Self-Organized Stationary States of Tokamaks.

We demonstrate that in a 3D resistive magnetohydrodynamic simulation, for some parameters it is possible to form a stationary state in a tokamak where a saturated interchange mode in the center of the discharge drives a near helical flow pattern that acts to nonlinearly sustain the configuration by adjusting the central loop voltage through a dynamo action. This could explain the physical mechanism for maintaining stationary nonsawtoothing "hybrid" discharges, often referred to as "flux pumping."

Long term results after transpupillary thermotherapy in eyes with occult choroidal neovascularisation associated with age related macular degeneration: a prospective trial.

AIM: To evaluate long term results after transpupillary thermotherapy (TTT) in eyes with exudative age related macular degeneration. METHODS: In a prospective clinical study eyes with occult or predominantly occult choroidal neovascularisation and no pretreatment were scheduled to have a TTT with a power of 630 mW. Visual acuity for far and near distances as well as contrast sensitivity were evaluated 6, 12, and 24 months postoperatively and statistically analysed. RESULTS: 47 eyes fulfilled the inclusion criteria. Overall, 70% of the patients showed an improved (14%) or had unchanged (56%) ETDRS vision after 24 months. Reading vision was stabilised (51%) or better (5%) in 56% of the eyes at this time. However, the increasing number of eyes with severe deterioration resulted in a significant decrease of both parameters over time (p = 0.0002 and p = 0.0003, respectively). Contrast sensitivity could be maintained (70%) or improved (9%) in 79%. Statistical analyses indicated a trend but no significant decrease over time (p = 0.056). CONCLUSION: Although in the majority of patients far and near distance acuity could be stabilised on average a significant decrease over time after TTT was observed. Statistical comparison of months 12 and 24 showed no further deterioration.

DMBT1 encodes a protein involved in the immune defense and in epithelial differentiation and is highly unstable in cancer.

The gene deleted in malignant brain tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor for brain, gastrointestinal, and lung cancer. It codes for a protein of unknown function belonging to the superfamily of scavenger receptor cysteine-rich proteins. We aimed at getting insights into the functions of DMBT1 by expression analyses and studies with a monoclonal antibody against the protein. The DMBT1 mRNA is expressed throughout the immune system, and Western blot studies demonstrated that isoforms of DMBT1 are identical to the collectin-binding protein gp-340, a glycoprotein that is involved in the respiratory immune defense. Immunohistochemical analyses revealed that DMBT1 is produced by both tumor-associated macrophages and tumor cells and that it is deregulated in glioblastoma multiforme in comparison to normal brain tissue. Our data further suggest that the proteins CRP-ductin and hensin, both of which have been implicated in epithelial differentiation, are the DMBT1 orthologs in mice and rabbits, respectively. These findings and the spatial and temporal distribution of DMBT1 in fetal and adult epithelia suggest that DMBT1 further plays a role in epithelial development. Rearrangements of DMBT1 were found in 16 of 18 tumor cell lines, and hemizygous deletions were observed in a subset of normal individuals, indicating that the alterations in tumors may be a result of both pre-existing deletions uncovered by a loss of heterozygosity and secondary changes acquired during tumorigenesis. Thus, DMBT1 is a gene that is highly unstable in cancer and encodes for a protein with at least two different functions, one in the immune defense and a second one in epithelial differentiation.

Deleted in Malignant Brain Tumors 1 is a versatile mucin-like molecule likely to play a differential role in digestive tract cancer.

Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor gene for brain, lung, and digestive tract cancer. In particular, alterations of the gene and/or a loss of expression have been observed in gastric, colorectal, and esophageal carcinomas. Initial evidence has accumulated that DMBT1 may represent a multifunctional protein. Because the consequences of a loss of DMBT1 function may be different depending on its original function in a particular tissue, we wondered if it is appropriate to assume a uniform role for DMBT1 in digestive tract carcinomas. We hypothesized that a systematic characterization of DMBT1 in the human alimentary tract would be useful to improve the understanding of this molecule and its role in digestive tract carcinomas. Our data indicate that the expression pattern and subcellular distribution of DMBT1 in the human alimentary tract is reminiscent of epithelial mucins. Bovine gallbladder mucin is identified as the DMBT1 homologue in cattle. An elaborate alternative splicing may generate a great variety of DMBT1 isoforms. Monolayered epithelia display transcripts of 6 kb and larger, and generally show a lumenal secretion of DMBT1 indicating a role in mucosal protection. The esophagus is the only tissue displaying an additional smaller transcript of approximately 5 kb. The stratified squamous epithelium of the esophagus is the only epithelium showing a constitutive targeting of DMBT1 to the extracellular matrix (ECM) suggestive of a role in epithelial differentiation. Squamous cell carcinomas of the esophagus show an early loss of DMBT1 expression. In contrast, adenocarcinomas of the esophagus commonly maintain higher DMBT1 expression levels. However, presumably subsequent to a transition from the lumenal secretion to a targeting to the ECM, a loss of DMBT1 expression also takes place in adenocarcinomas. Regarding DMBT1 as a mucin-like molecule is a new perspective that is instructive for its functions and its role in cancer. We conclude that DMBT1 is likely to play a differential role in the genesis of digestive tract carcinomas. However, although DMBT1 originally has divergent functions in monolayered and multilayered epithelia, carcinogenesis possibly converges in a common pathway that requires an inactivation of its functions in the ECM.

Intravitreal anti-vascular endothelial growth factor combined with half-fluence photodynamic therapy for choroidal neovascularization in chronic central serous chorioretinopathy.

PurposeTo evaluate the results of indocyanine green angiography (ICGA)-guided verteporfin photodynamic therapy (PDT) with half-fluence rate combined with intravitreal application of anti-VEGF in treating choroidal neovascularization (CNV) in chronic central serous chorioretinopathy (CSCR).Patients and methodsIn this retrospective cohort study 17 consecutive patients with secondary CNV due to chronic CSCR had their diagnosis verified with fluorescein angiography (FA) and ICGA at baseline. All eyes received either intravitreal ranibizumab (IVR) or bevacizumab (IVB). On the consecutive day following the initial IVR/IVB treatment, ICGA-guided verteporfin (6 mg/m(2)) PDT with half-fluence rate (25 J/cm(2)) was performed on every patient. IVR or IVB was rescheduled on a pro re nata regimen. Main outcome measures were changes in visual acuity (VA) according to the ETDRS letter score and changes in the central foveal thickness (CFT).ResultsBest-corrected VA at baseline was 65.6 letters (±6.7; n=17) according to the ETDRS letter score. At 12 months, mean ETDRS letter score improved to 71.2 letters (P=0.34). CFT was 309 µm and decreased to 216 µm at month 12 control (P=0.0004). Nine eyes (52.9%) received additional treatment with IVR/IVB due to recurrence of subretinal fluid, with an overall mean number of IVR/IVB treatment of 1.8±3.6 per patient with no systemic side effects during 12 months' follow-up.ConclusionsIVR or IVB combined with ICGA-guided half-fluence PDT with verteporfin is effective in treating CNV in chronic CSCR, with choroidal hyperpermeability in ICGA, resulting in stable vision and significant reduction of CFT.

The genomic structure of the DMBT1 gene: evidence for a region with susceptibility to genomic instability.

Increasing evidence has accumulated for an involvement of the inactivation of tumour suppressor genes at chromosome 10q in the carcinogenesis of brain tumours, melanomas, and carcinomas of the lung, the prostate, the pancreas, and the endometrium. The gene DMBT1 (Deleted in Malignant Brain Tumours 1) is located at chromosome 10q25.3-q26.1, within one of the putative intervals for tumour suppressor genes. DMBT1 is a member of the scavenger-receptor cysteine-rich (SRCR) superfamily and displays homozygous deletions or lack of expression in glioblastoma multiforme, medulloblastoma, and in gastrointestinal and lung cancers. Based on these properties, DMBT1 has been proposed to be a candidate tumour suppressor gene. We have determined the genomic sequence of DMBT1 to allow analyses of mutations. The gene has at least 54 exons that span a genomic region of about 80 kb. We have identified a putative exon with coding potential for a transmembrane domain. Our data further suggest that alternative splicing gives rise to isoforms of DMBT1 with a differential utilization of SRCR domains and SRCR interspersed domains. The major part of the gene harbours locus specific repeats. These repeats may point to the DMBT1 locus as a region susceptible to chromosomal instability.

Optical coherence tomography guided retreatment of photodynamic therapy.

