Cell-intrinsic sphingosine kinase 2 promotes macrophage polarization and renal inflammation in response to unilateral ureteral obstruction.

Sphingosine Kinase-2 (Sphk2) is responsible for the production of the bioactive lipid Sphingosine-1 Phosphate, a key regulator of tissue repair. Here we address the in vivo significance of Sphingosine Kinase -2 in renal inflammation/fibrosis in response to unilateral ureteral obstruction using both genetic and pharmacological strategies. Obstructed kidneys of Sphk2-/- mice showed reduced renal damage and diminished levels of the renal injury markers TGFß1 and αSMA when compared to wild type controls. We found a consistently significant increase in anti-inflammatory (M2) macrophages in obstructed Sphk2-/- kidneys by flow cytometry and a decrease in mRNA levels of the inflammatory cytokines, MCP1, TNFα, CXCL1 and ILß1, suggesting an anti-inflammatory bias in the absence of Sphk2. Indeed, metabolic profiling showed that the pro-inflammatory glycolytic pathway is largely inactive in Sphk2-/- bone marrow-derived macrophages. Furthermore, treatment with the M2-promoting cytokines IL-4 or IL-13 demonstrated that macrophages lacking Sphk2 polarized more efficiently to the M2 phenotype than wild type cells. Bone marrow transplant studies indicated that expression of Sphk2-/- on either the hematopoietic or parenchymal cells did not fully rescue the pro-healing phenotype, confirming that both infiltrating M2-macrophages and the kidney microenvironment contribute to the damaging Sphk2 effects. Importantly, obstructed kidneys from mice treated with an Sphk2 inhibitor recapitulated findings in the genetic model. These results demonstrate that reducing Sphk2 activity by genetic or pharmacological manipulation markedly decreases inflammatory and fibrotic responses to obstruction, resulting in diminished renal injury and supporting Sphk2 as a novel driver of the pro-inflammatory macrophage phenotype.

Prognostic implications of lymph node involvement in bladder cancer: are we understaging using current methods?

To review the current and newer, alternative methods for evaluating lymph nodes for tumor involvement in bladder cancer as relapse rates for organ-confined disease remain high despite improvements in surgical technique, suggesting the possibility of understaging. To propose a research agenda based on these findings. A PubMed literature search was performed to identify studies examining the prognostic implications of and outcomes associated with lymph node involvement in bladder cancer as well as those that utilized newer methodologies to identify the possibility for metastatic disease. Lymph node involvement remains one of the strongest predictors of clinical outcome in bladder cancer. Histologic and molecular techniques for identification of lymph node metastasis provide a sensitivity and specificity equal to if not higher than standard pathologic evaluation. Further research into this field would help to elucidate the potential utility of these techniques with regard to proper staging and potential relevance to clinical outcomes.

Membranoproliferative glomerulonephritis in a postpartum woman with sickle cell disease.

Renal insufficiency occurs in a considerable proportion of patients with sickle cell disease. Common advanced glomerular lesions include focal segmental glomerulosclerosis and nonimmune membranoproliferative glomerulonephritis. Due to the paucity of data supporting an immune-mediated pathophysiology, anti-inflammatory and immunosuppressive therapies have not been successfully evaluated in such patients. We present a case of membranoproliferative glomerulonephritis in a postpartum patient with sickle cell disease, where treatment with steroids was helpful.

Henoch-Schönlein Purpura Presenting as a Rash and Proteinuria in a 59-Year-Old Woman.

Henoch-Schönlein purpura is a disease of unknown etiology. it is predominantly seen in children, although adults are also affected, and comprises a rash, arthritis, abdominal pain, and renal dysfunction. there is no effective treatment, although the syndrome is self-limiting and generally subsides without sequelae. The authors present a case of Henoch-Schönlein purpura in a 59-year-old woman who presented with a rash of six months' duration and a high level of urinary protein.

Palpable lesions resistant to corticosteroids.

A woman with a history of leukocytoclastic vasculitis is resistant to treatment with prednisone. The lesions are particularly prominent over the buttocks, waist, and sock line. The patient's symptoms are described in detail. Various possible solutions are described in detail. Various possible solutions are discussed.