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The purpose of this study was to investigate epithelial and neuronal changes in patients with refractory/relapsed multiple myeloma (RRMM) before/during belantamab mafodotin (belamaf) treatment using confocal microscopy.Retrospective case series.RRMM patients underwent best-corrected visual acuity (BCVA) testing and slitlamp examination/photography, followed by corneal confocal microscopy (CCM), to evaluate the epithelium and subbasal nerve plexus (SNP) to measure corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) before and during belamaf treatment.In 14 eyes of 7 patients (4 female, 68 ± 10 years of age) with complete follow-up (4 ± 2 months), the median BCVA dropped from 20/25 (20/25-20/20) to 20/40 (20/200-20/32) in the worse eye at the end of follow-up. Microcystic epithelial changes and ocular surface disease were demonstrated biomicroscopically. CCM showed "grape-like" hyperreflective spots in the central basal epithelium that changed to polymorphous-structured cysts in the superficial epithelium, with no pathology detected at the(peri-)limbal structures. The baseline, normal SNP morphology with a mean CNFD, CNBD, and CNFL of 20.25 ± 7.06/mmThis study is the first to illustrate neurotoxic effects of belamaf on the human cornea.

BackgroundOcular toxoplasmosis is common across all regions of the world. Understanding of the epidemiology and approach to diagnosis and treatment have evolved recently. In November 2020, an international group of uveitis-specialised ophthalmologists formed the International Ocular Toxoplasmosis Study Group to define current practice.Methods192 Study Group members from 48 countries completed a 36-item survey on clinical features, use of investigations, indications for treatment, systemic and intravitreal treatment with antiparasitic drugs and corticosteroids, and approach to follow-up and preventive therapy.ResultsFor 77.1% of members, unilateral retinochoroiditis adjacent to a pigmented scar accounted for over 60% of presentations, but diverse atypical presentations were also reported. Common complications included persistent vitreous opacities, epiretinal membrane, cataract, and ocular hypertension or glaucoma. Most members used clinical examination with (56.8%) or without (35.9%) serology to diagnose typical disease but relied on intraocular fluid testing—usually PCR—in atypical cases (68.8%). 66.1% of members treated all non-pregnant patients, while 33.9% treated selected patients. Oral trimethoprim–sulfamethoxazole was first-line therapy for 66.7% of members, and 60.9% had experience using intravitreal clindamycin. Corticosteroid drugs were administered systemically by 97.4%; 24.7% also injected corticosteroid intravitreally, almost always in combination with an antimicrobial drug (72.3%). The majority of members followed up all (60.4%) or selected (35.9%) patients after resolution of acute disease, and prophylaxis against recurrence with trimethoprim–sulfamethoxazole was prescribed to selected patients by 69.8%.ConclusionOur report presents a current management approach for ocular toxoplasmosis, as practised by a large international group of uveitis-specialised ophthalmologists.

ZusammenfassungImmunmediierte inflammatorische Erkrankungen (IMID) sind eine klinisch heterogene Gruppe von Erkrankungen, die genetische, ätiologische und auch klinische Überschneidungen aufweisen. Nach dem heutigen Stand der Forschung liegen den sog. primären IMID gemeinsame pathogene Mechanismen und zytokinassoziierte Signaltransduktionswege zugrunde. Zu den primären IMID zählen unter anderem chronisch-entzündliche Darm‑, Haut- und Augenerkrankungen sowie rheumatische Erkrankungen. Patienten, die an einer primären IMID erkrankt sind, weisen ein erhöhtes Risiko für die Entwicklung einer sekundären IMID auf. Die vorliegende Arbeit skizziert die Abgrenzung zwischen primären und sekundären IMID unter Berücksichtigung von Komplikationen und Komorbiditäten. Ausgehend von den Fächern Gastroenterologie, Dermatologie, Rheumatologie und Ophthalmologie wird ein möglicher optimaler interdisziplinärer Umgang mit IMID-Patienten diskutiert. Im speziellen werden Leitsymptome, die auf eine IMID hinweisen, und diagnostische Maßnahmen beschrieben, die vor Überweisung eines Patienten zum entsprechenden Spezialisten durchgeführt werden sollten. Da einzelne Patienten, die unter mehreren IMID leiden, eine therapeutische Herausforderung darstellen, können hierfür interdisziplinäre Sprechstunden bzw. sog. Immunoboards in der klinischen Praxis hilfreich sein.

The objective was to compare retinal morphology and function following intravitreal injections of bevacizumab (Avastin) or triamcinolone (Volon A) in patients with early diabetic macular edema (DME). The study was planned as a randomized, prospective, interventional clinical trial. A total of 30 diabetic patients with treatment-naive, clinically significant macular edema were included in this study and randomized to two equal groups. One group initially received three injections of 2.5 mg bevacizumab in monthly intervals. The second group received a single injection of 8 mg triamcinolone, followed by two sham interventions. Functional and anatomic results were evaluated monthly using ETDRS vision charts and spectral-domain optical coherence tomography. According to the study protocol, retreatment after 3 months was dependent on functional and anatomic outcome in a PRN regimen. Baseline best corrected visual acuity (BCVA) was 0.30 logMAR and central retinal subfield thickness (CSRT) was 505 μm in the bevacizumab group and 0.32 logMAR and 490 μm CSRT in the triamcinolone group. After 3 months, BCVA improved to 0.23 logMAR (bevacizumab) and 358 μm CRST and 0.26 logMAR (triamcinolone) and 308 μm CSRT. After 12 months, BCVA further recovered in the bevacizumab group (0.18 logMAR) but slightly decreased in the triamcinolone group (0.36 logMAR). Intravitreal bevacizumab and triamcinolone are both equally effective in reducing CSRT in early DME. After 6 months, rehabilitation of vision was comparable in both treatment arms, whereas at the final follow-up at month 12, BCVA was superior in the bevacizumab than in the triamcinolone sample. This may be related to cataract development following steroid treatment, as well as to substance-specific mechanisms within the angiogenic versus the inflammatory cascade.

