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MacKinnon S, Oystreck DT, Andrews C, Chan W-M, Hunter DG, Engle EC.
Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology 2014;121(7):1461-8.
AbstractOBJECTIVE: To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort. DESIGN: Prospective, observational study. PARTICIPANTS: Attendees of 3 consecutive Moebius syndrome conferences held in the United States, with a prior diagnosis of Moebius syndrome, were invited to participate. METHODS: Participants underwent standardized ophthalmologic examination for Moebius syndrome minimum diagnostic criteria (MDC) (congenital, nonprogressive facial palsy, and abduction deficit) and genetic testing for HOXA1, HOXB1, and TUBB3 mutations. MAIN OUTCOME MEASURES: The number of patients meeting MDC and the number of patients with confirmed genetic mutation. RESULTS: A total of 112 participants from 107 families enrolled. Nineteen percent of participants (21/112) did not meet accepted MDC for Moebius syndrome because they had abduction deficits without facial palsy or facial palsy with full ocular motility. All 5 families with 2 affected individuals had at least 1 family member in this category, including 2 siblings with comitant strabismus who harbored a HOXB1 mutation. Four unrelated participants, also not meeting MDC, had large-angle exotropia, vertical gaze deficiency, and ptosis consistent with congenital fibrosis of the extraocular muscles type 3 (CFEOM3); 1 patient harbored a novel TUBB3 mutation, and 3 patients harbored previously reported de novo TUBB3 mutations. Three percent of participants (3/112) met MDC but also had restricted vertical gaze. The remaining 88 participants (79%) met MDC and had full vertical gaze. This group had relatively homogeneous findings, and none had a family history of Moebius syndrome. Two previously undescribed phenomena were observed in this category: (1) volitional Bell's phenomenon and (2) intorsion with fixation. CONCLUSIONS: Although the genetic contributors to classic Moebius syndrome remain elusive, accuracy in clinical evaluation will properly subdivide patients to facilitate genetic testing as new candidate genes are identified. Failure to test ocular motility may lead to misdiagnosis of Moebius syndrome, especially in patients who have facial palsy with full ductions. Patients with exotropia, vertical gaze limitation, and ptosis do not have classic Moebius syndrome and may have TUBB3 mutations associated with CFEOM3. To optimize genetic analysis, we propose adding "full vertical motility" to the MDC for Moebius syndrome.
Maiello G, Chessa M, Solari F, Bex PJ.
Simulated disparity and peripheral blur interact during binocular fusion. J Vis 2014;14(8):13.
AbstractWe have developed a low-cost, practical gaze-contingent display in which natural images are presented to the observer with dioptric blur and stereoscopic disparity that are dependent on the three-dimensional structure of natural scenes. Our system simulates a distribution of retinal blur and depth similar to that experienced in real-world viewing conditions by emmetropic observers. We implemented the system using light-field photographs taken with a plenoptic camera which supports digital refocusing anywhere in the images. We coupled this capability with an eye-tracking system and stereoscopic rendering. With this display, we examine how the time course of binocular fusion depends on depth cues from blur and stereoscopic disparity in naturalistic images. Our results show that disparity and peripheral blur interact to modify eye-movement behavior and facilitate binocular fusion, and the greatest benefit was gained by observers who struggled most to achieve fusion. Even though plenoptic images do not replicate an individual’s aberrations, the results demonstrate that a naturalistic distribution of depth-dependent blur may improve 3-D virtual reality, and that interruptions of this pattern (e.g., with intraocular lenses) which flatten the distribution of retinal blur may adversely affect binocular fusion.
Malik AN, Vierbuchen T, Hemberg M, Rubin AA, Ling E, Couch CH, Stroud H, Spiegel I, Farh KK-H, Harmin DA, Greenberg ME.
Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat Neurosci 2014;17(10):1330-9.
AbstractExperience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons. We find that the subset of enhancers enriched for monomethylation of histone H3 Lys4 (H3K4me1) and binding of the transcriptional coactivator CREBBP (also called CBP) that shows increased acetylation of histone H3 Lys27 (H3K27ac) after membrane depolarization of cortical neurons functions to regulate activity-dependent transcription. A subset of these enhancers appears to require binding of FOS, which was previously thought to bind primarily to promoters. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease.
Marques LM, Lapenta OM, Merabet LB, Bolognini N, Boggio PS.
Tuning and disrupting the brain-modulating the McGurk illusion with electrical stimulation. Front Hum Neurosci 2014;8:533.
