DNA methylation is important for controlling the profile of gene expression and is catalyzed by DNA methyltransferase (MTase), an enzyme that is abundant in brain. Because significant DNA damage and alterations in gene expression develop as a consequence of cerebral ischemia, we measured MTase activity in vitro and DNA methylation in vivo after mild focal brain ischemia. After 30 min middle cerebral artery occlusion (MCAo) and reperfusion, MTase catalytic activity and the 190 kDa band on immunoblot did not change over time. However, [(3)H]methyl-group incorporation into DNA increased significantly in wild-type mice after reperfusion, but not in mutant mice heterozygous for a DNA methyltransferase gene deletion (Dnmt(S/+)). Dnmt(S/+) mice were resistant to mild ischemic damage, suggesting that increased DNA methylation is associated with augmented brain injury after MCA occlusion. Consistent with this formulation, treatment with the MTase inhibitor 5-aza-2'-deoxycytidine and the deacetylation inhibitor trichostatin A conferred stroke protection in wild-type mice. In contrast to mild stroke, however, DNA methylation was not enhanced, and reduced dnmt gene expression was not protective in an ischemia model of excitotoxic/necrotic cell death. In conclusion, our results demonstrate that MTase activity contributes to poor tissue outcome after mild ischemic brain injury.

Uracil-DNA glycosylase (UNG) is involved in base excision repair of aberrant uracil residues in nuclear and mitochondrial DNA. Ung knockout mice generated by gene targeting are viable, fertile, and phenotypically normal and have regular mutation rates. However, when exposed to a nitric oxide donor, Ung(-/-) fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death. After combined oxygen-glucose deprivation, Ung(-/-) primary cortical neurons have increased vulnerability to cell death, which is associated with early mitochondrial dysfunction. In vivo, UNG expression and activity are low in brains of naive WT mice but increase significantly after reversible middle cerebral artery occlusion and reperfusion. Moreover, major increases in infarct size are observed in Ung(-/-) mice compared with littermate control mice. In conclusion, our results provide compelling evidence that UNG is of major importance for tissue repair after brain ischemia.

Aim: To investigate optic nerve function using the pattern-reversed visual evoked potentials (VECP) before and after bony orbital decompression in dysthyroid optic neuropathy (DON) due to Grave´s disease.Methods: A total of 30 eyes of 15 patients (n=14 female) were observed over 30 ± 13 months after bony 3-wall orbital decompression. We examined visual acuity (VA), VECP P100 amplitudes and latencies as well as proptosis using Hertel´s exophthalmometry.

Background: Vision impairment in children and young adults may derive from choroidal neovascularisation (CNV) related to numerous conditions. The aim of this study is to highlight the applicability of photodynamic therapy using verteporfin (PDT) in these patients. Methods: In 16 eyes of 16 consecutive patients aged 30 years or younger, prospective open-label PDT was performed. Outcomes of visual acuity as well as changes in CNV lesion parameters were evaluated. Results: The mean patient age at first PDT was 19.7 (SD 8.7) years (range 6-30). 81% of the patients retained stable vision within two lines or exceedingly improved vision during follow-up of 34 (24) months. Significant vision gain was denoted in seven paediatric patients (2.7 (1.4) lines, mean (SD); p = 0.019) as well as in a subgroup of 12 patients not affected by active uveitis (2.6 (2.0) lines, p = 0.0005). Two patients with multifocal choroiditis and panuveitis (MCP) experienced vision losses of five and 11 lines after four PDT sessions despite receiving additional steroidal treatment. Except for one patient with MCP and two patients who dismissed followup, a mean of 2.2 (1.3) PDTs per patient sufficiently inactivated CNV lesions during follow-up. In the area of the former PDT spot, alterations of the pigment epithelium increased by 40% without correlation to changes in vision. Conclusions:The results indicate good PDT efficacy and tolerability most promising in a subgroup of patients with vision-impairing CNV not associated with active uveitis. PDT in young patients with CNV remains a valuable treatment with good risk-benefit profile over the long term.Choroidal neovascularisation (CNV) may develop in children and young adults due to pathological myopia, the presumed ocular histoplasmosis syndrome (POHS), retinochoroiditis as well as secondary to angioid streaks, trauma or idiopathically.

Uracil-DNA glycosylase (UNG) is involved in base excision repair of aberrant uracil residues in nuclear and mitochondrial DNA. Ung knockout mice generated by gene targeting are viable, fertile, and phenotypically normal and have regular mutation rates. However, when exposed to a nitric oxide donor, Ung -/-fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death. After combined oxygen-glucose deprivation, Ung -/-primary cortical neurons have increased vulnerability to cell death, which is associated with early mitochondrial dysfunction. In vivo, UNG expression and activity are low in brains of naive WT mice but increase significantly after reversible middle cerebral artery occlusion and reperfusion. Moreover, major increases in infarct size are observed in Ung -/-mice compared with littermate control mice. In conclusion, our results provide compelling evidence that UNG is of major importance for tissue repair after brain ischemia.