RESUMEN
Seizures is a relatively common presentation with a wide differential diagnosis. However, seizures presenting secondary to underlying pulmonary emboli are rare and, without prompt recognition and management, this easily treatable condition can be potentially fatal. The few available case reports discussing seizures and PE reveal a high mortality rate which underscores the importance of prompt diagnosis. A 38-year-old woman presented to the emergency room having experienced loss of consciousness and a generalized tonic-clonic seizure at home. In the emergency room, her presenting signs and symptoms included tachycardia, worsening dyspnea, mild hypoxemia, and elevated D-dimer. Pertinent history findings revealed she recently received depot hormonal contraceptive treatments. Her initial workup included an EKG which showed sinus tachycardia without evidence of right heart strain. Subsequently a chest CT with angiography revealed massive bilateral pulmonary emboli. DVT studies also revealed a unilateral acute DVT. The patient was promptly started on therapeutic anticoagulation and stabilized. Fortunately, the patient remained symptom-free and eventually was discharged with close follow-up. The goal of this report is to make clinicians more aware of the possibility that seizures, along with the appropriate clinical findings, can be caused by acute PE.
RESUMEN
Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88(-/-) or IL-1R(-/-) keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88(-/-) keratinocytes form only a few small tumors in orthotopic grafts, IL-1R-deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1α, IL-1R, and MyD88 leading to phosphorylation of IκBα and NF-κB activation. Blocking IL-1α-mediated NF-κB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes.
