C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

Transscleral thermotherapy with laser-induced and conductive heating in hamster Greene melanoma.

The purpose of this study was to investigate the cytotoxic effect of heat as induced by transscleral thermotherapy (TSTT), which may be of interest in the treatment of patients with choroidal melanoma. The aim of TSTT is to heat both the sclera and the tumor up to a cytotoxic temperature of about 60 degrees C. TSTT was performed in hamsters with subcutaneously implanted Greene melanoma covered by a specimen of human donor sclera of thickness 0.5, 0.7 or 0.9 mm. A newly developed applicator, which combines conductive episcleral heating at 60 degrees C with laser-induced heating, was used at laser powers ranging from 500 to 1500 mW delivered by an 810 nm diode laser, beam diameter 3 mm, and exposure time 1 min. Temperatures were measured at the scleral surface and at the sclera-tumor interface. The extent of tumor necrosis was examined by light microscopy and the sclera was examined by polarized light microscopy. Maximal depth of tumor necrosis without scleral damage was 4.4 (SD 1.5) mm. The temperature at the scleral surface after TSTT was 58.8 (SD 2.4) degrees C. The temperature at the sclera-tumor interface ranged from 56.4 (SD 3.7) degrees C at 500 mW to 65.3 (SD 4.4) degrees C at 1250 mW laser power. Structural changes to the scleral collagen started to develop at 1250 mW. TSTT with combined laser-induced and conductive heating caused cytotoxic temperatures in the tumor and the sclera, which were well tolerated by the scleral collagen.

Transscleral thermotherapy: short- and long-term effects of transscleral conductive heating in rabbit eyes.

OBJECTIVE: To determine the highest safe treatment temperature, at 30- and 60-second exposure durations, for transscleral thermotherapy (TSTT) of choroidal melanoma. METHODS AND DESIGN: Transscleral conductive heating was performed in 15 rabbits at 50 degrees C to 70 degrees C for 30 or 60 seconds. The thermal lesions in the ocular fundus were monitored for 4 months with ophthalmoscopic, photographic, and fluorescein angiographic examination. Histologic examination included polarized light microscopy. RESULTS: The effect of TSTT was similar for both exposure durations. Vascular occlusion in the retina and choroid developed at temperatures of 55 degrees C and higher. After heating at 60 degrees C, scleral collagen fibers developed a minimal undulation; at 65 degrees C, they became clearly undulated. The undulation resolved in the 3 to 4 months after heating. Heating at 70 degrees C caused persistent severe damage to the sclera. Retinal tears developed after heating at 65 degrees C and 70 degrees C. CONCLUSIONS: A temperature of 65 degrees C was found to be the highest temperature that did not cause permanent damage to the sclera at both exposure durations. A temperature of 60 degrees C may be the optimal temperature for TSTT of choroidal melanoma because retinal tears may develop at 65 degrees C. CLINICAL RELEVANCE: In TSTT, the temperature levels reached are cytotoxic for choroidal melanoma as well as intrascleral tumor cells. Occlusion of choroidal vessels induced by TSTT may contribute to tumor necrosis because these vessels serve as feeder vessels for the tumor.