Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. We conducted a genome-wide association study in a series of families enriched for AMD and completed a meta-analysis of this new data with results from reanalysis of an existing study of a late-stage case-control cohort. We tested the top findings for replication in 1896 cases and 1866 controls and identified two novel genetic protective factors for AMD. In addition to the complement factor H (CFH) (P=2.3 × 10⁻64) and age-related maculopathy susceptibility 2 (ARMS2) (P=1.2 × 10⁻6°) loci, we observed a protective effect at rs429608, an intronic SNP in SKIV2L (P=5.3 × 10⁻¹5), a gene near the complement component 2 (C2)/complement factor B (BF) locus, that indicates the protective effect may be mediated by variants other than the C2/BF variants previously studied. Haplotype analysis at this locus identified three protective haplotypes defined by the rs429608 protective allele. We also identified a new potentially protective effect at rs2679798 in MYRIP (P=2.9 × 10⁻4), a gene involved in retinal pigment epithelium melanosome trafficking. Interestingly, MYRIP was initially identified in the family-based scan and was confirmed in the case-control set. From these efforts, we report the identification of two novel protective factors for AMD and confirm the previously known associations at CFH, ARMS2 and C3.

Stability of biodegradable radioactive rhenium (Re-186 and Re-188) microspheres after neutron-activation.

Our objective was to determine if microspheres made from the biodegradable polymer poly(lactic acid) that contained rhenium could withstand the conditions of direct neutron activation necessary to produce therapeutic amounts of radioactive rhenium. The radiation damage of the polymer produced by gamma-doses of up to 1.05 MGy from Re-186 and Re-188 was examined by scanning electron microscopy and size exclusion chromatography. At a thermal neutron flux of 1.5 x 10(13)n/cm2/s the microspheres melted after 3 h in the nuclear reactor, but suffered little damage after 1 h of radiation and released less than 5% of the radioactivity during incubation in buffer at 37 degrees C. The radioactive microspheres produced in this manner have a specific activity too low for radioembolization for treatment of liver tumors, but could be injected directly into tumors or applied topically to the wound bed of partially resected tumors.

Dosimetry of a W-188/Re-188 beta line source for endovascular brachytherapy.

PURPOSE: The objective was to determine the dosimetry of a potential endovascular brachytherapy source consisting of a coiled tungsten wire mounted on the distal end of a drive wire and neutron-activated to contain the parent-daughter nuclides tungsten-188 (188W) and rhenium-188 (188Re). METHODS: A coiled tungsten wire 40 mm in length was neutron-activated by double-neutron capture for 78 hours at 1.9 x 10(15) h/cm2/s to contain 925 MBq (25 mCi) of 188W/188Re in equilibrium. The dose-fall off from this source was determined using three independent methods: (a) Thermoluminescence dosimetry with small LiF-100 rods, (b) Gafchromic film dosimetry, and (c) Bang gel dosimetry. In addition, a Monte Carlo simulation was performed to compute the beta-dose. RESULTS: Each of the three measurement methods recorded similar values for the dose fall-off within the distances useful for endovascular brachytherapy. The Monte Carlo calculations closely approximated the measured results in the treatment range between 1 and 3 mm and may thus be useful for evaluating changing geometries in the development of catheters and source setups. A 2 min restenosis treatment delivering 20 Gy at a radius of 2 mm would require a source of 1384.8 MBq/cm (37.4 mCi/cm). CONCLUSIONS: The dose distribution from a 188W/188Re source is similar to that of a 90Y-source. An added advantage of the 188W/188Re source is that it can be used for at least two months and still provides fast treatment times because of the parent isotope's half-life of 69 days. The additional gamma emission from the source is too small to impose a serious radiological hazard. The high atomic number and density of the source material allows direct fluoroscopic imaging without additional markers.

Hepatic tumor radioembolization in a rat model using radioactive rhenium (186Re/188Re) glass microspheres.

PURPOSE: The aim of this study was to fully characterize newly developed radioactive rhenium glass microspheres in vivo by determining their biodistribution, stability, antitumor effect, and toxicity after hepatic arterial injection in a syngeneic rat hepatoma model. The dose response of the tumors to increasing amounts of radioactive 186Re and 188Re microspheres was also determined. METHODS AND MATERIALS: Rhenium glass microspheres were made radioactive by neutron activation and then injected into the hepatic artery of Sprague-Dawley rats containing 1-week-old Novikoff hepatomas. The biodistribution of the radioactivity and tumor growth were determined 1 h and 14 days after injection. RESULTS: Examination of the biodistribution indicated a time-dependent, up to 7-fold increase in Novikoff hepatoma uptake as compared to healthy liver tissue uptake. After 14 days, the average T:L ratio was 1.97. Tumor growth in the rats receiving radioactive microspheres was significantly lower than in the group receiving nonradioactive microspheres (142% vs. 4824%, p = 0.048). Immediately after injection, 0.065% of the injected radioactivity was measured in the thyroid; it decreased to background levels within 24 h. CONCLUSION: Radioactive rhenium microspheres are effective in diminishing tumor growth without altering hepatic enzyme levels. The microspheres are safe with respect to their radiation dose to healthy tissue and radiation release in vivo and can be directly imaged in the body with a gamma camera. Furthermore, rhenium microspheres have an advantage over pure beta-emitting microspheres in terms of preparation and neutron-activation time. In sum, this novel radiopharmaceutical may provide an innovative and cost-effective approach for the treatment of nonresectable liver cancer.