CNS cell distribution and axon orientation determine local spinal cord mechanical properties.

Mechanical signaling plays an important role in cell physiology and pathology. Many cell types, including neurons and glial cells, respond to the mechanical properties of their environment. Yet, for spinal cord tissue, data on tissue stiffness are sparse. To investigate the regional and direction-dependent mechanical properties of spinal cord tissue at a spatial resolution relevant to individual cells, we conducted atomic force microscopy (AFM) indentation and tensile measurements on acutely isolated mouse spinal cord tissue sectioned along the three major anatomical planes, and correlated local mechanical properties with the underlying cellular structures. Stiffness maps revealed that gray matter is significantly stiffer than white matter irrespective of directionality (transverse, coronal, and sagittal planes) and force direction (compression or tension) (K(g) = ∼ 130 P(a) vs. K(w) = ∼ 70 Pa); both matters stiffened with increasing strain. When all data were pooled for each plane, gray matter behaved like an isotropic material under compression; however, subregions of the gray matter were rather heterogeneous and anisotropic. For example, in sagittal sections the dorsal horn was significantly stiffer than the ventral horn. In contrast, white matter behaved transversely isotropic, with the elastic stiffness along the craniocaudal (i.e., longitudinal) axis being lower than perpendicular to it. The stiffness distributions we found under compression strongly correlated with the orientation of axons, the areas of cell nuclei, and cellular in plane proximity. Based on these morphological parameters, we developed a phenomenological model to estimate local mechanical properties of central nervous system (CNS) tissue. Our study may thus ultimately help predicting local tissue stiffness, and hence cell behavior in response to mechanical signaling under physiological and pathological conditions, purely based on histological data.The authors thank the CECAD Imaging Facility (and their staff members), Andreas Christ, Jochen Guck, Jolanta Kozlowski, Ryan MacDonald, Graham Sheridan, and Alex Winkel for helpful discussions and/or technical support. This work was supported by Köln Fortune Program/Faculty of Medicine, University of Cologne (Fellowship to D.E.K.), German National Academic Foundation (Scholarship to D.E.K.), Herchel Smith Foundation (Fellowship to E.M.), DAAD-PROMOS-Program (Scholarship to J.H.), Deutsche Forschungsgemeinschaft (grant KU2760/2-1 to S.K.), UK Medical Research Council (Career Development Award to K.F.), and the Human Frontier Science Program (Young Investigator Grant to K.F.).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.bpj.2015.03.03

Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations

Association of ocular blood flow and contrast sensitivity in normal tension glaucoma

Purpose!#!To investigate the relationship of ocular blood flow (via arteriovenous passage time, AVP) and contrast sensitivity (CS) in healthy as well as normal tension glaucoma (NTG) subjects.!##!Design!#!Mono-center comparative prospective trial METHODS: Twenty-five NTG patients without medication and 25 healthy test participants were recruited. AVP as a measure of retinal blood flow was recorded via fluorescein angiography after CS measurement using digital image analysis. Association of AVP and CS at 4 spatial frequencies (3, 6, 12, and 18 cycles per degree, cpd) was explored with correlation analysis.!##!Results!#!Significant differences regarding AVP, visual field defect, intraocular pressure, and CS measurement were recorded in-between the control group and NTG patients. In NTG patients, AVP was significantly correlated to CS at all investigated cpd (3 cpd: r =  - 0.432, p< 0.03; 6 cpd: r =  - 0.629, p< 0.0005; 12 cpd: r =  - 0.535, p< 0.005; and 18 cpd: r =  - 0.58, p< 0.001), whereas no significant correlations were found in the control group. Visual acuity was significantly correlated to CS at 6, 12, and 18 cpd in NTG patients (r =  - 0.68, p< 0.002; r =  - 0.54, p< .02, and r =  - 0.88, p< 0.0001 respectively), however not in healthy control patients. Age, visual field defect MD, and PSD were not significantly correlated to CS in in the NTG group. MD and PSD were significantly correlated to CS at 3 cpd in healthy eyes (r = 0.55, p< 0.02; r =  - 0.47, p< 0.03).!##!Conclusion!#!Retinal blood flow alterations show a relationship with contrast sensitivity loss in NTG patients. This might reflect a disease-related link between retinal blood flow and visual function. This association was not recorded in healthy volunteers