The purpose of the study was to perform a detailed, quantitative protein analysis of the aqueous (AF) and vitreous fluids (VF) from human eyes with idiopathic epiretinal membranes (iERM). The complementary approaches of quantitative liquid chromatography mass spectrometry (LCMS) and multiplex protein assays were utilised to reveal the protein composition in ocular fluids of this retinal disorder. In a prospective clinical trial, AF and VF was collected during surgery from twenty four eyes corresponding to twenty four patients with iERM. VF and AF from eight patients were labelled with the 4-plex iTRAQ reagent and analysed by LCMS. Each iTRAQ 4-plex experiment consisted of the AH and VH from two patients. A total of 323 proteins were identified in the AF and VF from eyes with iERM. Grouping the proteins according to involvement in biological processes, showed that the majority were involved in the classical and alternative pathway of complement activation (n = 27), proteolysis (n = 26) and cell adhesion (n = 28). iTRAQ relative quantitation revealed minimal variation in the protein content between both ocular compartments with only 3.96% of the identified proteins significantly, differentially-expressed. Eight proteins were expressed at a higher level in the VF compared to the AF; and 4 proteins were expressed at a lower level in the VF compared to the AF. For the multiplex bead assays, 29 growth factors and cytokines were assessed in the AF and VF from 16 additional patients with iERM. The protein profile was shown to be similar between VF and AF for the majority of factors except PDGF-AA. This factor was expressed at a higher level in the VF compared to the AF. The data presented in this study revealed that the majority of the proteins identified by LCMS and multiplex bead assays were present in both ocular compartments in similar quantities. This study is a first step, ‘discovery phase’ towards revealing and quantitating the protein content in the aqueous and vitreous fluid in human eyes with iERM.

In a mental rotation task, children 5 and 6 years of age and adults had to decide as quickly as possible if a photograph of a hand showed a left or a right limb. The visually presented hands were left and right hands in palm or in back view, presented in four different angles of rotation. Participants had to give their responses with their own hands either in a regular, palms-down posture or in an inverted, palms-up posture. For both children and adults, variation of the posture of their own hand had a significant effect. Reaction times were longer the more awkward it was to bring their own hand into the position shown in the stimulus photograph. These results, together with other converging evidence, strongly suggest that young children's kinetic imagery is guided by motor processes, even more so than adults'.

Background and Purpose— There is considerable variability in the antiplatelet effects of the thienopyridine agent “clopidogrel.” We tested for an association of gene sequence variations in P2Y12 and occurrence of neurological adverse events in patients with symptomatic peripheral artery disease (PAD) during clopidogrel treatment. Methods— We studied 137 patients undergoing antiplatelet therapy with clopidogrel and 336 patients with aspirin for the occurrence of neurological events (ischemic stroke and/or carotid revascularization). Prevalence of 2 previously described exonic polymorphisms of the P2Y12 gene, 34C>T and 52G>T, was determined by polymerase chain reaction. Results— Genotype frequencies for mutated, heterozygous, and wild-type alleles for the 34C>T and the 52G>T polymorphisms were 9% (n=40), 44% (n=210), and 47% (n=223), and 4% (n=17), 27% (n=127), and 70% (n=329), respectively. During the median follow-up of 21 months, neurological events occurred in 8% of patients. In patients with aspirin therapy, neither polymorphism was associated with neurological events. However, in clopidogrel patients, carriers of at least one 34T allele had a 4.02-fold increased adjusted risk for neurological events compared with carriers of only 34C alleles (95% confidence interval, 1.08 to 14.9). Neither polymorphism was associated with all-cause mortality. Conclusions— In PAD patients, clopidogrel response variability exists, which may result in increased risk for cerebrovascular events. Sequence alterations of the target receptor gene represent one possible mechanism for clopidogrel failure. Whether identification of the 34C>T polymorphism as a contributor to this process could serve as risk stratification tool, an indicator for higher clopidogrel doses, or the use of alternate agents warrants further investigation.

Increasing evidence suggests that the visual analysis of other people's actions depends upon the observer's own body representation or schema. This raises the question of how differences in observers' body structure and schema impact their perception of human movement. We investigated the visual experiences of two persons born without arms, one with and the other without phantom sensations. These participants, plus six normally-limbed control observers, viewed depictions of upper limb movement under conditions of apparent motion. Consistent with previous results (Shiffrar M, Freyd JJ (1990) Psychol Sci 1:257), normally-limbed observers perceived rate-dependent paths of apparent human movement. Specifically, biologically impossible motion trajectories were reported at rapid display rates while biologically possible trajectories were reported at slow display rates. The aplasic individual with phantom experiences showed the same perceptual pattern as control participants, while the aplasic individual without phantom sensations did not. These preliminary results suggest that phantom experiences may constrain the visual analysis of the human body. These results further suggest that it may be time to move beyond the question of whether aplasic phantoms exist and instead focus on the question of why some people with limb aplasia experience phantom sensations while others do not. In this light, the current results suggest that somesthetic representations are not sufficient to define body schema. Instead, neural systems matching action observation, action execution and motor imagery likely contribute to the definition of body schema in profound ways. Additional research with aplasic individuals, having and lacking phantom sensations, is needed to resolve this issue.