AIM: To evaluate the results of a retreatment modality of photodynamic therapy (PDT) based on optical coherence tomography (OCT) and fluorescein angiography (FA). To quantify the effect of PDT with the help of measurement of the retinal thickness. METHODS: Eyes with predominantly classic subfoveal choroidal neovascularisation (CNV) due to age related macular degeneration were included. PDT was performed every three months, when needed. OCT, FA, and measures of distance acuity were performed at baseline, after 6 weeks, 3 months, and from then on every 3 months. A control group of a consecutive series of eyes that had been retreated based only on FA results was installed. RESULTS: Forty eyes of 38 patients were included. The average age was 73 years. The maximum retinal thickness decreased from 404 mum at baseline to 281.6 mum at month 12. Furthermore there was a significant decrease of retinal thickness in both subgroups. The number of retreatments was reduced, when activity was diagnosed using OCT and FA. (2.4 v 4.0). The distance acuity correlated significantly with the maximum retinal thickness (p=0.0042). CONCLUSION: Information about the activity of a neovascular lesion can be obtained with the help of OCT. The retreatment modalities can be optimised by using OCT and FA and the number of retreatments can be reduced.

Ultrastructural evidence for lymphatic capillaries in the primate choroid.

In the choroid of three cynomolgus monkeys (Macaca irus) and of one baboon (Papio anubis) lymphatic capillaries were demonstrated by transmission electron microscopy.

Effect of accelerated iron ions on the retina.

The eyes of rats were exposed to doses of 0.1 and 2.5 Gy of 450-MeV/amu 56Fe particles (LET approximately 195 keV/microns). The beam axes were oriented perpendicular to the central retina of the animals. Retinas were harvested immediately (less than 10 min), 24 h, 15 days, 136 days, and 186 days after the experiment. The retinas of animals of equivalent ages were sampled at the same intervals. By Day 15, the spatial densities of the pigment epithelial, photoreceptor, and bipolar cells in retinas irradiated with 2.5 Gy were 15 to 20% lower than those of the controls. The cellular density of the pigment epithelium returned to the control level by Day 186 while photoreceptor and bipolar cell numbers remained depressed. One and fifteen days after irradiation, the choroidal vessels showed signs of radiation damage. Exposure to 0.1 Gy did not affect the cellular density within the retina at the interval examined (186 days). None of the retinas showed evidence of track-specific injury that could be interpreted as microlesions or tunnel lesions.

The effect of accelerated argon ions on the retina.

It has been postulated that high energy heavy ions cause a unique form of damage in living tissue, which results from the high linear energy transfer of accelerated single particles. We have searched for these single-particle effects, so-called "microlesions," in composite electron micrographs of retinas of rats which had been irradiated with a dose of 1 Gy of 570 MeV/amu argon ions. The calculated rate of energy deposition of the radiation in the retina was about 100 keV/micron and the influence was four particles per 100 micron 2. Different areas of the irradiated retinas which combined would have been expected to be traversed by approximately 2400 particles were examined. We were unable to detect ultrastructural changes in the irradiated retinas distinct from those of controls. The spatial cellular densities of pigment epithelial and photoreceptor cells remained within the normal range when examined at 24 h and at 6 months after irradiation. These findings suggest that the retina is relatively resistant to heavy-ion irradiation and that under the experimental conditions the passage of high energy argon ions does not cause retinal microlesions that can be detected by ultrastructural analysis.

The fiber system of the choroidocapillaris.

In the central choroid of three cynomolgus monkeys (Macaca irus) and a baboon (Papio anubis) the shape of the choroidocapillary sinus is determined by a system of interstitial collagen fibers, the "fiber system of the choroidocapillaris". The inner leaflet of this system is Bruch's membrane. The outer leaflet consists of interwoven collagen bundles, covering the roof of the capillary sinus. Straight bundles of collagen fibers passing through connective tissue columns in the choroidocapillary sinus connect both leaflets. Forces created by changes in the arterial tone in the vascular stroma may be transmitted by the choroidocapillary fiber system to the elastic layer of Bruch's membrane.

Radiation retinopathy: electron microscopy of retina and optic nerve.

