The effect of etonogestrel on VEGF, oestrogen and progesterone receptor immunoreactivity and endothelial cell number in human endometrium

Contraceptive use often leads to disrupted endometrial bleeding patterns in women. In this study, two different contraceptive regimes (Mircette, a monophasic oral contraceptive and Implanon, a long-acting gestagen) were used and their effects on the immunoreactivity of vascular endothelial growth factor (VEGF), oestrogen receptor (ER), progesterone receptor (PR) and endothelial cell number were determined. During the untreated normal cycle, there was a significant increase (P = 0.005) in glandular VEGF immunoreactivity and a significant decrease (P < 0.05) in PR immunoreactivity in the mid- and late secretory phases compared with the proliferative phase. There was a significant positive correlation (gamma = 0.38, P = 0.046) between stromal VEGF immunoreactivity and endothelial cell number. This correlation was also apparent during treatment with Implanon, but not with Mircette. Disrupted bleeding patterns were associated with Implanon and, to a lesser extent, with Mircette. Both contraceptives significantly reduced glandular VEGF immunoreactivity. Implanon significantly increased (P = 0.016) glandular PR staining, but Mircette significantly reduced (P = 0.027) stromal PR staining when compared with secretory before-treatment biopsies. There were no changes in endothelial cell number or glandular or stromal ER during the normal cycle, or with use of either contraceptive. There was no association between the parameters measured with bleeding patterns and histological category.     

CAMs and FGF cause a local submembrane calcium signal promoting axon outgrowth without a rise in bulk calcium concentration

Binding of basic fibroblast growth factor (bFGF) and cell adhesion molecules to the nerve cell membrane promotes axon outgrowth. This response can be blocked by antagonists of voltage-gated calcium channels, yet no change of cytosolic calcium concentration in the growth cone can be detected upon binding of the growth factor bFGF or the cell adhesion molecule L1. Using barium as a charge carrier, we show that bFGF and L1 open a calcium influx pathway in growth cones of rat sensory neurons without changing the membrane voltage. L1 does not activate influx in cells expressing a dominant negative mutant of the fibroblast growth factor receptor (FGFR) tyrosine kinase. FGFR-activated influx is blocked by specific antagonists of L- and N-type voltage-gated calcium channels and by an inhibitor of diacylglycerol lipase. We propose that both L1 and bFGF act via the FGFR to generate polyunsaturated fatty acids which in turn cause calcium channels to flicker open and shut. Short-lived domains of raised calcium at the cytosolic mouth of open channels activate axon outgrowth without raising bulk cytosolic calcium concentration. In confirmation of this model, the rapidly-acting calcium buffer BAPTA is significantly more effective at blocking FGF-induced axon outgrowth when compared with the slower buffer EGTA. Generation of short-lived calcium domains may provide a crucial mechanism for axon guidance during development and for promoting regeneration of damaged axons.     

Ophthalmic and visual profile of guide dog owners in Scotland

BACKGROUND/AIMS: Out of an estimated 90,000 visually impaired people in Scotland, 509 make use of a guide dog. Initial research in Northern Ireland suggests that the ophthalmic profile of guide dog owners (GDOs) is highly specific. The aim of this study was to compare the ophthalmic and visual characteristics of Scottish GDOs with other groups of visually impaired people. METHODS: A random sample of GDOs from central and northern Scotland (n = 82) underwent a detailed assessment of residual vision (distance and near acuity, visual fields, contrast, and glare sensitivity). Comparative data were obtained from two populations of visually impaired non-GDOs-one group attending hospital ophthalmic and low vision clinics (n = 50) the other social services rehabilitation clients (n = 35). All participants completed a questionnaire to elicit ophthalmic history, age, and registration details. RESULTS: GDOs were found to be significantly younger and more profoundly visually impaired than non-GDOs. The main causes of visual impairment were retinitis pigmentosa (23%), optic atrophy (15%), and retinopathy of prematurity (7%). Ninety nine per cent of GDOs were registered blind and had been visually impaired for an average of 39 years. Only 31% were totally blind. CONCLUSION: GDOs represent a unique minority of the visually impaired population. Epidemiological registration trends would suggest that the numbers of young profoundly visually impaired people are unlikely to increase relative to their elderly counterparts. This has implications on the future demand for guide dog ownership.     

Stereopsis and binocular vision after surgery for unilateral infantile cataract.

PURPOSE: To assess the prevalence and level of binocular function in children with unilateral congenital or very early infantile cataract. METHODS: We retrospectively reviewed the charts of all patients with unilateral congenital or very early infantile cataract who underwent operation before 4 months of age, at the W. K. Kellogg Eye Center/University of Michigan Hospitals, from 1985 to 1995. Amblyopia was treated with a reduced patching schedule consisting of 1 hour per day per month of age for the first 6 months of life, in an attempt to improve binocular function by allowing more hours of binocular interaction during the presumed critical period for development of binocular cortical pathways. RESULTS: Thirteen patients met the inclusion criteria. Seven patients had persistent hyperplastic primary vitreous (PHPV) cataract and 6 had non-PHPV cataract. Overall, visual acuity of 20/80 or better developed in 69% of patients; 100% of eyes with non-PHPV cataract achieved visual acuity of 20/60 or better. Stereopsis of 400 arc seconds or better was detectable in 62% of patients, including 3 with PHPV cataract and 3 who required strabismus surgery in the first year of life. Three children had better than 150 arc seconds of stereopsis. The incidence of large-angle strabismus was 54%. CONCLUSIONS: Binocular cooperation, including gross and fine stereopsis, can develop in children with unilateral aphakia as a result of early removal of infantile cataracts. A less-strenuous patching schedule than has been historically advocated may foster this process, while restoring and maintaining good central visual acuity in patients with excellent compliance with contact lens and occlusion regimens.     

