Jendo A. Oosterhuis

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.

Results of ruthenium irradiation of uveal melanoma

The follow-up results are presented for the radiotherapeutic treatment of 49 patients with uveal eye melanoma using ruthenium-106 (106Ru/106Rh) applicators. Graded doses were applied and the degree of regression was found to be correlated with the dose at the top of the tumour. Complete regression is found in 66% of the patients treated with a top dose above 150 Gy, in which case the initial tumour prominence diminishes in about three years to a stable disease or to a flat scar. At this dose a marginal increase in complications was observed as compared with lower dose groups. Useful vision could be preserved in 75% of the eyes.

Analysis of tear fluid proteins in insulin-dependent diabetes mellitus

Abstract. Secretory immunoglobulin A, lactoferrin, lysozyme and tear specific pre‐albumin were analyzed in stimulated tear fluid of 25 diabetic patients without retinopathy and in 29 diabetic patients with (pre‐) proliferative retinopathy using high performance liquid chromatography. Results were compared to those obtained in 26 healthy controls to determine the effect of diabetes mellitus on the exocrine function of the main lacrimal gland. Sodium dodecyl sulfate polyacrylamide gel electrophoresis onto minigels was performed on 20 tear samples for verification of high performance liquid chromatography fractions recorded. The mean total protein values in tear fluid (Bradford assay) of diabetics without retinopathy, with retinopathy and healthy controls did not differ significantly (mean in mg/ml ± sd: 6.4 ± 2.2, 5.9 ± 2.0 and 5.7 ± 1.7, respectively; Mann‐Whitney: p>0.2). High performance liquid chromatography showed an increased secretory immunoglobulin A and decreased peak 5 OD280 (+56% and ‐38%, respectively; p< 0.02) in patients without retinopathy, whereas in patients with retinopathy lysozyme was increased (+27%; p< 0.01) and tear specific pre‐albumin and peak 5 OD280 decreased (‐24% and ‐42%, respectively; p< 0.04), when compared to healthy controls. These inconsistent differences do not uniformly suggest an exocrine dysfunction of the main lacrimal gland in diabetic patients.

Corneal autofluorescence in diabetic and penetrating keratoplasty patients as measured by fluorophotometry.

At first it was verified that the major part of the fluorophotometer signal obtained when measuring corneal autofluorescence originated from fluorescence and not from scatter of excitation light at the corneal surface. The minimum percentage of the signal which can be attributed to fluorescence was determined using a fluorescence blocking filter placed in the excitation and fluorescence light path, respectively. The minimum percentages in two healthy controls, two diabetic patients and two patients after penetrating keratoplasty ranged from 75% to 93% (mean 84%). Then the corneal autofluorescence was determined in 22 healthy controls, 18 non-insulin-dependent diabetes mellitus (NIDDM). 23 insulin-dependent diabetes mellitus (IDDM) and 21 penetrating keratoplasty patients in order to detect a possible difference in autofluorescence as a result of diabetes or penetrating keratoplasty. The means of the corneal peak autofluorescence values in the NIDDM, IDDM and penetrating keratoplasty patient groups were significantly higher than that in the healthy control group (mean values in ng equivalent fluorescin ml-1: 18.0 +/- 4.2 S.D., 20.6 +/- 5.1 S.D., 17.9 +/- 5.5 S.D. and 13.7 +/- 3.7 S.D., respectively; P less than 0.01). The mean values in the NIDDM and IDDM patients did not differ significantly (P = 0.09). The autofluorescence values were independent of age in all four groups (linear correlation coefficient: r less than 0.47). The corneal peak autofluorescence was linearly correlated with the diabetes duration in the NIDDM and IDDM patients [r = 0.6, P = 0.02; increase: 0.36 ng equiv. fluorescein ml-1 yr diabetes-1]. Our results show that corneal autofluorescence is an easily obtained parameter which can be of assistance in evaluating corneal metabolism.

Results of ruthenium irradiation of uveal melanomas: the Dutch experience

BACKGROUND AND PURPOSE To update our results of the treatment of uveal melanomas using ruthenium applicators in 49 patients treated with graded doses and subsequently in 52 patients with maximal scleral doses of 800 Gy and an effective top dose of at least 160 Gy. MATERIAL AND METHODS One hundred and one patients were treated with brachytherapy only, in 25 patients it was combined with transpupillary thermotherapy (TTT). RESULTS A complete remission was found in 62.6% of the patients and in 31.3% a stable disease with an average follow-up of 74.6 months. Above a top dose of 120 Gy only in one of 95 patients continuous tumour growth after treatment was observed. Useful vision could be preserved in 51.5% of the patients. The initial tumour prominence and top dose strongly correlated with treatment outcome. CONCLUSIONS Ruthenium application for uveal melanomas with the doses we have used is successful, with a substantial number of patients having their eyes preserved, their tumour controlled and their vision retained. Further improvements can be obtained with ruthenium irradiation with lower maximal scleral doses combined with TTT.

