Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression

The secreted Bv8 protein has been recently characterized as a regulator of myeloid cell mobilization and a neutrophil-derived mediator of tumor angiogenesis in several xenografts, but its role in tumor progression in an endogenous setting was unknown. The rat insulin promoter (RIP)-T-antigen (Tag) is a well characterized transgenic mouse model of multistage pancreatic beta-cell tumorigenesis. Also, the role of neutrophils in RIP-Tag angiogenic switching, as assessed by systemic ablation using anti-Gr1 antibodies at different stages of tumor progression, has been recently described. Here, we show that early treatment of RIP-Tag mice with anti-Bv8 antibodies resulted in a significant reduction in the number of angiogenic islets relative to control antibody-treated mice, implicating Bv8 in the angiogenic switch during neoplasia. Histological analysis showed a significant reduction in vascular surface areas in hyperplastic and angiogenic lesions in pancreatic islets from anti-Bv8-treated mice. Anti-Bv8 treatment also inhibited the mobilization and homing of CD11b+Gr1+ cells to the peripheral blood and the emerging neoplastic lesions. However, anti-Bv8 treatment had no effect on tumor vascularization or burden when initiated at later stages of tumor progression. The stage-dependent efficacy of anti-Bv8 treatment appears remarkably similar to that reported after neutrophil ablation, suggesting that Bv8 is an important mediator of neutrophil-dependent angiogenesis in this transgenic model. In summary, our studies verify a role for Bv8 in the mobilization and recruitment of myeloid cells and in the induction of tumor angiogenesis in the early stages of neoplastic progression.     

When to stop renal replacement therapy in anticipation of renal recovery in AKI: The need for consensus guidelines

There is wide variation in clinical practice regarding timing of discontinuation of renal replacement therapy (RRT) in patients with acute kidney injury (AKI). Prolonged, unnecessary RRT treatment can contribute to length of stay, overall hospital costs, and risk of complications associated with RRT. In addition, prolonged RRT can paradoxically lengthen the time for which the patient remains dialysis‐dependent. Well‐designed, randomized clinical trials have utilized varied discontinuation criteria specifically related to urine output and creatinine clearance, which impedes the comparison of outcomes from such studies. Other observational studies have attempted to assess the sensitivity and specificity of various criteria for discontinuation of RRT. Whether diuretics influence renal recovery has not been fully elucidated as well. In this article, we propose a starting framework for RRT discontinuation criteria to guide clinicians and clinical researchers. We emphasize the importance of frequent clinical assessment while considering discontinuation of RRT for AKI patients with a creatinine clearance >15 mL/min on a timed urine collection and/or a urine output >400 mL/24 h without diuretics, or >2000 mL/24 h with diuretics. We also discuss newer biomarkers, methods of GFR estimation, and imaging techniques that may play a greater role in the future. Clinical trials objectively comparing the success of RRT discontinuation criteria will be required to provide high‐quality evidence for our proposed guidelines.     

Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis

Ocular allergy is an inflammatory response of the conjunctival mucosa that also affects the cornea and eyelids. Allergic conjunctivitis includes seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC). In general, allergic conditions involve mast cell degranulation that leads to release of inflammatory mediators and activation of enzymatic cascades generating pro-inflammatory mediators. In chronic ocular inflammatory disorders associated with mast cell activation such as VKC and AKC constant inflammatory response is observed due to predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines. Antihistamines, mast-cell stabilizers, nonsteroidal anti-inflammatory agents, corticosteroids and immunomodulatory agents are commonly indicated for the treatment of acute and chronic allergic conjunctivitis. In recent years newer drug molecules have been introduced in the treatment of allergic conjunctivitis. This article reviews recent patents and emerging therapeutics in the treatment of allergic conjunctivitis.