Intrastromal bevacizumab in the management of corneal neovascularization: a retrospective review

Graefe's Archive for Clinical and Experimental Ophthalmology - To evaluate the long-term safety and efficacy of intrastromal bevacizumab for treatment of deep corneal neovascularization in...     

Norepinephrine modulates glutamatergic transmission in the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) and its adrenergic input are key components in stress-induced reinstatement and maintenance of drug use. Intra-BNST injections of either beta-adrenergic receptor (beta-AR) antagonists or alpha2-adrenergic receptor (alpha2-AR) agonists can inhibit footshock-induced reinstatement and maintenance of cocaine- and morphine-seeking. Using electrophysiological recording methods in an in vitro slice preparation from C57/Bl6j adult male mouse BNST, we have examined the effects of adrenergic receptor activation on excitatory synaptic transmission in the lateral dorsal supracommissural BNST (dBNST) and subcommissural BNST (vBNST). Alpha2-AR activation via UK-14,304 (10 microM) results in a decrease in excitatory transmission in both dBNST and vBNST, an effect predominantly dependent upon the alpha2A-AR subtype. Beta-AR activation via isoproterenol (1 microM) results in an increase in excitatory transmission in dBNST, but not in vBNST. Consistent with the work with receptor subtype specific agonists, application of the endogenous ligand norepinephrine (NE, 100 microM) elicits two distinct effects on glutamatergic transmission. In dBNST, NE elicits an increase in transmission (62% of dBNST NE experiments) or a decrease in transmission (38% of dBNST NE experiments). In vBNST, NE elicits a decrease in transmission in 100% of the experiments. In dBNST, the NE-induced increase in synaptic transmission is blocked by beta1/beta2- and beta2-, but not beta1-specific antagonists. In addition, this increase is also reduced by the alpha2-AR antagonist yohimbine and is absent in the alpha2A-AR knockout mouse. In vBNST, the NE-induced decrease in synaptic transmission is markedly reduced in the alpha2A-AR knockout mouse. Further experiments demonstrate that the actions of NE on glutamatergic transmission can be correlated with beta-AR function.     

COSTING ACUTE MYOCARDIAL INFARCTION IN NEW SOUTH WALES,AUSTRALIA, BASED ON INCIDENCE RATHER THAN PREVALENCE METHODS

Estimating the economic costs of a disease is an important prerequisite to determining the costs and benefits of various preventive programs. For preventive programs, incidence-based costing is a more appropriate means of estimation than is prevalence-based costing. In this study the cost of acute myocardial infarction (AMI) in New South Wales has been estimated using an incidence-based approach. The calculated cost of AMI in 1979 was $301.0 million, made up of $32.3 million as direct costs and $268.7 million as indirect costs. In a sensitivity analysis, the cost was shown to be most sensitive to the incidence of AMI, the discount rate, and the assumption of a wage for housework. Both the direct costs and indirect costs per case are substantially higher in the United States than in Australia, and this reflects higher physician charges, higher hospital costs, and in the case of indirect costs, higher average weekly earnings.     

Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients.

PURPOSE: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. EXPERIMENTAL DESIGN: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. RESULTS: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. CONCLUSIONS: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.     

Development of three parallel cytochrome P450 enzyme affinity detection systems coupled on-line to gradient high-performance liquid chromatography.

A high resolution screening (HRS) technology is described, in which gradient high-performance liquid chromatography (HPLC) is connected on-line to three parallel placed bioaffinity detection systems containing mammalian cytochromes P450 (P450s). The three so-called enzyme affinity detection (EAD) systems contained, respectively, liver microsomes from rats induced by beta-naphthoflavone (CYP1A activity), phenobarbital (CYP2B activity), and dexamethasone (CYP3A activity). Each P450-EAD system was optimized for enzyme, substrate, and organic modifier (isopropyl alcohol, methanol, and acetonitrile) in flow injection analysis mode. Characteristic P450 ligands were used to validate the P450-EAD systems. IC(50) values of the ligands were measured and found to be similar to those obtained with conventional microtiter plate reader assays. Detection limits (n = 3; signal-to-noise ratio = 3) of potent inhibitors ranged from 1 to 3 pmol for CYP1A activity, 4 to 17 pmol for CYP2B activity, and 4 to 15 pmol for CYP3A activity. The three optimized P450-EAD systems were subsequently coupled to gradient HPLC and used to screen compound mixtures for individual ligands. Finally, to increase analysis efficiency, a HRS system was constructed in which all three P450-EAD systems were coupled on-line and in parallel to gradient HPLC. The triple parallelized P450-EAD system was shown to enable rapid profiling of individual components in complex mixtures for inhibitory activity to three different P450s.     

‘Translation is not enough’: using the Global Person Generated Index (GPGI) to assess individual quality of life in Bangladesh,Thailand, and Ethiopia

Currently few subjective measures of Quality of Life (QoL) are available for use in developing countries, which limits their theoretical, methodological, and practical contribution (for example, exploring the relationship between economic development and QoL, and ensuring effective and equitable service provision). One reason for this is the difficulty of ensuring that translated measures preserve conceptual, item, semantic, operational, measurement; and functional equivalence (Herdman, M., Fox-Rushby, J., & Badia, X. (1998). Quality of Life Research, 7, 331), which is illustrated by an account of the translation, pre-piloting, and administration of a new individualised QoL measure, the Global Person Generated Index or 'GPGI'. The GPGI is based on the widely used Patient Generated Index (Ruta, Camfield, & Martin, (2004) Quality of Life Research, 13, 1545.) and offers many of the advantages of the participatory approaches commonly used in developing countries, with added methodological rigour, and quantitative outcomes. It was successfully validated in Bangladesh, Thailand, and Ethiopia, using quantitative and qualitative methods--open-ended, semi-structured interviews (SSIs), conducted immediately post-administration. Both the measure and method of 'qualitative validation' described later in the paper offer an exciting alternative for future researchers and practitioners in this field. The quantitative results suggest the GPGI shows cultural sensitivity, and is able to capture both the areas that are important to respondents, and aspects of life one would expect to impact on QoL in developing countries. There were strong correlation between scores from the GPGI and SSIs for the area of health, and moderate correlations for 'material wellbeing' (MWB)('Material wellbeing' refers to respondents' perceptions of their achievement in the areas of farming, debt reduction, assets, crops, livestock, job, land, property, and agriculture) and children. Weak to moderate correlations were observed between the Satisfaction with Life Scale and the GPGI; however, the highest coefficient was between the GPGI and the most conceptually similar item. Statistically significant differences were seen in GPGI scores between rich and poor, urban and rural respondents, and different countries. Health and material wellbeing scores, derived from the SSIs, also showed a linear relationship with GPGI scores, with a suggestion of curvilinearity at the higher levels, as predicted by a general QoL causal model. In conclusion, the GPGI has great potential for use in this area, especially when supported by extensive interviewer training, and supplemented with a cognitive appraisal schedule.