The lupus susceptibility locus Sle3 is not sufficient to accelerate atherosclerosis in lupus-susceptible low density lipoprotein receptor-deficient mice.

Cardiovascular disease risk is increased in individuals suffering from systemic lupus erythematosus. Understanding the mechanism(s) of systemic lupus erythematosus-accelerated atherosclerosis is critical for the development of effective therapies. Our laboratory previously demonstrated that radiation chimeras of systemic lupus erythematosus-susceptible B6.Sle1.2.3 and low density lipoprotein receptor (LDLr)(-/-) mice have augmented atherosclerosis, which is associated with increased T-cell burden and activation in the lesion. The goals of this study were to further define specific immune mechanisms that mediate accelerated atherosclerosis and to determine whether the gene interval Sle3, which is linked to lupus-associated T-cell dysregulation, was sufficient to modulate atherogenesis. We transferred B6.Sle3 or C57Bl/6-derived bone marrow cells into lethally irradiated LDLr( -/-) mice (hereafter referred to as LDLr.Sle3 and LDLr.B6, respectively). Sixteen weeks after transplantation, the mice were placed on a western-type diet for 8 weeks. Our analyses revealed that LDLr.Sle3 mice had increased auto-antibody production against double-stranded DNA and cardiolipin compared with LDLr.B6 controls. We also found an increase in atherosclerosis-associated oxLDL antibodies. Antibody isotypes and serum cytokine analysis suggested that the humoral immune response in LDLr.Sle3 mice was skewed toward a Th2 phenotype. This finding is consistent with lupus-associated immune dysregulation. Additionally, LDLr.Sle3 mice had decreased serum cholesterol and triglyceride levels. However, there was no difference in lesion area or cellular composition of lesions between the two groups. These data demonstrate that, despite no change in lesion area, transfer of Sle3-associated T-cell dysregulation alone to LDLr-deficient mice is sufficient to decrease serum cholesterol and to exacerbate humoral immune responses that are frequently associated with atherosclerosis.

Continuous fentanyl infusion: use in severe cancer pain.

OBJECTIVE: To describe the use of a continuous fentanyl infusion in an adult cancer patient. CASE SUMMARY: A 66-year-old white woman diagnosed with metastatic pancreatic carcinoma required hospital admission for pain control after receiving five different chemotherapy regimens. Morphine 2 mg/h i.v. was initiated and the dosage was titrated upward to a total of 6613 mg/d by hospital day 16. As hospital supplies of opioids became depleted over a holiday weekend, therapy was changed to a continuous infusion of hydromorphone 70 mg/h on hospital day 17, then changed to a continuous fentanyl infusion beginning with a dosage of 500 micrograms/h. The fentanyl dosage was titrated to 4250 micrograms/h by hospital day 20. She died comfortably on hospital day 22 while receiving this dosage. DISCUSSION: Continuous infusions of opioids, particularly morphine and hydromorphone, are frequently used for control of cancer pain and are safe and effective when administered by this route. Transdermal fentanyl has been shown to effectively manage chronic cancer pain, and use of continuous subcutaneous fentanyl has been reported. However, reports of continuous intravenous fentanyl infusion in the cancer pain literature are limited. Our patient achieved good pain control with a continuous infusion of fentanyl 4250 micrograms/h. CONCLUSIONS: Continuous fentanyl infusion should be considered for the treatment of cancer pain in patients requiring high doses who become refractory to other opioids, when other opioids cause intolerable adverse effects, when patients have a true morphine allergy, or when high-dose requirements threaten to deplete existing stock of alternate opioids.

Tranexamic acid in oncology.

Tranexamic acid has the potential to be a pharmacologic adjunct for the prophylaxis of hemorrhagic complications occurring in the oncology population. The studies and cases reviewed here suggest that tranexamic acid administration may be a therapeutic option for bleeding prophylaxis in APL where enhanced fibrinolysis accompanies the disease state. Because of the lack of a control in these reports, and the small sample size, it is not possible to extrapolate these conclusions regarding the efficacy of tranexamic acid in preventing hemorrhage in the larger thrombocytopenic oncology population. However, these reports concluded that its administration is safe, with few adverse effects and no thromboembolic events noted. A large, well-designed, controlled clinical trial is needed before a recommendation for the routine use of tranexamic acid in the oncology population can be established.