Familial central serous retinopathy

Abstract• Purpose: To study the familial occurrence of central serous retinopathy (CSR).• Methods: We pooled data from eight eye clinics in Western Europe.• Results: We collected 11 families that each had two to four members with CSR. In 10 families siblings and in one family a mother and son were affected. Sixty percent of the patients were male and 40% female. CSR was found in 55 (92%) of 60 eyes, 44 (80%) showing a chronic course. In 25 patients (83%) both eyes were affected. Most recent visual acuity was 0.5 or less in 17 (39%) and 0.2 or less in 8 (18%) of the eyes with chronic CSR.• Conclusion: Our findings of familial occurrence and a chronic disorder that is progressive, diffuse, and bilateral suggest an inborn disposition to develop a clinically manifest disintegration of the retinal pigment epithelium in adulthood.

Tumor destruction by intermediate level hyperthermia

The tumoricidal effect of hyperthermia was studied in Greenes amelanotic hamster melanoma transplanted into the anterior chamber of rabbit eyes. To achieve optimal depth penetration, hyperthermia was induced with near infrared light of 820-870 nm, during 15 minutes, at a beam diameter of 2.5-6.0 mm resulting in an intermediate level hyperthermia of 45-60 degrees C. At 45 degrees C no tumor destruction occurred, at 50 degrees C the effect varied from no destruction to total thickness tumor destruction. At 55-60 degrees C total tumor destruction with additional lens damage occurred. In comparison photocoagulation with white light revealed only necrosis up to half the tumor thickness.

A new autosomal dominant vascular retinopathy syndrome

We describe a new syndrome with autosomal dominant transmission whose most striking feature is vascular retinopathy. The retinopathy is often associated with migraine, Raynauds phenomenon and mental changes, mainly forgetfulness, aggression and depression. To define this syndrome we collected medical data on 110 family members. General ophthalmological examination and fluorescein angiography were performed in 61 persons. The retinopathy, as diagnosed in 22 persons, is characterized by central and peripheral microangiopathy, areas of capillary non-perfusion, haemorrhages, cotton wool spots and, in a more advanced stage, occlusion of large retinal vessels, which can induce a neovascular response. A vascular occlusive disorder may be the common aetiological factor of the various manifestation of this syndrome.

Function and morphology of the retinal pigment epithelium after light-induced damage.

The purpose of this study was to determine the threshold energy for light‐induced functional damage of the retinal pigment epithelium at various wavelengths. Retinas of 58 pigmented and 21 albino rabbits were exposed to low intensity broadband blue light (400–520 nm), yellow light (510–740 nm), and narrowband blue light (408, 417, 439, 455, 485, 501 nm, respectively; Δλ = 10–13 nm). The intensity values were 50, 280, and 5 mW · cm−2, respectively, and the illumination time was 0.5 up to 5 h. The cumulative dose of light energy was calculated from these data (J · cm−2). The blood‐retinal barrier dysfunction was evaluated in vivo using fluorophotometry to measure the leakage of fluorescein into the vitreous after intravenous injection and in vitro using light and electron microscopy after an in vivo intraarterial injection of horseradish peroxidase (HRP). The threshold energy for fluorescein leakage was 50 J · cm−2 for blue light and 1,600 J · cm−2 for yellow light. After broadband blue light exposure, the HRP reaction product was seen in the cytoplasm of the retinal pigment epithelium (RPE) cells and in the subretinal space but only if fluorescein leakage had been observed. Threshold energy and fluorescein leakage as a function of light energy were similar for albino and pigmented rabbits (P > 0.5). Only after yellow light exposure in excess of 3,700 J · cm−2 was fluorescein leakage found. In that case complete disruption of the RPE was seen, but no HRP was observed in the RPE cytoplasm. Of the narrow‐band blue light exposures, only that at λ = 418 nm caused a significant increase in fluorescein leakage; the threshold energy was 18 J · cm.−2. Blue light was found to be at least 30 times more efficient than yellow light in causing dysfunction of the blood‐retinal barrier. The most efficient wavelength was 418 nm, corresponding with the absorption spectrum of cytochrome c oxidase. Melanin seemed to play no role. The presence or absence of melanin in the RPE appeared to have no influence on the threshold energy. Microsc Res Tech 36:77–88, 1997.

Spectral sensitivity of the blood-retinal barrier at the pigment epithelium for blue light in the 400-500 nm range.

To specify the spectral sensitivity of the retinal pigment epithelium (RPE) for blue light damage, pigmented rabbits were exposed to light of 408, 418, 439, 455, 485, and 500 nm (half-peak bandwidth approximately 12 nm). The range of radiant exposure was 15–275 J cm−2 (1.7–19 mW cm−2 for 0.5–5 h). Vitreous fluorophotometry was used to functionally evaluate the blood-retinal barrier at the RPE in vivo, and electron microscopy to visualize RPE ultrastructure in vitro. A significant increase in permeability of the blood-retinal barrier was seen only after exposure to light of 418 nm. Radiant exposure at threshold for permeability increase was 18 J cm−2. Electron microscopy of the RPE demonstrated dispersion and clumping of melanin granules. The results suggest that the RPE is most sensitive to light in the range 412–425 nm, possibly due to damage-mediating chromophores such as cytochromec oxidase and lipofuscin.