Intellectual decline after stroke: the Framingham Study

BACKGROUND AND PURPOSE: The causes and characteristics of cognitive decline after stroke are poorly defined, because most studies have relied on the diagnosis of dementia after stroke, without measurement of prestroke cognitive function. METHODS: The Mini-Mental State Examination (MMSE) was used to assess the cognitive performance of 74 subjects from the Framingham Study cohort who had suffered a stroke during a 13-year period. We compared their poststroke cognitive performance with the prestroke MMSE scores collected during their biennial examinations, and their prestroke/poststroke changes in MMSE score were then compared with those of 74 control subjects matched for age and sex. Cases and controls underwent testing for symptoms of depression using the Center for Epidemiologic Studies of Depression (CES-D) scale, and these findings were correlated with their cognitive performance. Changes in cognitive performance in the cases were correlated with the CT-documented characteristics of the stroke. RESULTS: The cases had a significantly lower mean+/-SE MMSE score at prestroke baseline (27.28+/-0.34) than did the control subjects (28.08+/-0.21), a difference that became more pronounced (23.57+/-0.92 versus 28.31+/-0.25; P<.001) after stroke. The poststroke decline in cognitive function in the cases was correlated only with a large, left-sided stroke on CT. The CES-D scores were significantly higher in the cases, but nondepressed cases had significantly lower MMSE scores than nondepressed controls. CONCLUSIONS: Stroke is followed by a significant decline in cognitive performance when prestroke and poststroke measurements are compared. Although depression is more frequent in the stroke patients, their intellectual decline appears to be independent from the presence of depression.     

fMRI changes in the brain associated with the carotid compression test

PURPOSE: The purpose of our investigation was to study in normal volunteers the response to a unilateral common carotid (CC) compression test using dynamic MRI sensitive to variations in blood magnetic susceptibility. METHOD: Nine volunteers, positioned in a 1.5 T MR scanner, performed a unilateral 40 to 45 s CC self-compression during the acquisition of single slice axial T2*-weighted FLASH images. RESULTS: In three subjects, the signal showed a significant 2% drop from baseline in the ipsilateral frontal temporal cortex during the compression. In another three subjects, a significant 1.5-2% signal decrease was observed in both hemispheres. In two subjects whose MR angiography showed abnormalities of the circle of Willis, the bilateral signal drop was more remarkable (3%). In one volunteer, the signal did not change. CONCLUSION: Increased deoxyhemoglobin within the brain microcirculation is the probable explanation for the signal drop. This method could be further tested in view of the widespread use of open interventional MR units.     

Synthesis and potent antifolate activity and cytotoxicity of B-ring deaza analogues of the nonpolyglutamatable dihydrofolate reductase inhibitor Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl- L-ornithine (PT523)

Six new B-ring analogues of the nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloy l-L-ornithine (PT523, 3) were synthesized with a view to determining the effect of modifications at the 5- and/or 8-position on dihydrofolate reductase (DHFR) binding and tumor cell growth inhibition. The 5- and 8-deaza analogues were prepared from methyl 2-L-amino-5-phthalimidopentanoate and 4-amino-4-deoxy-N10-formyl-5-deaza- and -8-deazapteroic acid, respectively. The 5,8-dideaza analogues were prepared from methyl 2-L-[(4-aminobenzoyl)amino]-5-phthalimidopentanoate and 2, 4-diaminoquinazoline-6-carbonitriles. The Ki for inhibition of human DHFR by the 5-deaza and 5-methyl-5-deaza analogues was about the same as that of 3 (0.35 pM), 11-fold lower than that of aminopterin (AMT, 1), and 15-fold lower than that of methotrexate (MTX, 2). However the Ki of the 8-deaza analogue was 27-fold lower than that of 1, and that of the 5,8-dideaza, 5-methyl-5,8-dideaza, and 5-chloro-5,8-dideaza analogues was approximately 50-fold lower. This trend was consistent with the published literature on the corresponding DHFR inhibitors with a glutamate side chain. In colony formation assays against the human head and neck squamous carcinoma cell line SCC25 after 72 h of treatment, the 5- and 8-deaza analogues were approximately as potent as 3, whereas the 5,8-dideaza analogue was 3 times more potent. 5-Methyl and 5-chloro substitution was also favorable, with the 5-methyl-5-deaza analogue being 2. 5-fold more potent than the 5-deaza analogue. However the effect of 5-methyl substitution was less pronounced in the 5,8-dideaza analogues than in the 5-deaza analogues. The 5-chloro-5,8-dideaza analogue of 3 was the most active member of the series, with an IC50 = 0.33 nM versus 1.8 nM for 3 and 15 nM for MTX. The 5-methyl-5-deaza analogue of 3 was also tested at the National Cancer Institute against a panel of 50 human tumor cell lines in culture and was consistently more potent than 3, with IC50 values in the low-nanomolar to subnanomolar range against most of the tumors. Leukemia and colorectal carcinoma cell lines were generally most sensitive, though good activity was also observed against CNS tumors and carcinomas of the breast and prostate. The results of this study demonstrate that B-ring analogues of 3 inhibit DHFR activity and tumor cell colony formation as well as, or better than, the parent compound. In view of the fact that 3 and its B-ring analogues cannot form polyglutamates, their high cytotoxicity relative to the corresponding B-ring analogues of AMT is noteworthy.     

Regional myocyte hypertrophy parallels regional myocardial dysfunction during post-infarct remodeling

The molecular genetic events involved in the etiology of human granulosa cell (GC) tumors, which represent approximately 7% of all malignant ovarian neoplasms, are unknown. Amplification and/or overexpression of the ERBB genes are a feature of many cancer types, and overexpression of erbB2 correlates with poor prognosis in epithelial ovarian cancer. In the present study, we used immunohistochemistry to determine the level and frequency of expression of different erbB receptors in GC tumors. Ten of 12 tumors expressed erbB4 at moderate to high levels in >50% of cancer cells, whereas erbB2 (6 of 12) and erbB3 (2 of 12) were expressed less frequently. Western blot experiments showed that the only available GC tumor cell line, COV434, also expressed erbB receptors. Heregulin (HRG)-beta2, a ligand for erbB3 and erbB4 receptors, stimulated tyrosine phosphorylation of the erbB receptors, which was accompanied by activation of Erk1 and Erk2, two mitogen-activated protein kinases with a functional role in mitogenesis. Importantly, HRG increased cell proliferation in COV434 cells, and treatment with HRG/PE40, a ligand toxin shown previously to be cytotoxic against human breast cancer cells overexpressing erbB receptors, led to a dramatic and irreversible decrease in cell number. These results indicate that erbB receptor signaling pathways may be critical in the control of GC tumor cell proliferation and that HRG/PE40 is a potential therapeutic agent for the treatment of GC tumors.