IntroductionNeoplastic and healthy natural killer (NK) cells express a family of inhibitory killer immunoglobulin-like receptors (KIR) with specificity for class I human-leukocyte antigens (HLAs) -A, -B, -C, and -E, which shield autologous tissues from cytotoxic effector function mediated by activating NK receptors (NKRs). [1][2][3][4] Signaling events triggered by NKRs include phosphorylation and activation of adaptor molecules (DAP10, DAP12, CD3, or FcR␥), and activation of phosphytidylinositol-3-kinase (PI3K), Ras, MEK, and MAPK (ERK1/ERK2).Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder associated with impaired hematopoiesis. It is classified as T-cell or NK-cell neoplasm based on whether the expanded population of LGL cells are CD3 ϩ or CD3 Ϫ , respectively. [5][6][7] In our previously published work, survival of leukemic NK LGL was shown to be coupled to a Ras/MAPK (p42/p44) signaling pathway. [8][9][10][11][12] A protocol to treat patients was therefore initiated with the Ras farnesyltransferase inhibitor (FTI) tipifarnib (Zarnestra; Johnson & Johnson Pharmaceuticals, Cranbury, NJ). Several prior investigations have shown aberrant NKR expression on leukemic NK and T cells. In this report, we determined the molecular events associated with NKR signaling that lead to pulmonary endothelial cell recognition in a patient with NK LGL leukemia and show that Ras/MAPK blockade leads to symptomatic improvement in PAH and improved bone marrow differentiation. MethodsLGL leukemia patient A 52-year-old female with lymphocytosis, neutropenia, and anemia since 2001 underwent evaluation before enrollment in a phase 2 clinical trial with the farnesyltransferase inhibitor tipifarnib (Johnson & Johnson). The patient was transfusion-dependent, requiring 2 units of packed red blood cells every 3 weeks, and had previously received several immunosuppressive treatments including methotrexate, cyclophosphamide or cyclosporin A, erythropoietin, and granulocyte colony-stimulating factor (G-CSF), all of which were either ineffective or intolerable. A comprehensive cardiology examine before tipifarnib demonstrated mild global left ventricular (LV) dysfunction with ejection fraction (EF) of 45% to 50% with no hemodynamically significant coronary artery disease (CAD) and elevated systolic pulmonary artery pressure (PAP) of 67 mm Hg. Both pretreatment and posttreatment evaluations of pulmonary hypertension were done with Doppler echocardiography using the same apparatus. Pretreatment diagnosis of pulmonary hypertension was confirmed with right heart catheterization, which showed elevated PAP (systolic 55, diastolic 25, and mean 36 mm Hg), transpulmonary gradient of 26 mm Hg, and increased pulmonary vascular resistance of 7.6 Wood units. Key cardiac parameters include the following: right arterial (RA) 5, right ventricular (RV) systolic 53 and diastolic 9, pulmonary artery (PA) systolic 55 and diastolic 25 (mean 36), pulmonary capillary wedge pressure (PCWP)-10, LV systolic 130 and diastolic 21, central aorta s...

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Current controversies regarding the management of verapamil overdose are reviewed. Removal of the drug by gastric lavage is a mainstay of therapy. Administration of syrup of ipecac is contraindicated. Although specific recommendations for calcium dosing in the overdose situation have not been rigorously studied, maintenance of a normal serum ionized calcium concentration is suggested. An exogenous catecholamine, rather than dopamine, may be the drug of choice for treating hypotension. Cardiopulmonary bypass provides a method for drug removal in cases of severe toxicity; however, this invasive method requires further study. Management of fluid/electrolyte, acid/base, and ventilation abnormalities is required to treat large ingestions of verapamil. Treatment guidelines for critical care clinicians are provided.

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