Role of the VEGFR3/VEGFD receptor axis in TGFbeta1 activation of primary prostate cell lines.

BACKGROUND: Reports indicate that vascular endothelial growth factor receptor type 3 (VEGFR3) regulates cellular functions such as invasion, proliferation, and chemo-resistance. However, the exact function of the VEGFR3 signaling axis in prostate epithelial cells is poorly characterized. METHODS: The goal of this study was to evaluate whether TGFbeta1 in combination with VEGFD can promote pre-malignant invasive activities of intermediate basal cells (IBC-10a) isolated from human prostate cancer (Gleason score 6). RESULTS: hTERT immortalized IBC-10a cells normally grew as confluent "cobblestoned" monolayers, but treatment with TGFbeta1 (10 ng/ml for 2-6 hr) dissociated the cell-cell junctions and induced VEGFR3 translocation to the cell surface. This event was not inhibited by 10 microM cycloheximide or puromycin, indicating transcription and protein synthesis were not required. We further discovered that TGFbeta1 in combination with VEGFD induced a significant increase in the invasive activity of IBC-10a cells (>26% and 53% after 24 and 48 hr, respectively) in modified Boyden Chamber assays. TGFbetaRII receptor antibodies specifically blocked TGFbeta1 induction of VEGFR3 translocation to the cell surface and blocked VEGFD-induced invasion. Zymograms revealed that TGFbeta1 (and not VEGFR3) stimulated the secretion of MMP-2 and MMP-9, presumably to promote cell invasion. The cell invasion assays confirmed that antibodies specific for TGFbetaII receptor, MMP-2 and MMP-9 and VEGFR3, independently blocked TGFbeta1-induced invasion. CONCLUSIONS: For the first time, we have demonstrated the mechanism by which TGFbeta1 stimulates VEGFD/VEGFR3 receptor axis activation leading to increased cell migration and invasion by primary intermediate basal cell cultures.

Fresnel prisms improve visual perception in stroke patients with homonymous hemianopia or unilateral visual neglect.

We randomly assigned 39 patients with stroke and homonymous hemianopia or unilateral visual neglect to treatment with 15-diopter plastic press-on Fresnel prisms (n = 18) or to serve as controls (n = 21). Baseline evaluations of visual perception and activities-of-daily-living (ADL) function were similar for both groups. After 4 weeks, the prism-treated group performed significantly better than controls on the following: (1) Motor Free Visual Perception Test; (2) Line Bisection Task; (3) Line Cancellation Task; (4) Harrington Flocks Visual Field Screener; and (5) Tangent Screen Examination. There was no significant difference in Barthel ADL assessment at 4 weeks. Thus, treatment with 15-diopter Fresnel prisms improves visual perception test scores but not ADL function in stroke patients with homonymous hemianopia or unilateral visual neglect.

Tobacco use in Alzheimer's disease.

Cholinergic abnormalities in Alzheimer's disease (AD) may be important in the pathogenesis of memory impairment. Tobacco use, which might reflect changes in central nicotinic receptors, was examined by chart review of 272 patients (M:F 86:186) with "probable" AD by NIH criteria, and by interviewing next-of-kin of 39 patients (M:F 15:24) and spouse controls. On chart review, 37% of females and 98% of males had used tobacco, but only 10% of females and 14% of males were still smoking at AD onset. Interval between stopping smoking and AD onset was 18.3 +/- 7.7 years in females and 16.6 +/- 6.8 years in males. Losing the taste for smoking preceded cessation in 60.3% of females and 16.2% of males. Only 7.9% of females and 4.4% of males had withdrawal symptoms. Next-of-kin interview revealed that patients and controls were comparable in demographic data, alcohol use, and smoking habits. 24% of patients and 37% of controls had stopped smoking, often due to losing the taste for smoking (32% of patients; 18% of controls). Withdrawal symptoms occurred in 21% of patients and 41% of controls. Relative to controls, patients less frequently had increased appetite (28% vs 47%), but more often had changed sex drive (22% vs 0%) and altered preference for specific alcoholic beverages (11% vs 0%), after stopping smoking. In AD, the loss of desire to smoke, lack of nicotine withdrawal, and altered appetites long precede cognitive symptoms, suggesting preclinical changes in central nicotinic receptors, as well as possible diagnostic and therapeutic strategies.

Urinary and gait disturbances as markers for early multi-infarct dementia.

In a retrospective study of 84 outpatients with multiinfarct dementia, urinary and gait disturbances were found in 50% and 27%, respectively, and often preceded dementia and discrete stroke-like episodes by more than 5 years. Compared to patients without urinary disturbance, those with urinary dysfunction were predominantly male and more behaviorally impaired, but were similar in age, cognitive score, depression score, computerized tomography findings, and relative survival. Compared to patients without gait disturbance, those with gait abnormality had a higher Hachinski ischemic score and depression score and were more behaviorally impaired. Urinary and gait abnormalities may be markers for cerebrovascular disease and vascular dementia even in the absence of frank stroke. Damage to bifrontal outflow tracts may be the common pathophysiological mechanism underlying the behavioral and motor symptoms characteristic of vascular dementias.