A 4 1/2 year old female was treated for embryonal rhabdomyosarcoma of the left orbit in 1975 with radiation (59.5 Gy in 5 weeks), followed by chemotherapy. An electroretinogram (ERG) in March, 1988 revealed cone responses 3% of normal and no rod responses in the left eye, and normal responses in the right eye. The eye was enucleated in April 1988. In the fovea no choroidocapillaris was seen at the intact Bruch's membrane, and the pigment epithelium was preserved only in small patches. No photoreceptor cells were seen in the areas devoid of pigment epithelial cells. The parafoveal and peripheral (30 degrees eccentricity) retina was better preserved. The thickness of the layer of rods and cones and of Henle's fiber layer was reduced. Very few outer segments were present. Macrophages had invaded the retinal tissue in moderate numbers. The retinal vessels were ensheathed by several layers of collagen fibrils. The spatial densities of pigment epithelial, cone, rod, and bipolar cells had been reduced. The optic nerve contained a total number of 1,022,000 nerve fibers.

Erbium:YAG laser vitrectomy: clinical results.

PURPOSE: To evaluate the intraoperative use of a new erbium:yttrium aluminum garnet (YAG) laser vitrectomy system. METHODS: An erbium:YAG laser combined with an infusion-suction system (Wavelight Laser Technology, Erlangen, Germany), equipped with a flexible fiber optic and a hand piece with a 20-gauge end tip and a side opening of 0.6 mm was used. Cutting rates were 2 to 30 Hz, and energies were 20 to 40 mJ. Between January 1998 and January 1999 the erbium:YAG laser system was used in 67 consecutive patients (68 eyes) where vitrectomy was indicated. The patients had a complete eye examination before surgery and postoperatively at 1 to 3 days, 1 week, 3 weeks, and 6 weeks. During surgery, the total time needed for vitrectomy, the laser time itself, amount of energy used, cutting rate, suction, and perfusion, as well as manipulative difficulties and/or complications, were documented. RESULTS: The average laser time was 4.5 minutes for a basic vitrectomy with a setting of 20 mJ, 20 Hz, and suction 100 to 200 mm Hg. Hemorrhages, loose intravitreal, and preretinal membranes of different densities were cut well with adjustment of energy. After a minimal observation time of 6 months (median, 12.7 months) no laser-associated complications were found. CONCLUSIONS: The erbium:YAG laser, combined with an infusion-suction system, offers a new technology for vitreous surgery. Its advantages, compared with mechanical vitrectomy cutters, are higher cutting rates and the modulation of energy. Modifications of the end tip are needed to develop this system further.

[Photodynamic therapy for severe myopia]. / Photodynamische Therapie bei hoher Myopie.

INTRODUCTION: In the modern western world quality of life depends on the ability of reading. Our study was designed to prove the possibility of stabilization of reading acuity, central visual field and multifocal electroretinogram (mERG) after photodynamic therapy (PDT) in cases of pathologic myopia. PATIENTS AND METHODS: In our study 20 eyes were included. At baseline, after 6 weeks,3 months and afterwards every 3 months we investigated distance acuity, reading acuity, 10 degrees static threshold perimetry, mERG, optical coherence tomography and fluorescence angiograophy. RESULTS: After 1 year 85% of eyes lost less than 1.5 lines of distance acuity, the reading acuity could be stabilized in 80%, the central visual field in 60% and the ERG in 55%. Patients less than 60 years old showed better results than older patients. DISCUSSION AND CONCLUSION: PDT was found to be very effective because the membranes were classic without any occult parts in 100%. They were small and superficially located and the scotomas were small. There was a good correlation between functional and morphological results.

New approaches in the management of choroidal neovascular membrane in age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population. The prevalence is reported to be 1.2-1.4% in several population-based epidemiological studies. Currently 25-30 million people worldwide are blind due to AMD. With the aging world population it is bound to increase significantly, and could become a significant public health problem in next two decades, with serious socio-economic implications. Several strategies are today available to treat the wet form of AMD, which is responsible for significant visual loss. These were until recently confined to laser photocoagulation, and subretinal surgery, but today two other modalities, namely, radiation and photodynamic therapy, are available. These treatment modalities however, are aimed at preservation of vision only, and not at reversing the process of the disease. Further research on antiangiogenic drugs and gene therapy could significantly help AMD patients.

Systemic bevacizumab (Avastin) therapy for exudative neovascular age-related macular degeneration. The BEAT-AMD-Study.