We performed a multicenter case-control study to evaluate the impact of the glycoprotein 1b alpha (-5)T/C Kozak polymorphism on the risk of ischemic cerebrovascular events. The genetic analysis in 1399 patients (745 men; median age, 70 years; interquartile ratio, 58-78) and 1066 control subjects (549 men; median age, 47 years; interquartile ratio, 39-59) was carried out with mutagenically separated polymerase chain reaction. Homozygous C/C genotype carriers had a 3.5-fold increased risk for ischemic cerebrovascular events (95% confidence interval, 1.5-7.9, P = 0.003) over T/T or T/C genotype carriers together. The effect was independent of well-established atherosclerotic risk factors. Our findings could be explained by the reported gene dose effect of the Kozak polymorphism on the density of the glycoprotein 1b alpha/IX/V receptors on platelets. According to our data, the (-5)C Kozak allele may represent a candidate genetic susceptibility factor for ischemic cerebrovascular events.

Heme oxygenase-1 (HO-1) has been demonstrated to exert potent anti-oxidant and anti-inflammatory effects in the context of atherosclerotic vascular disease, and therefore was referred to as a potential vascular protective factor. A (GT)n dinucleotide repeat polymorphism in the HO-1 promoter has been shown to modulate HO-1 gene expression. Short ( or =25) repeat (class L) alleles after adjustment for potentially confounding factors. Genotype distributions of S/S, S/L and L/L in patients were 9.8% (n=39), 45.1% (n=180) and 45.1% (n=180), which was similar to the distribution in controls with 11.5% (n=46), 44.5% (n=177) and 44.0% (n=175). In the presence of vascular risk factors, the HO-1 genotype became functionally relevant: in patients without hyperlipidemia the S/S genotype exerted a protective effect on the development of ischaemic cerebrovascular events (OR 0.2; 95% CI 0.1-0.6), while this effect was no longer present in hyperlipidemic patients. Short (

Summary. A frequent polymorphism in the factor XIII (FXIII) A-subunit gene, leading to a Val to Leu amino acid exchange at position 34, suggested to affect clot stability, has been associated with a decreased risk for venous thromboembolism and myocardial infarction. Its role in the development of stroke is still under investigation. Ninety-four patients with primary arterial intracerebral haemorrhage (mean age ± standard deviation: 69 ± 14 years; 48 men, 46 women), 718 patients with ischaemic stroke (63 ± 14 years; 395 men, 323 women) and 369 healthy control subjects (59 ± 14 years; 299 men, 170 women) were analysed for FXIII Val34Leu. No differences in genotype distribution between all three groups were observed. Also, no significant differences in the genotype distribution were found between subgroups of patients stratified according to age, sex, aetiology, history of hypertension, antiplatelet or anticoagulant medication and other vascular risk factors. In contrast to previously reported findings in smaller collectives, our data suggest that an association of the FXIII Val34Leu polymorphism with a decreased risk of ischaemic stroke or an increased risk of intracerebral haemorrhage is highly unlikely. Thus, screening for the FXIII Val34Leu polymorphism will not contribute significantly to the risk prediction of cerebrovascular disease.

Purpose To compare choroidal thickness of different areas on swept-source optical coherence tomography (SSOCT) line and cube scans for their interchangeable use. Design Validity analysis. Methods SSOCT line and cube scans were obtained from 21 patients with various choroidal thicknesses. Subfoveal center point choroidal thickness, mean central millimeter choroidal thickness, and mean 6-mm-area choroidal thicknesses were obtained from both eyes by 2 independent graders in a reading center setting. Cross-correlations were performed using Passing and Bablok regression models. A 95% confidence interval of slope that included 1 was considered to indicate no significant difference. Average choroidal thickness of center point, Early Treatment Diabetic Retinopathy Study grid subfields, and total grid area of 6 mm on both scans and the correlation between different areas served as main outcome measures. Results No significant difference between line scans/corresponding subfields of cube scans (outer nasal 0.92–1.11, inner nasal 0.88–1.06, central 0.94–1.11, inner temporal 0.95–1.12, outer temporal 0.93–1.17). No significant difference between subfoveal center point measurement/mean of choroidal thickness in the central millimeter of cube scans (0.89–1.08). Significant difference of subfoveal center point measurement or mean of central millimeter area of cube scans to entire 6-mm area of cube scans (1.01–1.53 and 1.03–1.38). Conclusions Measurements on a single SSOCT horizontal line scan can represent the entire choroid but subfoveal center point measurements are only indicative for the central millimeter area. There is a consistent overestimation of choroidal thickness when trying to estimate overall choroidal thickness from any central measurement.

Purpose: To identify and quantify angiogenic and inflammatory cytokines in aqueous and vitreous humor in eyes with untreated uveal melanoma and to analyze clinicopathologic correlations. Methods: Intraocular fluid samples of patients (uveal melanoma aqueous n = 21, vitreous n = 34) and controls (cataract aqueous n = 41, vitreomacular traction aqueous n = 35, vitreous n = 36) were taken intraoperatively and analyzed using Luminex xMAP suspension array technology. Beadlyte kits were used for detection of 28 different cytokines. Results: Flt-3 ligand, interleukin (IL) 1α, IL-6, IL-8, interferon-γ inducible protein (IP)-10, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α, platelet-derived growth factor AA, and vascular endothelial growth factor were significantly elevated in aqueous and vitreous of melanoma eyes when compared with controls. Eotaxin was significantly elevated in aqueous, and IL-7 and RANTES were significantly elevated in vitreous samples of melanoma eyes. Interferon-γ inducible protein 10, macrophage inflammatory protein 1α (aqueous and vitreous), Flt-3 ligand, IL-6, IL-8, and MCP-1 (vitreous) correlated with tumor dimensions. Further correlations were found between infiltration of Bruch membrane and Flt-3 ligand, MCP-1 (aqueous and vitreous), IL-8, interferon-γ inducible protein 10, macrophage inflammatory protein 1α, and platelet-derived growth factor AA (vitreous). Analyzing 16 paired aqueous and vitreous melanoma samples, Flt-3 ligand, IL-7, interferon-γ inducible protein 10, MCP-1, and platelet-derived growth factor AA were significantly elevated in vitreous, and IL-1α and vascular endothelial growth factor in aqueous samples. Conclusion: A range of significantly elevated angiogenic, inflammatory, and chemotactic cytokines in eyes with uveal melanoma supports the link between inflammation and tumorigenesis.

