Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma.

Activating mutations of the genes for NRAS and BRAF, components of the p44/42 mitogen-activated protein kinase (MAPK) pathway, are common findings in melanoma. Recent evidence in several nonmelanoma cell systems supports the regulation of the inducible nitric oxide synthase (iNOS) gene by this pathway. On the basis of our data showing that melanoma iNOS expression predicts shortened patient survival, we formulated the hypothesis that activating mutations of NRAS or BRAF, which lead to constitutive activation of the p44/42 MAPK pathway, drive iNOS expression in human melanoma. In the present study, we have shown that inhibition of melanoma iNOS activity by S-methylisothiourea leads to decreased cell proliferation, confirming the importance of iNOS activity for melanoma cell growth. Regulation of melanoma iNOS expression by the p44/42 MAPK pathway was demonstrated by inhibition of the pathway by U0126, and by BRAF RNA interference. To explore this regulatory pathway in human tissue, 20 melanoma tumors were examined for NRAS and BRAF mutations, immunohistochemical evidence of ERK phosphorylation, and iNOS expression. A significant association was found among these three features. We conclude that in human melanoma, activating mutations of NRAS and BRAF drive constitutive iNOS expression and, implicitly, nitric oxide production, contributing to the poor survival of these patients.

Septic hip in pelvic fractures with urologic injury: a case report, review of the literature and discussion of the pathophysiology.

In patients with fractures of the pubic rami and acetabulum and a rupture of the bladder or urethra, there is a risk of septic arthritis developing in the traumatized hip. Infected material from the lacerated urinary tract can communicate by a fistulous tract with the hip joint. Since the symptoms of hip infection in this setting would differ significantly from acute hematogenous septic arthritis, the attending physician must be alert to this possibility for early diagnosis to be made and appropriate treatment instituted. Every attempt should be made to maintain the sterility of the urine throughout the course of treatment, in the hope of preventing the delayed sequelae of unrecognized hip infection. The possibility of this complication must be anticipated to prevent early joint destruction.

Osteochondritis dissecans: a histologic and microradiographic analysis of surgically excised lesions.

The excised fragments of six osteochondritis dissecans lesions of the lateral aspect of the medial femoral condyle were found to be composed of viable hyaline articular cartilage over-lying a totally cellular, metabolically active ossific nucleus, which in turn rested in a bed of fibrocartilage. At the interface between the fibrocartilage and the bone, enchondral ossification was seen histologically and verified by microradiographic evidence of bone formation and resorption. The present authors propose that this classical dissecans lesion is a reparative process and, in most cases, will proceed to complete union of the ossific nucleus with the remainder of the bone of the femoral condyle.