Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression.

Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch's membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.

[Work sampling in ophthalmological clinical studies. A multicenter field study]. / Zeiterfassung in ophthalmologischen klinischen Studien. Eine multizentrische Feldstudie.

BACKGROUND: Work in clinical studies is generally more elaborate and therefore more time-consuming in comparison to the clinical routine. The purpose of this study was to systematically investigate the time consumption in the German ophthalmological clinical trial centers. METHODS: The members of the working group of the German Ophthalmology Society clinical study centers (Arbeitsgemeinschaft DOG Klinische Studienzentren) were asked to fill in three questionnaires about best estimations for the time spent on study-related procedures and administration. Additionally, work sampling was performed for each employee at each study center over a period of 3 weeks. RESULTS: The questionnaires were completed by 9 of the 11 centers. Overall, 5504 working hours were recorded. On an average working day, the time spent for both documentation and administration averaged 4 h each. Operative interventions consumed a significant amount of time (2.8 h), as did ophthalmological examinations (2.5 h) and obtaining informed consent (1.5 h). The recorded time consumption for visual acuity testing, informed consent and documentation was well aligned with the best estimates of the three questionnaires. By contrast, interventions, ophthalmological examinations and biomaterial sample handling were underrated in the best estimations. DISCUSSION: A considerable amount of time in clinical studies is spent on documentation and administration. From work sampling, ophthalmological examinations and biomaterial sampling turned out to be surprisingly time consuming. This is probably due to preparation and postprocessing tasks. It is important to consider this when calculating the overall costs of a clinical study. In addition, many administrative activities cannot be attributed to specific patients and can therefore not be compensated on the basis of case payments alone. Additional remuneration is required to fully cover the costs in an ophthalmological study center.

[Pitfalls in retinal optical coherence tomography imaging]. / Fallstricke in der Netzhautbildgebung mittels optischer Kohärenztomographie.

Optical coherence tomography (OCT) imaging now plays an important role in the management of macular and retinal diseases. In addition to the many advantages of this noninvasive imaging modality, limitations and pitfalls should be taken into consideration. The aim of this review is to discuss several possible sources of error in the conduct and interpretation of OCT imaging. Ultimately, this article should add to a meaningful and focused use in clinical practice.

[Reticular drusen over time with SD-OCT]. / Retikuläre Drusen über die Zeit mittels SD-OCT.

AIM: The aim of the study was the analysis of reticular drusen (RDR) in patients with age-related macular degeneration using simultaneous confocal scanning laser ophthalmoscopy (cSLO) and spectral domain optical coherence tomography (SD-OCT) at different time points. METHODS: Included in this retrospective analysis were 47 eyes from 32 patients (median age 80.1 years, range 66-89 years) with RDR at baseline and at least one follow-up visit. Registration of the cSLO near-infrared reflectance image and the SD-OCT B-scan (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg) at different time points was carried out using the AutoRescan tool. RESULTS: While either no alterations or increase in the RDR area (n=19 eyes) or RDR density (n=15) were seen by cSLO imaging, the analysis of the SD-OCT B-scans at different time points revealed a more complex picture. An increase in two well visible lesions at the baseline visit was detected in 8 eyes at the first follow-up and in 3 eyes at the second follow-up examination. A regression was seen in 5 eyes at the first follow-up and in 3 eyes at the second follow-up visit. In most eyes (n=23), an increase of one with a parallel decrease of the second RDR lesion in the identical B-scan was identified at the first follow-up visit, whereas individual RDR showed an increase at the second follow-up examination that had initially shown a decrease in size at the first follow-up visit. CONCLUSIONS: The results indicate underlying dynamic processes in the development and changes of RDR over time. For a more accurate analysis, the exact registration of SD-OCT B-scans at different time points and the use of high-resolution very dense volume scans would be helpful in order to assess such discrete changes of miniscule intraretinal lesions over time.

[Predictive near-infrared SLO signs for tears of the retinal pigment epithelium due to age-related macular degeneration]. / Prädiktive nahinfrarot-SLO-merkmale für risse des retinalen pigmentepithels bei altersabhängiger makuladegeneration.

PURPOSE: The aim of this study was to identify potential predictive markers in confocal scanning laser ophthalmoscopy (cSLO)-based imaging for tears of the retinal pigment epithelium (RPE) in the presence of pigment epithelial detachments (PED) due to age-related macular degeneration (AMD). METHODS: Fifteen eyes of 15 patients (mean age 77 years, SD ± 6) with RPE tears and pre-existing PEDs were retrospectively analysed for the presence of increased signals on near-infrared imaging (NIR) using confocal scanning laser ophthalmoscopy (cSLO). RESULTS: In 87 % of the cases increased reflectance signals on NIR in the area of the PED were noted prior to the development of an RPE tear. On average, these signals were recorded 58 days (SD ± 40) before the rip was diagnosed. In 62 % of the patients these signals were localised opposite to the rip location at the rim of the PED. CONCLUSION: Increased reflectance signals on NIR imaging may serve as a predictive marker for RPE tears in patients with PED in AMD. These signals recordable with a non-invasive imaging method should be prospectively validated in a larger cohort of patients with PEDs. It may be useful in the management of patients exhibiting this manifestation of exudative AMD.