The purpose of this study was to determine the concentrations of angiogenic and inflammatory markers in human eyes with diffuse diabetic macular edema before and during therapy with intravitreal bevacizumab and their association with disease activity.In a prospective clinical trial, 10 eyes of 10 consecutive patients with vision loss because of diabetic macular edema were compared with 10 eyes of 10 age-matched controls. Bevacizumab was administered at baseline; retreatments were given monthly according to disease activity. During a follow-up of 6 months, aqueous humor samples were taken each time intravitreal therapy was administered. A multiplex assay was used for measurement of 12 different growth factors and cytokines.Aqueous humor of eyes with diabetic macular edema demonstrated a significantly increased expression of monocyte chemoattractant protein-1 and interleukin-8 and higher, but not significant, levels of interleukin-6 and vascular endothelial growth factor. Intravitreal therapy with bevacizumab resulted in a significant decrease of vascular endothelial growth factor below physiologic levels. This change was not associated with clinical disease activity as measured by visual acuity and central retinal thickness.Eyes with diabetic macular edema showed a different profile of monocyte chemoattractant protein-1 and interleukin-8 as compared with controls. The intraocular vascular endothelial growth factor expression decreased significantly after the first intravitreal injection of bevacizumab; this reduction was prolonged by consecutive monthly retreatment.

SummaryOverexpression of plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor tyrosine kinase activity and thus favours insulin resistance and atherosclerotic vascular disease. Recent findings indicate that the minor variant K121Q in the PC-1 gene confers an increased risk for early myocardial infarction independent of other established risk factors. We hypothesized that genetic variants in PC-1 may also influence the risk for cerebrovascular disease.Therefore, we assessed the association of the PC-1 K121Q variant in the coding region and a polymorphism (G2906C) in the 3’ untranslated region of the PC-1 gene with the risk of stroke.We analyzed 1014 patients with a history of ischaemic stroke from the Vienna stroke registry and 1001 control individuals without vascular disease.Genotype frequencies of both genetic variants were similar in patients and controls in the total study population. By multivariate analysis, no interactions were observed between the PC-1 genotype and established vascular risk factors. However, the PC-1 2906C allele was significantly more frequent in patients who suffered from stroke before the age of 40 years. In these patients the risk for ischaemic stroke was increased fourfold.

In this study, we report a comparative and quantitative analysis by mass spectrometry of the protein content of aqueous humour from cataract (control) patients. In addition to protein profiling, the approach is layered with quantitative proteomics using the iTRAQ® methodology. Aqueous humour from ten clinically-matched patients was collected and depleted of albumin and immunoglobulin G. Pairs of patient material were pooled and divided into three aliquots for subsequent analysis by alternative proteomic approaches. Excluding keratin, trypsin, residual albumin and immunoglobulins, a total of 198 protein groups were identified across the entire study. Relative protein quantitation with iTRAQ® revealed that 88% of the proteins had a maximal ±2-fold differential regulation between 3 of the 4 labelled samples, indicating minimal variation. The identified proteins were categorised by gene ontology and one third of the proteins were annotated as extracellular. The major molecular functions of the proteins in aqueous humour are binding (protein, metal ion, heparin, and DNA) and inhibition of proteolytic activity. Complementary to molecular function, the predominant biological processes for the proteins in aqueous humour are assigned to inflammatory and immune responses, and transport.

At present, subthalamic nucleus (STN) stimulation is the preferred procedure for the amelioration of motor symptoms in medication refractory Parkinson's disease. Results are however impaired by negative impacts on mood, cognition, incentive, and social judgment. Alternative targets are therefore explored. We describe a case with stimulation of subthalamic fibre tracts that showed clear improvement of cognitive and social abilities. Avoiding the STN may be advantageous in progressive Parkinson's disease to avoid non-motor complications and enhance quality of life.

The aim of the study was to evaluate functional and anatomical changes after intravitreal bevacizumab (Avastin) in eyes with persistent macular oedema secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).Twenty-nine consecutive eyes with macular oedema secondary to BRVO (21 eyes) or CRVO (eight eyes) were included in a prospective clinical trial. Eyes were treated with three initial intravitreal bevacizumab injections of 1 mg at a monthly interval. Retreatment was based on central retinal thickness (CRT) based on optical coherence tomography. If continuous injections were indicated up to month 6, the dose was increased to 2.5 mg.After 12 months of follow-up, mean visual acuity increased from 50 letters (20/100) at baseline to 66 letters (20/50(+1); +16 letters; p0.001) at month 12 and CRT decreased from 558 mum at baseline to 309 mum at month 12 (-249 mum; p0.001). Patients received a mean of eight out of 13 possible injections. No drug-related systemic or ocular side effects following intravitreal bevacizumab treatment were observed. Fluorescein angiography revealed no progression of avascular areas.Intravitreal therapy using bevacizumab appears to be a safe and effective treatment in patients with macular oedema secondary to retinal vein occlusion. However, the main limitations of this treatment modality are its short-term effectiveness and high recurrence rate.