AbstractIn the so-called McGurk illusion, when the synchronized presentation of the visual stimulus /ga/ is paired with the auditory stimulus /ba/, people in general hear it as /da/. Multisensory integration processing underlying this illusion seems to occur within the Superior Temporal Sulcus (STS). Herein, we present evidence demonstrating that bilateral cathodal transcranial direct current stimulation (tDCS) of this area can decrease the McGurk illusion-type responses. Additionally, we show that the manipulation of this audio-visual integrated output occurs irrespective of the number of eye-fixations on the mouth of the speaker. Bilateral anodal tDCS of the Parietal Cortex also modulates the illusion, but in the opposite manner, inducing more illusion-type responses. This is the first demonstration of using non-invasive brain stimulation to modulate multisensory speech perception in an illusory context (i.e., both increasing and decreasing illusion-type responses to a verbal audio-visual integration task). These findings provide clear evidence that both the superior temporal and parietal areas contribute to multisensory integration processing related to speech perception. Specifically, STS seems fundamental for the temporal synchronization and integration of auditory and visual inputs. For its part, posterior parietal cortex (PPC) may adjust the arrival of incoming audio and visual information to STS thereby enhancing their interaction in this latter area.
Matsumoto H, Murakami Y, Kataoka K, Lin H, Connor KM, Miller JW, Zhou D, Avruch J, Vavvas DG.
Mammalian STE20-like kinase 2, not kinase 1, mediates photoreceptor cell death during retinal detachment. Cell Death Dis 2014;5:e1269.
AbstractPhotoreceptor cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1(-/-) and MST2(-/-) mice we identified MST2, but not MST1, as a regulator of photoreceptor cell death in a mouse model of RD. MST2(-/-) mice demonstrated significantly decreased photoreceptor cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2(-/-) mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2(-/-) mice post-RD. Retinas of MST2(-/-) mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of photoreceptor cell death, MST2(-/-) mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated photoreceptor cell death in the detached retina and indicate its potential as a future neuroprotection target.
Matsumoto H, Kataoka K, Tsoka P, Connor KM, Miller JW, Vavvas DG.
Strain difference in photoreceptor cell death after retinal detachment in mice. Invest Ophthalmol Vis Sci 2014;55(7):4165-74.
AbstractPURPOSE: To evaluate the potential for mouse genetic background to effect photoreceptor cell death in response to experimental retinal detachment (RD). METHODS: Retinal detachment was induced in three inbred mouse strains (C57BL/6, BALB/c, and B6129SF2) by subretinal injection of sodium hyaluronate. A time course of photoreceptor cell death was assessed by TUNEL assay. Total photoreceptor cell death was analyzed through comparing the outer nuclear layer (ONL)/inner nuclear layer (INL) ratio 7 days post RD. Western blot analysis or quantitative real-time PCR (qPCR) were performed to assess cell death signaling, expression of endogenous neurotrophin, and levels of apoptosis inhibitors 24 hours after RD. Inflammatory cytokine secretion and inflammatory cell infiltration were quantified by ELISA and immunostaining, respectively. RESULTS: The peak of photoreceptor cell death after RD was at 24 hours in all strains. Photoreceptor cell death as well as monocyte chemoattractant protein 1 and interleukin 6 secretion at 24 hours after RD was the highest in BALB/c, followed in order of magnitude by C57BL/6 and B6129SF2. Conversely, nerve growth factor expression and ONL/INL ratio were the lowest in BALB/c. Apoptosis signaling was higher in C57BL/6, whereas necroptosis signaling was higher in C57BL/6 and BALB/c. Autophagic signaling was higher in BALB/c. X-linked inhibitor of apoptosis (XIAP) and survivin protein levels were lower in C57BL/6 and BALB/c, respectively. Macrophage/microglia infiltration was higher in C57BL/6 and BALB/c at 24 hours after RD. CONCLUSIONS: Photoreceptor cell death after RD was significantly different among the three strains, suggesting the presence of genetic factors that affect photoreceptor cell death after RD.
Mauris J, Woodward AM, Cao Z, Panjwani N, Argüeso P.
Molecular basis for MMP9 induction and disruption of epithelial cell-cell contacts by galectin-3. J Cell Sci 2014;127(Pt 14):3141-8.
