequently bitten subjects, pediatricians should provide parents with everything they need to know in order to confront the problem. However, this does not seem to be case and, as the treatment of bite wounds is frequently inappropriate and delayed, the risk of acute infection and sequelae is increased. The main aim of this review is to discuss the epidemiology, microbiology, and clinical characteristics of infections due to dog and cat bites in children, and suggest the best approach to their management. Analysis of the published literature shows that prompt treatment is necessary in order to reduce the risk of infection. The therapeutic measures include wound washing, specific prophylaxis (i.e., tetanus and/or rabies), and antibiotics in the case of immunocompromised patients or deep wounds (particularly if there is evidence of edema or crushing), facial bites, or any wound over a tendon or bone.     

Autoimmunity and cancer

In many autoimmune rheumatic diseases, there is an increased risk of cancer compared to the general population. The link between autoimmunity and cancer is dynamic and bidirectional. Recent advances in terms of knowledge of biology, epidemiology, and long-term outcomes for the autoimmune rheumatic diseases have revealed several new connections between these two entities. Data suggest that chronic inflammation from the rheumatic diseases or their therapies may contribute to the onset and promotion of cancer. Conversely, antitumor immune responses may become cross-reactive with self-tissues resulting in the development of autoimmunity. In this review, we discuss about the potential mechanisms that link autoimmune rheumatic diseases and cancer and the association of malignancies with common autoimmune disorders. The increased incidence of malignancy in autoimmune rheumatic diseases has been largely described, although the biology underpinning this relationship should be further investigated. The development of evidence-based cancer screening recommendations in patients with autoimmune rheumatic diseases is complex due to the heterogeneity of clinical rheumatic phenotypes, cancer sites at risk and exposure to anti-neoplastic and anti-rheumatic treatment. In order to lay the foundation of risk stratification and targeted cancer screening, larger longitudinal cohort studies that provide a more detailed framework of the links between cancer and autoimmunity are urgently needed.     

The UBIAD1 Prenyltransferase Links Menaquione‐4 Synthesis to Cholesterol Metabolic Enzymes

Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. UBIAD1 was recently shown to synthesize menaquinone‐4 (MK‐4, vitamin K₂), but causal mechanisms of SCD are unknown. We report a novel c.864G>A UBIAD1 mutation altering glycine 177 to glutamic acid (p.G177E) in six SCD families, including four families from Finland who share a likely founder mutation. We observed reduced MK‐4 synthesis by UBIAD1 altered by SCD mutations p.N102S, p.G177R/E, and p.D112N, and molecular models showed p.G177‐mutant UBIAD1 disrupted transmembrane helices and active site residues. We show UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, using yeast two‐hybrid screening and immunoprecipitation. Docking simulations indicate cholesterol binds to UBIAD1 in the substrate‐binding cleft and substrate‐binding overlaps with GGPP binding, an MK‐4 substrate, suggesting potential competition between these metabolites. Impaired MK‐4 synthesis is a biochemical defect identified in SCD suggesting UBIAD1 links vitamin K and cholesterol metabolism through physical contact between enzymes and metabolites. Our data suggest a role for endogenous MK‐4 in maintaining cornea health and visual acuity.     

BMP2 Regulation of CXCL12 Cellular,Temporal, and Spatial Expression Is Essential During Fracture Repair

The cellular and humoral responses that orchestrate fracture healing are still elusive. Here we report that bone morphogenic protein 2 (BMP2)‐dependent fracture healing occurs through a tight control of chemokine C‐X‐C motif‐ligand‐12 (CXCL12) cellular, spatial, and temporal expression. We found that the fracture repair process elicited an early site‐specific response of CXCL12⁺‐BMP2⁺ endosteal cells and osteocytes that was not present in unfractured bones and gradually decreased as healing progressed. Absence of a full complement of BMP2 in mesenchyme osteoprogenitors (BMP2^cKO/+) prevented healing and led to a dysregulated temporal and cellular upregulation of CXCL12 expression associated with a deranged angiogenic response. Healing was rescued when BMP2^cKO/+ mice were systemically treated with AMD3100, an antagonist of CXCR4 and agonist for CXCR7 both receptors for CXCL12. We further found that mesenchymal stromal cells (MSCs), capable of delivering BMP2 at the endosteal site, restored fracture healing when transplanted into BMP2^cKO/+ mice by rectifying the CXCL12 expression pattern. Our in vitro studies showed that in isolated endosteal cells, BMP2, while inducing osteoblastic differentiation, stimulated expression of pericyte markers that was coupled with a decrease in CXCL12. Furthermore, in isolated BMP2^cKO/cKO endosteal cells, high expression levels of CXCL12 inhibited osteoblastic differentiation that was restored by AMD3100 treatment or coculture with BMP2‐expressing MSCs that led to an upregulation of pericyte markers while decreasing platelet endothelial cell adhesion molecule (PECAM). Taken together, our studies show that following fracture, a CXCL12⁺‐BMP2⁺ perivascular cell population is recruited along the endosteum, then a timely increase of BMP2 leads to downregulation of CXCL12 that is essential to determine the fate of the CXCL12⁺‐BMP2⁺ to osteogenesis while departing their supportive role to angiogenesis. Our findings have far‐reaching implications for understanding mechanisms regulating the selective recruitment of distinct cells into the repairing niches and the development of novel pharmacological (by targeting BMP2/CXCL12) and cellular (MSCs, endosteal cells) interventions to promote fracture healing. © 2015 American Society for Bone and Mineral Research.     

Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis

Background

Acute pancreatitis is accompanied by acinar cell damage releasing potential toll-like receptor 3 (TLR3) ligands. So far, TLR3 is known as a pattern recognition receptor in the immune signaling cascade triggering a type I interferon response. In addition, TLR3 signaling contributes to programmed cell death through the activation of caspase 8. However, the functional role of TLR3 and its downstream toll-like receptor adaptor molecule 1 (TICAM1) in the inflamed pancreas is unknown.