To investigate concentrations of growth factors and inflammatory cytokines in eyes with neovascular age-related macular degeneration (AMD) before and during therapy with intravitreal ranibizumab and to identify associations with disease activity.Prospective clinical trial.Twenty-eight eyes of patients with neovascular AMD were compared with 28 eyes of age-matched patients with cataract as control.Ranibizumab was administered intravitreously once at baseline, and retreatments were given at monthly visits if optical coherence tomography (OCT) revealed macular edema or vision loss had occurred. Aqueous humor samples were taken each time intravitreal interventions were performed. Follow-up was 12 months. Luminex (Luminex Inc., Austin, TX) multiplex assays were used for measurement of 29 different growth factors and cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).Differences in the concentrations of growth factors and inflammatory cytokines in eyes with neovascular AMD compared with control eyes and the influence of therapy with intravitreal ranibizumab.A significantly increased expression of VEGF (P = 0.033) and a significantly decreased expression of PDGF (P = 0.038) were measured in the aqueous humor of eyes with neovascular AMD. Furthermore, a significant decrease of VEGF (P0.001) was observed after intravitreal injection of ranibizumab along with significant changes in visual acuity and central retinal thickness (P = 0.039 and P0.001). During follow-up with a flexible regimen, a correlation was identified between increased VEGF levels and persistent or recurrent macular edema. Changes in PDGF levels were strongly associated with alterations in VEGF concentration.Vascular endothelial growth factor and PDGF-AA seemed to be associated with disease activity of neovascular AMD. Intravitreal anti-angiogenic treatment with ranibizumab resulted in significantly decreased intraocular VEGF expression below physiologic levels compared with controls. This effect was measurable as long as 4 weeks after each injection and was prolonged by consecutive retreatment. With recurrence after discontinuation of treatment, VEGF levels increased again.

The purpose of the present study was to examine the impact of the congenital absence of one hand on cortical organization of the sensorimotor cortex (S1/M1). We investigated the tongue representation in S1/M1 in nine participants with normally developed limbs, comprising the control group, and in eight persons with a congenitally completely missing hand (i.e. unilateral hand amelia). All participants were examined by fMRI while performing horizontal tongue movements. The significantly activated clusters covering S1/M1 in both hemispheres were analyzed with respect to the number and intensity of activated voxels, as well as the location of the activation. In the right-handed control group, the number of activated voxels was significantly higher in the left as compared to the right hemisphere demonstrating a clear left hemispheric motor dominance for horizontal tongue movements. In the amelic individuals, no such hemispheric lateralization effect was observed. The neural activation pattern underlying tongue movement, however, was enlarged and displaced in the hemisphere contralateral to the missing limb when compared to the respective motor non-dominant, right hemisphere of the control group participants. The present findings suggest that congenital absence of one hand leads to an appreciably altered topological organization of S1/M1 consisting of an enlargement of the tongue representation and a shift towards the "hand" area which, however, had never received any input from a hand.

Purpose To evaluate ultrastructural changes in low-density lipoprotein (LDL) receptor knockout (R(-/-)) mice consuming different diets as a potential model of Bruch membrane (BM) lipoidal degeneration and to determine the distribution and concentration of VEGF(164) in this mouse model. Methods Eight-month-old LDL-R(-/-) mice and wild-type controls were fed a standard or a high-fat diet. Animals were killed, and plasma cholesterol levels were determined. Using transmission electron microscopy, BM thickness, lipid vacuole size, and retinal pigment epithelial height were measured. Degenerative alterations of choriocapillaris, RPE, and photoreceptors were described and graded. Using light microscopy, VEGF(164) immunohistoreactivity was graded. Neutral lipids were detected with oil red O. Results Choriocapillaris, BM, RPE, and photoreceptors of standard diet control animals showed a regular architecture. LDL-R(-/-) mice fed a standard diet showed more diffuse focal alterations than control mice fed a high-fat diet. Within the choriocapillaris, the basement membrane was thickened, endothelial fenestration numbers were reduced, and lumina narrowed. BM thickness increased with a loss of regular structure. With pronounced BM degeneration, lipid inclusions increased in number and size. A decrease in retinal pigment epithelial cell height was accompanied by signs of intracellular degeneration. Photoreceptor outer segments showed focal degeneration and the formation of vacuoles. All these changes were most pronounced in LDL-R(-/-) mice after a high-fat diet. VEGF(164) was found exclusively in the choriocapillaris, positively correlating with the amount of lipid accumulation in BM. Conclusions Feeding a standard or a high-fat diet to LDL-R(-/-) mice and wild-type controls resulted in a reproducible model of graded BM lipoidal degeneration that resembled alterations in aged human eyes. This model provides a valuable tool for investigating biological responses to lipoidal degeneration.

Execution and imagination of movement activate distinct neural circuits, partially overlapping in premotor and parietal areas, basal ganglia and cerebellum. Can long-term deafferented/deefferented patients still differentiate attempted from imagined movements? The attempted execution and motor imagery network of foot movements have been investigated in nine chronic complete spinal cord-injured (SCI) patients using fMRI. Thorough behavioral assessment showed that these patients were able to differentiate between attempted execution and motor imagery. Supporting the outcome of the behavioral assessment, fMRI disclosed specific patterns of activation for movement attempt and for motor imagery. Compared with motor execution data of healthy controls, movement attempt in SCI patients revealed reduced primary motor cortex activation at the group level, although activation was found in all single subjects with a high variability. Further comparisons with healthy subjects revealed that during attempt and motor imagery, SCI patients show enhanced activation and recruitment of additional regions in the parietal lobe and cerebellum that are important in sensorimotor integration. These findings reflect central plastic changes due to altered input and output and suggest that SCI patients may require additional cognitive resources to perform these tasks that may be one and the same phenomenon, or two versions of the same phenomenon, with quantitative differences between the two. Nevertheless, the retained integrity of movement attempt and motor imagery networks in SCI patients demonstrates that chronic paraplegics can still dispose of the full motor programs for foot movements and that therefore, attempted and imagined movements should be integrated in rehabilitative strategies.