[Imaging diagostics of geographic atrophy]. / Bildgebende Diagnostik bei geographischer Atrophie.

The development of imaging technologies has contributed to the understanding of the genesis and pathophysiological mechanisms of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Fundus autofluorescence (FAF) imaging allows accurate discrimination of the boundaries of atrophic patches. Furthermore, predictive markers for disease progression can be identified. Non-invasive FAF imaging now represents the gold standard for evaluating progressive enlargement of atrophic areas. By means of high resolution optical coherence tomography (OCT) microstructural retinal changes in GA can be identified. Anatomical endpoints are now being used in interventional GA trials and represent meaningful outcome parameters as surrogate markers in an overall slowly progressive disease which may not affect the fovea until later stages of the disease.

[Therapy approaches for geographic atrophy]. / Therapieansätze bei geographischer Atrophie.

Geographic atrophy, the dry form and late manifestation of age-related macular degeneration, is the next challenge following the breakthrough in the treatment of neovascular age-related macular degeneration (AMD). Various interventional pharmacologic approaches with different targets are already being tested in clinical interventional trials. These include reduction of retinal toxins, anti-inflammatory agents, complement inhibition, neuroprotection and alleviation of oxidative stress. Until efficacy and safety is demonstrated, aids for poor vision and further rehabilitative measures remain essential for patients with advanced dry AMD.

Discrete arcs of increased fundus autofluorescence in retinal dystrophies and functional correlate on microperimetry.

PURPOSE: To describe the occurrence of discrete arcs of increased fundus autofluorescence (FAF) associated with various retinal dystrophies and to assess their functional significance by fundus-controlled microperimetry. METHODS: Seven patients, three with pigmented paravenous retinochoroidal atrophy (PPRCA), one with sector retinitis pigmentosa (RP), one with typical RP, and two with macular dystrophy were assessed by retinal imaging including FAF imaging. Serial images were obtained within a review period of 6 and 10 years in a patient with PPRCA and macular dystrophy, respectively. Fundus-controlled microperimetry was performed in eight eyes of five patients to determine light increment sensitivity. RESULTS: A discrete arched line of increased FAF was observed without obvious correlate on fundus biomicroscopy. The orientation of this line differed from ring shape in RP and macular dystrophy, a semi-circle structure in sector RP to crescent shape with tiplike extensions towards branching retinal veins in PPRCA. Longitudinal investigation revealed slight migration of the arc in PPRCA and peripheral extension of the ring diameter in macular dystrophy. Microperimetry revealed that the arc of increased FAF sharply delineated areas of severely impaired retinal sensitivity. CONCLUSIONS: The findings indicate that arcs of increased FAF in PPRCA and other retinal dystrophies demarcate areas of impaired retinal function and may migrate over time. FAF imaging may therefore reveal the exact extent of neurosensory dysfunction that may exceed the dimensions anticipated by conventional examinations.

[Unilateral pigmented paravenous retinochoroidal atrophy]. / Unilaterale pigmentierte paravenöse retinochorioidale Atrophie.

We report the case of an asymptomatic unilateral pigmented paravenous retinochoroidal atrophy (PPRCA) in a 43-year-old patient. The right eye showed chorioretinal atrophy with bone-spicule-like pigmentations along the retinal veins. Visual acuity was 20 / 20 and perimetry revealed scotomas correlating to the chorioretinal atrophy. Electrophysiological examination showed decreased signals in ERG and EOG. Fundus autofluorescence and angiography findings are presented. Pathogenetically, a classification as hereditary retinal dystrophy (as in retinitis pigmentosa) as well as a post-inflammatory residuum are discussed.

[Classification of biomedical research reports as a reference for evidence-based medicine in ophthalmology. A survey considering as example the journal Der Ophthalmologe]. / Klassifikation biomedizinischer Forschungsberichte als Grundlage evidenzbasierter Medizin in der Augenheilkunde. Eine Untersuchung am Beispiel der Zeitschrift Der Ophthalmologe.

BACKGROUND: Evidence-based medicine requires careful appraisal of published data derived from experimental and clinical studies. Based on classification of biomedical research reports, evidence levels can be determined and recommendations for therapeutic decisions can be made. METHODS: A classification system for clinical studies was developed. It was evaluated in classifying the reports published in Der Ophthalmologe during 2003-2004 (study design: descriptive cross-sectional study, case series). RESULTS: In the 2-year interval, 70 longitudinal and 95 cross-sectional studies were published. The vast majority of the longitudinal studies were interventional cohort studies. Not considering case reports, 73% of the original articles were longitudinal prospective studies, 1% were retrospective (case-control) studies, and 26% were cross-sectional studies. CONCLUSIONS: The study design of all published articles could be classified using the classification system. This classification system proves to be applicable in the context of clinical studies in ophthalmology and may be helpful in the process of critical appraisal of the literature and synthesis of clinical evidence and an evidence-based recommendation.

A randomized trial comparing the hand-mounted JoStent with the premounted Multi-Link Duet stent in patients with coronary artery disease.