Acute Effect of Hypervolemic Hemodilution on Retrobulbar Hemodynamics in Anterior Ischemic Optic Neuropathy

Purpose. Ischemic ocular disorders may be treated by hypervolemic hemodilution. The presumed therapeutic benefit is based on a volume effect and improved rheological factors. The aim was to investigate the acute effect of intravenous hydroxyethyl starch on retrobulbar hemodynamics in patients with nonarteritic anterior ischemic optic neuropathy (NAION). Methods. 24 patients with acute NAION were included. Retrobulbar hemodynamics were measured using color Doppler imaging before and 15 min after intravenous infusion of 250 cc 10% hydroxyethyl starch (HES). Peak systolic velocity (PSV), end diastolic velocity (EDV), and Pourcelot’s resistive index (RI) were measured in the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (PCAs). Results. After infusion of HES blood flow velocities significantly increased in the CRA (PSV from 7.53±2.33 to 8.32±2.51  (p<0.001); EDV from 2.16±0.56 to 2.34±0.55  (p<0.05)) and in the PCAs (PSV from 7.18±1.62 to 7.56±1.55  (p<0.01); EDV from 2.48±0.55 to 2.66±0.6 cm/sec (p<0.01)). The RI of all retrobulbar vessels remained unaffected. Blood pressure and heart rate remained unchanged. Conclusions. Hypervolemic hemodilution has an acute effect on blood flow velocities in the CRA and PCAs in NAION patients. Increased blood flow in the arteries supplying the optic nerve head may lead to a better perfusion in NAION patients. This trial is registered with DRKS00012603

Transplantation of PEDF-transfected pigment epithelial cells inhibits corneal neovascularization in a rabbit model

Background: The purpose of this study was to investigate the effect of recombinant pigment epithelium-derived factor (rPEDF), secreted by ARPE-19 cells transfected with the human PEDF gene and transplanted subconjunctivally in normal and in rabbits in which corneal neovascularization was elicited by a chemical burn. Methods: Twenty grey Chinchilla Bastard rabbits were randomly assigned to four groups; neovascularization was induced in groups A, B, and C by alkali cauterization. Seven days later, group A received no cell implantation, non-transfected ARPE-19 cells were implanted subconjunctivally in group B, and PEDF-transfected ARPE-19 cells were implanted subconjunctivally in groups C and D (non-cauterized). In-vivo rPEDF secretion was analyzed by immunoblotting, and ELISA of extracts of conjunctival tissue samples taken at different time points. Digital photographs acquired on days 7, 14, and 21 after cauterization were evaluated for lead vessel length, vascular invasion area, and overall neovascularization rate. Results: At days 14 and 21 after cauterization, significant differences were observed between groups A, B, and C in lead vessel length (day 21: 5.91 ± 0.45, 5.11 ± 1.22, 3.79 ± 0.59mm, repectively), vascular invasion area (day 21: 35.5 ± 8.65, 34.86 ± 4.92, 19.2 ± 5.03mm2 respectively), and rate of corneal neovascularization. Compared to controls, neovascularization was reduced by 37.5% on day 14 and 47% on day 21. Analysis of conjunctival tissue extracts showed that rPEDF was secreted by the transplanted PEDF-transfected cells. Conclusion: Subconjunctivally transplanted, PEDF-transfected ARPE-19 cells secrete rPEDF, which inhibits the corneal neovascularization elicited by alkali cauterization

Transplantation of PEDF-transfected pigment epithelial cells inhibits corneal neovascularization in a rabbit model