Alpha-phenyl-tert-butyl-nitrone (PBN) reverses age-related maze learning performance and motor activity deficits in C57 BL/6 mice

Two experiments were performed to study the effects of age and repeated administration of alpha-phenyl-tert-butyl-nitrone (PBN), the free radical spin-trapping agent, upon spontaneous motor activity levels and radial arm maze performance in normal young (3 month old) and normal aged (15 month old) C57 BI/6 mice. In Experiment 1, the aged mice were found to show reduced locomotor and rearing behaviour in comparison with the young mice. In the radial eight-arm maze learning task, the aged mice performed at a comparable level to the young mice during the first learning trial (Day 1) but made significantly more errors and showed longer total latencies during the second trial presented 24h later. In Experiment 2, the aged and young mice were subchronically administered either PBN at a dose of 50mg/kg, s.c. over 12 days, or saline. Spontaneous motor activity was tested 72h after the last injection. 36h later the first test trial in the radial arm maze was presented; this was followed after a further 24h by the second test trial. Subchronic treatment with PBN increased locomotion counts in the aged (15 month old) mice during the 60min test period, but decreased rearing during the first 30min of the test period. In the radial arm maze, the performance deficit shown during the second test trial by the aged mice was abolished by repeated PBN administration; both the number of errors and the latencies to all eight pellets were significantly reduced in the aged mice that received PBN. PBN did not exert any effects upon the performance of the young mice. These results, considered in conjunction with other studies using gerbils or rats, implicate the involvement of free radical species in the deterioration of function in the aged C57 BI/6 mouse.     

T-maze learning, spontaneous activity and food intake recovery following systemic administration of the noradrenaline neurotoxin, DSP4

Following systemic administration of the noradrenaline (NA) neurotoxin, DSP4 (50 mg/kg), rats were found to be retarded in the rate at which they acquired the "right-turn" running response in a modified T-maze choice situation, as measured by the total number of errors per session and median latency to reach the goal box. Desipramine (DMI, 20 mg/kg), injected 30 min before DSP4 blocked the acquisition retardation. DSP4 was found to have a short-lasting effect upon spontaneous motor activity, while food and water intake recovery was complete within 7 days of the injection. Both the NA-accumulation data and endogenous NA concentrations indicated profound NA, but not 5-hydroxytryptamine (5-HT) and dopamine (DA), depletions in the cortex, hippocampus and cerebellum. These data seem to confirm the role of the locus coeruleus-noradrenaline (LC-NA) system in an instrumental learning situation.     

A MRI gradient waveform model for automated sequence calibration.

In order to set up magnetic resonance imaging (MRI) procedures of arbitrary voxel dimensions, slice orientation, and sequence timing in a reasonable time, some form of automatic gradient pulse calibration is required. One such method, involving simulation of gradient waveforms, is presented. Waveforms are modeled based on measurements of the step response. The model used divides each transition into three time regions: a "start" region in the first 0.3 ms, a "slew" region, and a "tail" region representing decay of the eddy current compensation error. In the "slew" region, the time derivative of the gradient, G' (t), is expressed as a function of G(t). The first two regions are nonlinear with respect to demand. The mean error in the simulated gradient is generally less than 0.04 mT m-1 in spin echo sequences. Image signal/noise ratios resulting from sequences calibrated using the model are within 5% of those of empirically calibrated sequences.     

Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer.

PURPOSE: The monoclonal antibody (MAb) trastuzumab (Herceptin) effectively treats HER2-overexpressing extracerebral breast neoplasms. Delivery of such macromolecule therapeutic agents to intracerebral metastases, however, is limited by the tight junctions characteristic of the cerebral vasculature. Direct intracerebral microinfusion (ICM) is a technique that bypasses this blood-brain barrier and allows for a greater delivery of drugs directly into intracerebral tumors. EXPERIMENTAL DESIGN: A human breast cancer cell line transfected to overexpress HER2, MCF-7/HER2-18, was transplanted into the cerebrum of athymic rats. Saline, trastuzumab, or an isotype-matched control MAb was delivered systemically or by ICM to assess toxicity and efficacy. RESULTS: No clinical or histological toxicity related to trastuzumab was evident under any of the conditions studied. Delivery of trastuzumab (2 mg/kg) i.p. led to a median survival of 26.5 days, whereas treatment with trastuzumab (2 mg/kg) by ICM increased the median survival by 96% to 52 days, with two of nine rats surviving >120 days (P = 0.009). Treatment with an isotype-matched control MAb (16 mg/kg) resulted in a median survival of 21 days, which did not differ significantly from the survival of rats treated by ICM with saline (16 days; P = 0.42). Treatment by ICM with trastuzumab (16 mg/kg) led to a median survival of 45 days, with 2 of 10 rats surviving >120 days. These results represent 181% and 114% increases in median survival over the saline and MAb controls, respectively (P < 0.001). CONCLUSION: ICM of trastuzumab is safe and superior to systemic delivery as therapy for HER2-overexpressing intracerebral neoplasms in an athymic rat model.