The objective of this multicenter randomized study was to compare the angiographic and clinical results achieved 1 year after coronary placement of two stent models: the hand-mounted JoStent and the premounted Multi-Link Duet stent. We included 505 patients who were randomly assigned to receive either the hand-mounted JoStent (n = 252) or the premounted Multi-Link Duet stent (n = 253). The primary endpoint of the study, late lumen loss, measured 1.12 mm in the JoStent group and 1.17 mm in the Multi-Link Duet group. These values were statistically equivalent (P = 0.02 from the equivalence test). No significant difference was observed in the incidence of restenosis, 24.2% in the JoStent and 25.2% in the Multi-Link Duet stent group, and target vessel revascularization, 13.9% in the JoStent and 15.4% in the Multi-Link Duet patients. In conclusion, the hand-mounted JoStent and the premounted Multi-Link Duet stent enable excellent procedural success rates and equally favorable 1-year angiographic and clinical outcomes.

Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO) trial.

BACKGROUND: Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results. METHODS AND RESULTS: A total of 651 patients with coronary lesions situated in native vessels >2.8 mm in diameter were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 microm) and 325 patients to the thick-strut stent (strut thickness of 140 microm). The primary end point was the angiographic restenosis (>/=50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the combined rate of death and myocardial infarctions at 1 year. The incidence of angiographic restenosis was 15.0% in the thin-strut group and 25.8% in the thick-strut group (relative risk, 0.58; 95% CI, 0.39 to 0.87; P=0.003). Clinical restenosis was also significantly reduced, with a reintervention rate of 8.6% among thin-strut patients and 13.8% among thick-strut patients (relative risk, 0.62; 95% CI, 0.39 to 0.99; P=0.03). No difference was observed in the combined 1-year rate of death and myocardial infarction. CONCLUSIONS: The use of a thinner-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting. These findings may have relevant implications for the currently most widely used percutaneous coronary intervention.

Influence of glycogen content, temperature, and Euro Collins solution on membrane potential and sodium activity of superfused porcine liver slices.

The influence of glycogen content, temperature, and Euro Collins (EC) solution on membrane potential (Vm) and intracellular sodium activity (aNai) were measured in cells of superfused porcine liver slices by means of double-barrelled ion-sensitive microelectrodes. Vm was -26.1mV in fasted pigs and -20.6mV after glucose feeding, when measured in HEPES-buffered solution (P less than 0.0001). aNai was not measurably affected by glucose feeding. During superfusion with Tyrode solution, lowering the temperature from 35.5 degrees C to 15.5 degrees C led to a fast Vm decrease of roughly 2mV followed by an increase of 1-3mV. At the same time, aNai increased from 12.8 to 18.2mM within 10 min. Superfusion with EC solution for 10 min caused comparable changes in fed and fasted pigs. Vm depolarized at either temperature by about 16mV. At 35.5 degrees C the initial aNai of 17.5mM was roughly halved, whereas at 15.5 degrees C it decreased from 21.0 to 14.3mM. The results suggest that the nutritional state markedly affects the electric properties of liver. However, the effect on membrane potential of high-potassium organ-protective solutions seems to be distinctly more pronounced. Moreover, cellular Na+ activity decreases in consequence of an extracellular Na+ reduction with protective solutions, which might be balanced to some extent by a simultaneous temperature decrease.

The cardioplegic solution HTK: effects on membrane potential, intracellular K+ and Na+ activities in sheep cardiac Purkinje fibres.

The effects of the cardioplegic solution HTK on membrane potential (EM) and intracellular K and Na activities (aiK, aiNa) were studied in sheep cardiac Purkinje fibres by means of conventional and ion-selective microelectrodes. HTK contains (mM): Na 15, K 10, Ca 0, Mg 4, histidine 180. (1) In control conditions EM was -74.3 +/- 3.3 mV (n = 25), aiK was 116.4 +/- 4.1 mM (n = 7) and aiNa was 8.2 +/- 1.4 mM (n = 15). (2) Exposure to HTK led to a depolarization to -59.7 +/- 3.6 mV (n = 25) which exceeded by about 5-7 mV that induced in a Tyrode solution of 10 mM K and in a modified HTK solution supplemented by 2 mM Ca (n = 6). (3) Addition of 0.5 mM barium eliminated the difference in the steady-state depolarization. (4) HTK superfusion increased aiK to 120.1 +/- 4.4 mM (n = 7) and decreased aiNa to 3.9 +/- 0.9 mM (n = 15). (5) The decrease in aiNa was insensitive to amiloride (1 mM) and to external alkalization but was slightly increased by addition of 2 mM calcium. (6) When the calcium in Tyrode solution was lowered from 2.0 mM to 0.05 mM, aiNa hardly decreased during subsequent exposure to unmodified HTK and it increased in the presence of 0.1 mM dihydroouabain. We propose the hypothesis (1) that the difference in membrane depolarization between HTK and a 10 mM K-Tyrode is caused by a decrease in K conductance by the HTK solution and (2) that the aiNa decline mainly results from a coupled Ca influx via Na-Ca exchange due to a delayed washout of external calcium.