Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+ (IgM+) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, EµSV-BCL2-22 and H2-Ld-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2+IL6+AID- and found that they developed-with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)-a severe IgM+ lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2+IL6+AID- model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM.

Pitfalls of regional cerebral blood flow analysis in cerebrovascular disease.

In 20 patients with unilateral cerebrovascular disease, regional cerebral blood flow (rCBF) was measured by F-18-fluoromethane inhalation and positron emission tomography (PET). The purpose was to study various strategies of rCBF data analysis that are currently used in SPECT and PET. Methods of quantitative data analysis standardize rCBF values relative to an intraindividual reference, and thus create ratios as estimators of rCBF in the ischemic regions-of-interest (ROI). These ratios were compared as well as the absolute rCBF values in the ischemic ROI graphically and by Spearman's rank correlation coefficient (r). The results demonstrated that previously reported methods of data analysis failed to represent rCBF in the ischemic ROI; r values were 0.467, -0.406, -0.453, and 0.329, respectively (N.S.). This failure was due to a more widespread reduction of rCBF even in patients with minimal ischemic deficits. In conclusion, previously reported strategies of rCBF analysis based on intraindividual standardization should not be used in patients with cerebrovascular disease since they may produce misleading results.

Contralateral flow reduction in unilateral stroke: evidence for transhemispheric diaschisis.

Using clinical presentation, angiography, computed tomography, and nuclear magnetic resonance imaging, 7 patients were identified who had strictly unilateral hemispheric infarction and unilateral cerebrovascular disease. In 6, cerebral blood flow measured by fluorine-18-fluoromethane inhalation and positron emission tomography was reduced in the contralateral hemisphere (p less than 0.05). Multiple regression analysis demonstrated a high correlation between contralateral flow reduction and the degree of flow impairment in the infarcted area (r = 0.941, p = 0.0014) but not with age, risk factor profile, blood pressure, PCO2, hematocrit, or duration of stroke. We conclude that transhemispheric diaschisis best explains the contralateral flow reduction seen in supratentorial ischemic stroke.