Corneal Toxicity Associated With Belantamab Mafodotin Is Not Restricted to the Epithelium: Neuropathy Studied With Confocal Microscopy.

PURPOSE: 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. DESIGN: Retrospective case series. METHODS: 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. RESULTS: 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/mm2, 19.49 ± 12.34/mm2, and 11.8 ± 3.74mm/mm2 respectively, showed severe fiber fragmentation during follow-up, and an observed complete loss of the SNP at the end of follow-up in all eyes. CONCLUSIONS: This study is the first to illustrate neurotoxic effects of belamaf on the human cornea.

Choroidal Line Scan Measurements in Swept-Source Optical Coherence Tomography as Surrogates for Volumetric Thickness Assessment.

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.

Extent of Detached Retina and Lens Status Influence Intravitreal Protein Expression in Rhegmatogenous Retinal Detachment.

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], TGFß-3, and platelet-derived growth factor [PDGF]-AB/BB). Linear regression analysis revealed that IL-8 and TGFß-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.

Quantitative proteomics of aqueous and vitreous fluid from patients with idiopathic epiretinal membranes.

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.

Intraocular activation of angiogenic and inflammatory pathways in uveal melanoma.

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.

Proteomic analysis of human cataract aqueous humour: Comparison of one-dimensional gel LCMS with two-dimensional LCMS of unlabelled and iTRAQ®-labelled specimens.

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.

Preserved cognition after deep brain stimulation (DBS) in the subthalamic area for Parkinson's disease: a case report.

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.

Angiogenic and inflammatory markers in the intraocular fluid of eyes with diabetic macular edema and influence of therapy with bevacizumab.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab.

PURPOSE: 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. DESIGN: Prospective clinical trial. PARTICIPANTS AND CONTROLS: Twenty-eight eyes of patients with neovascular AMD were compared with 28 eyes of age-matched patients with cataract as control. METHODS: 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). MAIN OUTCOME MEASURES: 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. RESULTS: 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 (P<0.001) was observed after intravitreal injection of ranibizumab along with significant changes in visual acuity and central retinal thickness (P = 0.039 and P<0.001). 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. CONCLUSIONS: 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.

Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab.

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.

Sensorimotor tongue representation in individuals with unilateral upper limb amelia.

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.

Ultrastructural changes in a murine model of graded Bruch membrane lipoidal degeneration and corresponding VEGF164 detection.

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.

Mental rotation of congenitally absent hands.

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.

Preservation of motor programs in paraplegics as demonstrated by attempted and imagined foot movements.

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.

The Thr715Pro polymorphism of the P-selectin gene is not associated with ischemic stroke risk.

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.

Factor VII gene haplotypes and risk of ischemic stroke.

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.

Motor processes in children's imagery: the case of mental rotation of hands.

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'.

Association of a functional polymorphism in the clopidogrel target receptor gene, P2Y12, and the risk for ischemic cerebrovascular events in patients with peripheral artery disease.

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.

Hand movement observation by individuals born without hands: phantom limb experience constrains visual limb perception.

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.