We compared motor imagery performance of normally limbed individuals with that of individuals with one or both hands missing since birth (i.e., hand amelia). To this aim, 14 unilaterally and 2 bilaterally amelic participants performed a task requiring the classification of hands depicted in different degrees of rotation as either a left or a right hand. On the same task, 24 normally limbed participants recapitulated previously reported effects; that is, that the hand motor dominance and, more generally, a lifelong use of hands are important determinants of left–right decisions. Unilaterally amelic participants responded slower to hands corresponding to their absent, compared with their existing, hand. Moreover, left and right hand amelic participants showed prolonged reaction times to hands (whether left or right) depicted in unnatural orientations compared with natural orientations. Among the bilateral amelics, the individual with phantom sensations, but not the one without, showed similar differentiation. These findings demonstrate that the visual recognition of a hand never physically developed is prolonged, but still modulated by different rotation angles. They are further compatible with the view that phantom limbs in hand amelia may constrain motor imagery as much as do amputation phantoms. (JINS, 2008,14, 81–89.)

Objective: To evaluate efficacy and safety of intravitreal bevacizumab (Avastin) in eyes with macular oedema secondary to central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). Methods: Twenty-eight consecutive patients (28 patients, 29 eyes, 8 CRVO, 21 BRVO) were enrolled in the study. Three intravitreal injections of 1 mg bevacizumab (0.04 ml) were administered at 4-week intervals; further retreatment was based on optical coherence tomography (OCT) findings. Follow-up examinations were done at days 1, 7 and 28 and at monthly intervals thereafter. Results: Mean baseline central retinal thickness (CRT) in OCT was 558 µm (range 353–928 µm) and mean BCVA was 20/100. One day after the first injection, CRT significantly decreased to 401 μm (p −2 (p Conclusion: Intravitreal injections of bevacizumab appear to be a safe and effective therapy in the treatment of macular oedema secondary to retinal vein occlusion.

Data concerning genetic factors that may influence the risk of primary intracerebral hemorrhage (PICH) are scarce. One previous study, indicated that the carriers of the (-323)Ins allele of the coagulation factor VII (FVII) have an increased risk of PICH. Another recent study, tested the effect of apolipoprotein E. We analyzed, whether the (-401)G --> T polymorphism, which is in linkage disequilibrium (LD) with the 10-bp Ins/Del polymorphism at position (-323), or the (-402)G --> A polymorphisms of the FVII gene are associated with an increased risk for PICH. We performed a small case-control study in 85 patients with PICH and in 85 healthy control subjects. To each patient a control was individually matched for age, gender, and hypertension. We did not find any significant differences in allele frequencies for the A allele of the FVII (-402)G --> A polymorphism (0.25 vs. 0.25; P = 0.900, OR = 1, ns.) nor for the T Allele of the FVII (-401)G --> T polymorphism (0.09 vs. 0.12; P = 0.480, OR = 1.38, ns.). The analysis of haplotype distributions did not reveal significant differences. Our results do not support the hypothesis that the investigated polymorphisms in the FVII gene are significantly associated with the risk for PICH.

Background and Purpose— A Thr>Pro polymorphism at codon 715 in the coding region of the P-selectin gene has recently been described. Individuals carrying the Pro715 allele were reported to have a reduced risk of myocardial infarction. A possible association of this polymorphism with the risk of ischemic stroke is currently under discussion. Methods— We investigated the prevalence of the 715 Thr>Pro polymorphism in 450 patients aged younger than 60 years with ischemic stroke or transient ischemic attack and in 450 controls without vascular disease matched for age and gender. We also investigated possible interactions of the polymorphism with other vascular risk factors, stroke severity and stroke etiology. Results— The distribution of the two allelic variants of the 715Thr>Pro polymorphism did not differ significantly between patients and control subjects (78% versus 81% for Thr/Thr, 21% versus 18% for Thr/Pro and 1% versus 1% for Pro/Pro in patients and controls, respectively; adjusted odds ratio for carriers of the C allele: 1.0 [0.8 to 1.2; P =0.695]). We found no significant interaction of this polymorphism with vascular risk factors, stroke severity, or stroke etiology. Conclusions— Our study supports results from previous investigation showing that the 715Thr>Pro polymorphism of the P-selectin gene was not associated with a risk or clinical characteristics of ischemic stroke.

PURPOSE The aim of the study was to compare intravitreal cytokines and chemokines to clinical parameters in patients with rhegmatogenous retinal detachment (RRD). METHODS In this prospective study vitreous samples were taken undiluted from 60 patients with RRD and 20 age-matched controls with idiopathic epiretinal membranes at the beginning of primary vitrectomy. The following clinical parameters were assessed from RRD patients prior to surgery: number of quadrants detached, RD height, lens status, symptom duration, and refractive power. Concentrations of 40 different proteins in the vitreous of RRD eyes were measured by multiplex protein array, compared with controls and correlated to clinical parameters. RESULTS Ten cytokines and chemokines were significantly upregulated in the vitreous of RRD eyes compared with controls (tissue inhibitors of metalloproteinases [TIMP]-1 and -2, macrophage inflammatory protein [MIP]-1α, monocyte chemoattractant protein [MCP]-1, IL-6, and -8, inducible protein (IP)-10, brain-derived neurotrophic factor [BDNF], TGFβ-3, and platelet-derived growth factor [PDGF]-AB/BB). Linear regression analysis revealed that IL-8 and TGFβ-3 increased with the number of retinal quadrants detached, while TIMP-1 rose in eyes with greater RD heights. Concentrations of IP-10 and myeloperoxidase (MPO) peaked in eyes with two or more quadrants detached, while TIMP-2 was highest expressed in the vitreous of eyes with great RD height. In pseudophakic eyes with higher detachment height levels of vascular cell adhesion molecule (VCAM)-1 were significantly increased, while neural cell adhesion molecule (NCAM) was decreased in pseudophakic patients with shallow RD height. CONCLUSIONS Extent of RRD and lens status significantly influence intravitreal proinflammatory, profibrotic, and proapoptotic protein expression. These data contribute to the fundamental understanding of pathophysiological mechanisms in RRD and may serve as a basis for development of adjunct therapeutics to facilitate functional restoration.