The purpose of this study was to investigate the effect of recombinant pigment epithelium-derived factor (rPEDF), secreted by ARPE-19 cells transfected with the human PEDF gene and transplanted subconjunctivally in normal and in rabbits in which corneal neovascularization was elicited by a chemical burn

Does hemispheric vascular regulation differ significantly in glaucoma patients with altitudinal visual field asymmetry? A single-center, prospective study

Purpose!#!Vascular risk factors and ocular perfusion are heatedly discussed in the pathogenesis of glaucoma. The retinal vessel analyzer (RVA, IMEDOS Systems, Germany) allows noninvasive measurement of retinal vessel regulation. Significant differences especially in the veins between healthy subjects and patients suffering from glaucoma were previously reported. In this pilot-study we investigated if localized vascular regulation is altered in glaucoma patients with altitudinal visual field defect asymmetry.!##!Methods!#!15 eyes of 12 glaucoma patients with advanced altitudinal visual field defect asymmetry were included. The mean defect was calculated for each hemisphere separately (-20.99 ± 10.49 profound hemispheric visual field defect vs -7.36 ± 3.97 dB less profound hemisphere). After pupil dilation, RVA measurements of retinal arteries and veins were conducted using the standard protocol. The superior and inferior retinal vessel reactivity were measured consecutively in each eye.!##!Results!#!Significant differences were recorded in venous vessel constriction after flicker light stimulation and overall amplitude of the reaction (p &amp;lt; 0.04 and p &amp;lt; 0.02 respectively) in-between the hemispheres. Vessel reaction was higher in the hemisphere corresponding to the more advanced visual field defect. Arterial diameters reacted similarly, failing to reach statistical significance.!##!Conclusion!#!Localized retinal vessel regulation is significantly altered in glaucoma patients with asymmetric altitudinal visual field defects. Veins supplying the hemisphere concordant to a less profound visual field defect show diminished diameter changes. Vascular dysregulation might be particularly important in early glaucoma stages prior to a significant visual field defect

Intraocular lens power calculation for plus and minus lenses in high myopia using partial coherence interferometry

Purpose We assessed the accuracy of lens power calculation in highly myopic patients implanting plus and minus intraocular lenses (IOL). Methods We included 58 consecutive, myopic eyes with an axial length (AL) > 26.0 mm, undergoing phacoemulsification and IOL implantation following biometry using the IOLMaster 500. For lens power calculation, the Haigis formula was used in all cases. For comparison, refraction was back-calculated using the Barrett Universal II (Barrett), Holladay I, Hill-RBF (RBF) and SRK/T formulae. Results The mean axial length was 30.17 +/- 2.67 mm. Barrett (80%), Haigis (87%) and RBF (82%) showed comparable numbers of IOLs within 1 diopter (D) of target refraction. Visual acuity (BSCVA) improved (p 28-days postsurgery). The median absolute error (MedAE) of Barrett 0.49 D, Haigis 0.38, RBF 0.44 and SRK/T 0.44 did not differ. The MedAE of Haigis was significantly smaller than Holladay (0.75 D; p = 0.01). All median postoperative refractive errors (MedRE) differed significantly with the exception of Haigis to SRK/T (p = 0.6): Barrett - 0.33 D, Haigis 0.25, Holladay 0.63, RBF 0.04 and SRK/T 0.13. Barrett, Haigis, Holladay and RBF showed a tendency for higher MedAEs in their minus compared to plus IOLs, which only reached significance for SRK/T (p = 0.001). Barrett (p < 0.001) and RBF (p = 0.04) showed myopic, SRK/T (p = 002) a hyperopic shift in their minus IOLs. Conclusions In highly myopic patients, the accuracies of Barrett, Haigis and RBF were comparable with a tendency for higher MedAEs in minus IOLs. Barrett and RBF showed myopic, SRK/T a hyperopic shift in their minus IOLs