Progression of white matter lesions and hemorrhages in cerebral amyloid angiopathy.

OBJECTIVE: To determine the rate of progression of white matter lesions and hemorrhages in a cohort with cerebral amyloid angiopathy (CAA). METHODS: The authors analyzed data from 26 patients with possible (3) or probable (23) CAA, diagnosed by the Boston Criteria. Brain maps of white matter hyperintensities, normalized to head size (nWMH), were created by blinded computer-assisted segmentation of MRI images obtained at baseline and after a median follow-up interval of 1.1 year. RESULTS: There was a substantial nWMH volume increase over the interscan interval (median 0.5 mL/year, interquartile range 0.1 to 2.8, p < 0.001). The median yearly increase, expressed as a percentage of the baseline WMH volume, was 18%. The characteristic most strongly associated with nWMH volume increase was the baseline nWMH volume (r = 0.57, p = 0.002). The volume of nWMH progression was also associated with history of cognitive impairment (median 5.0 mL/year in cognitively impaired subjects vs 0.3 mL/year in cognitively unimpaired, p = 0.02) but not age or hypertension. This association remained present in an analysis stratified by baseline WMH volume. New hemorrhages, including asymptomatic microbleeds, were seen in 46% of subjects. The number of new MRI hemorrhages correlated strongly with baseline nWMH (r = 0.53, p = 0.005) but not with nWMH progression (r = 0.22, p = 0.28). CONCLUSIONS: There is a progressive increase in white matter lesions in subjects with cerebral amyloid angiopathy. The association of white matter lesions with incident lobar hemorrhages suggests that white matter damage may reflect a progressive microangiopathy due to cerebral amyloid angiopathy.

Antiplatelet use after intracerebral hemorrhage.

BACKGROUND: Survivors of intracerebral hemorrhage are at risk for recurrent intracerebral hemorrhage and ischemic cardiovascular and cerebrovascular disease. OBJECTIVE: To determine whether antiplatelet therapy increases the risk of recurrent intracerebral hemorrhage. METHODS: The authors reviewed data from consecutive survivors of primary intracerebral hemorrhage enrolled in a single-center prospective cohort study. Survivors were followed by telephone interview; recurrent intracerebral hemorrhage and post-index antiplatelet agent use and duration were recorded. Cox proportional hazards models was used with antiplatelet agent exposure as a time-dependent variable to assess the effect of antiplatelet agent use on recurrent intracerebral hemorrhage, stratified by lobar and deep hemispheric location. RESULTS: Recurrent intracerebral hemorrhage was more common in survivors of lobar hemorrhage compared with survivors of deep hemorrhage (cumulative 2-year rate 22% vs 4%; p = 0.007). Antiplatelet agents were prescribed in 22% of intracerebral hemorrhage survivors (27/127 lobar, 19/80 deep hemispheric), most commonly for prevention of ischemic heart disease. Antiplatelet agent use was not associated with intracerebral hemorrhage recurrence in survivors of either lobar hemorrhage (hazard ratio [HR] 0.8, 95% CI 0.3 to 2.3, p = 0.73) or of deep hemorrhage (HR 1.2, 95% CI 0.1 to 14.3, p = 0.88). CONCLUSION: Antiplatelet agent use is relatively common following intracerebral hemorrhage but did not appear to be associated with a large increased risk of intracerebral hemorrhage recurrence in this observational study.

Cellular and biochemical characterization of the anti-inflammatory effects of DuP 654 in the arachidonic acid murine skin inflammation model.

The possible utility of DuP 654, a potent 5-lipoxygenase inhibitor, for treating human inflammatory skin disease was investigated in murine skin treated with 1.0 mg arachidonic acid (AA). When DuP 654 was applied to murine skin treated with AA, it inhibited the resulting inflammation and influx of cells. High performance liquid chromatography and radioimmunoassay analysis of lipid extracts from AA-treated ears indicated that the influx of polymorphonuclear leukocytes (PMN) was temporally preceded by an appearance of significant amounts of 5-HETE (6.7 +/- 1.4 ng/ear) and Leukotriene B4 LTB4 0.92 +/- 0.2 ng/ear) when compared with extracts of untreated ears (5-HETE, 02 +/- 0.3 ng/ear; LTB4, less than 0.1 ng/ear). The levels of the 5-lipoxygenase products were reduced by treatment with 10 micrograms/ear DUP 654. Lipid extracts from AA-treated ears contain chemotactic activity for human PMN and this chemotactic activity in the AA-treated ears could be reduced but not eliminated by immunosorption with anti-LTB4 antibodies coupled to protein A-agarose. The appearance of the chemotactic activity was inhibited by DuP 654. Taken together, these data suggest that DuP 654 may have utility in human inflammatory skin disease.

Inhibition of rat neutrophil functional responses by azapropazone, an anti-gout drug.

Azapropazone at concentrations of 0.1 to 1 mM inhibited by 30-70% rat neutrophil migration, aggregation, and degranulation in response to the synthetic chemotactic peptide fMet-Leu-Phe. Binding studies using fNle-Leu-[3H]Phe, a radiolabeled analog of fMet-Leu-Phe, showed that azapropazone did not inhibit these responses by interfering with fMet-Leu-Phe binding. Azapropazone also decreased both the apparent rate of production and maximal levels of superoxide anion (O2-) generated by cells stimulated with 100 ng/ml phorbol-12-myristate-13-acetate (PMA). The concentrations of azapropazone that inhibit these neutrophil responses in vitro approximate those previously found in vivo after administration of therapeutic doses of drug to rats or humans. Taken together, the data suggest that the efficacy of azapropazone in gouty arthritis may be partly due to its ability to inhibit key neutrophil functional responses in vivo.