Background: Coagulation factor VII (FVII) plays an important role in the activation of blood coagulation and clot formation. Recent studies have provided evidence for an association between common polymorphic markers in the FVII gene and plasma FVII concentrations. The 353R>Q sequence variation, and 3 common sequence variations in the promoter of the FVII gene—the 10-bp insertion/deletion at position −323 and the −401G>T and −402G>A sequence variations—are well-known determinants of circulating FVII concentrations. Methods: To clarify the role of these sequence variations in the pathogenesis of ischemic stroke, we performed a case–control study with 242 patients with ischemic stroke before the age of 60 years and 239 healthy controls. Results: The −323 insertion/deletion and the 353R>Q and −401G>T sequence variations were in strong linkage disequilibrium, and the resulting haplotypes occurred with equal frequencies in patients and controls. The variant form of FVII (−402G>A) occurred only in combination with the common (wild-type) sequences at all other loci. This haplotype was more frequent in patients than in healthy controls (28% vs 22%). The difference in the prevalence of carriers of this haplotype among patients and controls was statistically significant (P = 0.03; odds ratio = 1.6; 95% confidence interval, 1.1–2.6). Conclusion: According to our results, the FVII −402A allele seems to increase the risk of early ischemic cerebrovascular events, whereas the 353R>Q, G−401T, and −323ins/del sequence variations, which are in close linkage disequilibrium, apparently do not influence the risk of stroke.

Ischemic stroke is a multifactorial disease and a major cause of death and disability throughout the world. Acquired risk factors (e.g., hypertension, cigarette smoking, and diabetes mellitus) account only for ∼69% of the population-attributable risk. Thus, it is likely that other, as yet unidentified, factors contribute to the development of stroke (1). Both epidemiologic and animal-based studies suggest that alterations in a variety of candidate genes, including hemostatic genes, genes controlling homocysteine metabolism, the gene that encodes angiotensin-converting enzyme, and the gene that encodes endothelial nitric oxide synthase, are important in the pathogenesis of ischemic stroke (2)(3). Apparently the genetic influences are polygenic. In addition, ischemic stroke comprises many different phenotypes. According to previous studies, genetic factors seem to have different effects depending on stroke etiology [e.g., lacunar stroke and polymorphisms in the gene encoding interleukin-6 (4)]. In combination with acquired risk factors such as smoking, the presence of one or a combination of several predisposing genes may favor the occurrence of stroke. Cytochrome P-450 (CYP) 2C9 belongs to a large family of heme-containing enzymes that catalyze the oxidation of various drugs and endogenous substrates. CYP2C9 is produced in the liver, is responsible for 50% of the epoxygenase activity in the human liver, and metabolizes a wide variety of clinically important drugs (5). Interestingly, CYP2C isoforms also seem to play a role in the regulation of vascular tone. CYP2C9 is expressed in the endothelium and, via production of endothelium-derived hyperpolarizing factor (EDHF), may cause vasorelaxation as a result of hyperpolarization of vascular smooth muscle cells by activation of Ca2+-activated K+ channels (6). EDHF production seems to be inhibited by NO and/or prostacyclin and has been described as an important regulator of vascular tone under certain pathologic conditions and in certain vascular beds, such as …

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the regulation of fibrinolysis and extracellular matrix turnover. PAI-1 4G/5G insertion/deletion polymorphism in the PAI-1 promoter region has been shown to modulate PAI-1 plasma levels. We investigated the relationship between this polymorphism and the prevalence of diabetic nephropathy and retinopathy in patients with type 2 diabetes in the Austrian population. PATIENTS AND METHODS: 147 consecutive patients with type 2 diabetes mellitus (96 men, 51 women; median age, 65 years; IQR, 59–71) were analyzed for the PAI-1 4G/5G genotype. RESULTS: The genotype distribution in the individuals tested was as follows: 17% (n = 25) 5G/5G, 54% (n = 80) 4G/5G, and 29% (n = 42) 4G/4G. Patients homozygous for allele 4G had a significantly higher risk of diabetic proliferative retinopathy than patients without signs of diabetic retinopathy or nonproliferative retinopathy (OR, 7.3; 95% CI, 1.4–38.8; P = 0.02). No significant associations were observed between the PAI-1 genotype and the presence of albuminuria. CONCLUSION: According to our results, diabetic proliferative retinopathy might be associated with the prevalence of PAI-1 genotype 4G/4G.