BACKGROUND: Double-blinded, randomised, prospective, pilot-study to determine the effect of systemic bevacizumab therapy. METHODS: Subjects with fibrovascular pigment epithelial detachment, subfoveal choroidal neovascularisation extending under the geometric centre of the foveal avascular zone and/or macular thickness of at least 300 microm in both eyes were included. Sixteen eyes were included and randomised equally to receive either three infusions of 5 mg/kg Avastin or 100 ml of 0.9% sodium chloride every 2 weeks. The main outcome measure was the lesion size. The follow-up time was 24 weeks. RESULTS: Throughout the 24-week follow-up, the lesion size and macular thickness decreased in the Avastin group by 0.5 (SD 0.08) mm and 103.6 (14.9) microl respectively. In both groups, visual acuity remained stable in seven eyes and decreased in one eye. At the end of follow-up, 50% of the eyes in the Avastin group became fibrotic, 37.5% remained unchanged, and 12.5% developed a subretinal bleeding. There was a treatable rise in blood pressure after Avastin treatment. CONCLUSION: Systemic Avastin could be offered to patients with exudative age-related macular degeneration in both eyes and/or patients who refuse intravitreal injections if blood pressure is normal and there is no history of thrombosis.

Optical coherence tomography: limits of the retinal-mapping program in age-related macular degeneration.

AIM: The retinal-mapping program of Stratus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA, USA) calculates the retinal volume of the central region between the retinal surface and the retinal pigment epithelium (RPE). This study evaluates the retinal-mapping program for studies dealing with AMD. METHODS: The scans of both eyes of patients examined from August to October 2006 because of macular degeneration were evaluated retrospectively. Independent examiners tested whether the two lines indicating the retinal surface and the RPE were positioned correctly by the threshold algorithm that corresponded with correct measurements. RESULTS: The scans of 233 eyes of 117 patients were evaluated (39.3% were men and 60.7% women, with a mean age of 76.9 years). Overall, in 57.1% both lines were positioned correctly. False-positioned lines were recorded in 9.0% due to low scan quality and in 33.9% due to a doubled or interrupted hyper-reflective band of the RPE. Threshold algorithm misinterpretation was significantly more frequent in occult lesions with and without fibrosis than in non-exudative lesions, and were significantly correlated to distance acuity (p<0.0001). CONCLUSION: The retinal-mapping program for examination of AMD provided correct results in only 57.1% of eyes. A manual correction of false-positioned lines would be needed to improve accuracy.

Quantitative morphology of the primate peripheral retina (Macaca irus).

By using electron microscopy to study the quantitative morphology of the retina, it was possible to determine the spatial density of all principal retinal cells at a defined retinal location. In two retinas of cynomolgus monkeys at a position of 30 degrees nasal of the fovea centralis, the following cell densities were determined from composite electron micrographs: retinal pigment epithelium: 3,400 cell/mm2; rod cells: 115,000 and 168,000 cells/mm2; cone cells: 8,200/mm2; horizontal cells: 7,000/mm2; bipolar cells: 50,000/mm2; amacrine cells: 11,500/mm2; Müller cells: 16,000/mm2; and ganglion cells: 5,350 and 6,750/mm2.

Quantitative morphology of the central fovea in the primate retina.

Electron micrograph composites of tangenital sections of the fovea centralis of three cynomolgus monkeys (Macaca irus) and one baboon (Papio anubis) were used to determine the spatial density of the principal retinal cells. In the center of the foveola, the density of cones ranged from 113,000 to 230,000/mm2, and pigment epithelial cells from 4,900 to 7,000/mm2. At a distance of 500 microns from the foveolar center the density of the cone cell pedicles ranged from 29,000 to 36,300/mm2, and the density of horizontal cells ranged from 19,000 to 25,100/mm2. Densities of bipolar, Müller, and amacrine cells were determined in only two monkeys and in the baboon. The fact that the cone cell pedicles have a larger diameter than the foveolar cones explains the geometry of the fovea. The morphology of the junction between foveolar cone outer segments and the pigment epithelium reflects the complex metabolism of this functional unit. The comparison with the peripheral primate retina suggests that the densities of horizontal and bipolar cells, but not of amacrine and Müller cells, are correlated with the density of cone cell pedicles.

Discontinuities of the external limiting membrane in the fovea centralis of the primate retina.

In the center of the fovea centralis of retinas of three cynomolgus monkeys, one baboon and one male human, the external limiting membrane contains circumscribed areas in which zonulae adherentes are lacking between cone inner segments and apices of Müller cells. These discontinuities of the external limiting membrane begin about 300 microns from the foveolar center, involving only a few cones. Towards the center of the fovea the discontinuities become larger.