Cytochrome P-450 (CYP) genes encode for membrane-bound, heme-containing enzymes that catalyze the oxidation of various drugs and endogenous substrates such as vitamin D, steroids, or fatty acids, including arachidonic acid (AA). CYP enzymes of the P-450 2C9 subfamily are produced in the liver, are responsible for 50% of the epoxygenase activity in human liver, and metabolize a wide variety of clinically important drugs, including losartan, torsemide, and S -warfarin (1). Furthermore, CYP2C9 may also play a role in the regulation of vascular tone. In addition to nitric oxide (NO) and prostacyclin, endothelial cells synthesize and release endothelium-derived hyperpolarizing factor (EDHF), which causes hyperpolarization of underlying vascular smooth muscle cells via activation of Ca2+-activated K+ channels (2). EDHF has been described as an important regulator of vascular tone under certain pathologic conditions and in certain vascular beds, such as the coronary microcirculation (3). Interestingly, EDHF production seems to be inhibited by NO and/or prostacyclin. There is now compelling evidence that the hyperpolarizing factor produced by coronary arteries is a CYP epoxygenase-derived metabolite of AA. Recently, it has been shown that decreased concentrations of CYP2C attenuate EDHF-mediated vascular response in porcine coronary artery endothelial cells (4). This effect appears to be directly attributable to the regulation of an enzyme homologous to CYP2C9 and the generation of the CYP metabolite 11,12-epoxyeicosatrienoic acid (5). Changes in the amino acid sequence of CYP2C9 can affect both the activity and substrate specificity of CYP2C9. Previously, three alleles were identified in the Caucasian population: CYP2C9*1 , CYP2C9*2 , and CYP2C9*3 . The CYP2C9*1 allele encodes the wild-type protein, and the CYP2C9*2 allele contains a C-to-T transition, leading to substitution of cysteine by arginine at amino acid position 144. The CYP2C9*3 allele is defined by an A-to-C nucleotide substitution that leads to an exchange of …

Heme oxygenase-1 (HO-1) has been demonstrated to exert potent anti-oxidant and anti-inflammatory effects in the context of atherosclerotic vascular disease, and therefore was referred to as a potential vascular protective factor. A (GT)n dinucleotide repeat polymorphism in the HO-1 promoter has been shown to modulate HO-1 gene expression. Short (25) GT repeats were associated with HO-1 up-regulation, and therefore may influence susceptibility to ischaemic vascular events. We investigated the association of HO-1 repeat length with the risk of cerebrovascular events in a case control study and assessed possible interrelations with vascular risk factors. We determined the number of GT repeats in the HO-1 promoter in 399 patients with ischaemic cerebrovascular events and 398 healthy controls and compared the frequencies of short (25) repeat (class S) and long (or =25) repeat (class L) alleles after adjustment for potentially confounding factors. Genotype distributions of S/S, S/L and L/L in patients were 9.8% (n=39), 45.1% (n=180) and 45.1% (n=180), which was similar to the distribution in controls with 11.5% (n=46), 44.5% (n=177) and 44.0% (n=175). In the presence of vascular risk factors, the HO-1 genotype became functionally relevant: in patients without hyperlipidemia the S/S genotype exerted a protective effect on the development of ischaemic cerebrovascular events (OR 0.2; 95% CI 0.1-0.6), while this effect was no longer present in hyperlipidemic patients. Short (25 GT) repeats in the HO-1 gene promoter confer a reduced risk for cerebrovascular events in individuals with normal plasma lipid levels. This may explain controversial findings in different populations.

A frequent polymorphism in the factor XIII (FXIII) A-subunit gene, leading to a Val to Leu amino acid exchange at position 34, suggested to affect clot stability, has been associated with a decreased risk for venous thromboembolism and myocardial infarction. Its role in the development of stroke is still under investigation. Ninety-four patients with primary arterial intracerebral haemorrhage (mean age +/- standard deviation: 69 +/- 14 years; 48 men, 46 women), 718 patients with ischaemic stroke (63 +/- 14 years; 395 men, 323 women) and 369 healthy control subjects (59 +/- 14 years; 299 men, 170 women) were analysed for FXIII Val34Leu. No differences in genotype distribution between all three groups were observed. Also, no significant differences in the genotype distribution were found between subgroups of patients stratified according to age, sex, aetiology, history of hypertension, antiplatelet or anticoagulant medication and other vascular risk factors. In contrast to previously reported findings in smaller collectives, our data suggest that an association of the FXIII Val34Leu polymorphism with a decreased risk of ischaemic stroke or an increased risk of intracerebral haemorrhage is highly unlikely. Thus, screening for the FXIII Val34Leu polymorphism will not contribute significantly to the risk prediction of cerebrovascular disease.

Purpose To investigate concentrations of growth factors and inflammatory cytokines in eyes with central (CRVO) and branch (BRVO) retinal vein occlusion before and during therapy with bevacizumab and to identify associations with disease activity. Methods In a prospective clinical trial, 13 eyes of patients with CRVO (n = 5) or BRVO (n = 8) were included. Bevacizumab was administered intravitreously at baseline and months 1 and 2. Retreatments were given at monthly visits if OCT showed edema or when vision loss occurred. Aqueous humor samples were taken each time injections were performed. Follow-up was 15 months. Samples from patients with cataract served as the control. Multiplex bead assays were used for measurement of 28 growth factors and cytokines. Results During therapy with bevacizumab, VEGF levels were reduced to below detection in the first 2 months. Whenever criteria for retreatment were met, VEGF was measurable again. The decrease in VEGF was associated with a decrease in central retinal thickness (CRT) and improvement in visual acuity (VA). Significantly increased concentrations of VEGF, IL-6, IL-8, IP-10, MCP-1, and PDGF-AA were observed in aqueous humor samples of patients with CRVO compared with the control samples. Conclusions VEGF levels were significantly elevated in patients with CRVO compared with control subjects. Intravitreal injections of bevacizumab resulted in a substantial decrease of VEGF under physiologic levels and remained low under the loading dose of three consecutive monthly retreatments. Macular edema was related to VEGF levels in the aqueous humor.