AbstractDynamic modulation of the physical contacts between neighboring cells is integral to epithelial processes such as tissue repair and cancer dissemination. Induction of matrix metalloproteinase (MMP) activity contributes to the disassembly of intercellular junctions and the degradation of the extracellular matrix, thus mitigating the physical constraint to cell movement. Using the cornea as a model, we show here that a carbohydrate-binding protein, galectin-3, promotes cell-cell detachment and redistribution of the tight junction protein occludin through its N-terminal polymerizing domain. Notably, we demonstrate that galectin-3 initiates cell-cell disassembly by inducing matrix metalloproteinase expression in a manner that is dependent on the interaction with and clustering of the matrix metalloproteinase inducer CD147 (also known as EMMPRIN and basigin) on the cell surface. Using galectin-3-knockout mice in an in vivo model of wound healing, we further show that increased synthesis of MMP9 at the leading edge of migrating epithelium is regulated by galectin-3. These findings establish a new galectin-3-mediated regulatory mechanism for induction of metalloproteinase expression and disruption of cell-cell contacts required for cell motility in migrating epithelia.
Michan S, Juan AM, Hurst CG, Cui Z, Evans LP, Hatton CJ, Pei DT, Ju M, Sinclair DA, Smith LEH, Chen J.
Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy. PLoS One 2014;9(1):e85031.
AbstractProliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy.
Miller JW.
The Harvard angiogenesis story. Surv Ophthalmol 2014;59(3):361-4.
AbstractI shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease.
Mott KR, Allen SJ, Zandian M, Akbari O, Hamrah P, Maazi H, Wechsler SL, Sharpe AH, Freeman GJ, Ghiasi H.
Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. PLoS One 2014;9(1):e87617.
AbstractCD80 plays a critical role in stimulation of T cells and subsequent control of infection. To investigate the effect of CD80 on HSV-1 infection, we constructed a recombinant HSV-1 virus that expresses two copies of the CD80 gene in place of the latency associated transcript (LAT). This mutant virus (HSV-CD80) expressed high levels of CD80 and had similar virus replication kinetics as control viruses in rabbit skin cells. In contrast to parental virus, this CD80 expressing recombinant virus replicated efficiently in immature dendritic cells (DCs). Additionally, the susceptibility of immature DCs to HSV-CD80 infection was mediated by CD80 binding to PD-L1 on DCs. This interaction also contributed to a significant increase in T cell activation. Taken together, these results suggest that inclusion of CD80 as a vaccine adjuvant may promote increased vaccine efficacy by enhancing the immune response directly and also indirectly by targeting to DC.
Mouw KW, Sethi RV, Yeap BY, MacDonald SM, Chen Y-LE, Tarbell NJ, Yock TI, Munzenrider JE, Adams J, Grabowski E, Mukai S, Shih HA.
Proton Radiation Therapy for the Treatment of Retinoblastoma. Int J Radiat Oncol Biol Phys 2014;90(4):863-9.
AbstractPURPOSE: To investigate long-term disease and toxicity outcomes for pediatric retinoblastoma patients treated with proton radiation therapy (PRT). METHODS AND MATERIALS: This is a retrospective analysis of 49 retinoblastoma patients (60 eyes) treated with PRT between 1986 and 2012. RESULTS: The majority (84%) of patients had bilateral disease, and nearly half (45%) had received prior chemotherapy. At a median follow-up of 8 years (range, 1-24 years), no patients died of retinoblastoma or developed metastatic disease. The post-PRT enucleation rate was low (18%), especially in patients with early-stage disease (11% for patients with International Classification for Intraocular Retinoblastoma [ICIR] stage A-B disease vs 23% for patients with ICIR stage C-D disease). Post-PRT ophthalmologic follow-up was available for 61% of the preserved eyes (30 of 49): 14 of 30 eyes (47%) had 20/40 visual acuity or better, 7 of 30 (23%) had moderate visual acuity (20/40-20/600), and 9 of 30 (30%) had little or no useful vision (worse than 20/600). Twelve of 60 treated eyes (20%) experienced a post-PRT event requiring intervention, with cataracts the most common (4 eyes). No patients developed an in-field second malignancy. CONCLUSIONS: Long-term follow-up of retinoblastoma patients treated with PRT demonstrates that PRT can achieve high local control rates, even in advanced cases, and many patients retain useful vision in the treated eye. Treatment-related ocular side effects were uncommon, and no radiation-associated malignancies were observed.
Murakami Y, Matsumoto H, Roh M, Giani A, Kataoka K, Morizane Y, Kayama M, Thanos A, Nakatake S, Notomi S, Hisatomi T, Ikeda Y, Ishibashi T, Connor KM, Miller JW, Vavvas DG.
Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ 2014;21(2):270-7.
AbstractThere is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3(-/-) mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced retinal degeneration. Moreover, after poly(I : C) injection, Rip3(-/-) mice displayed decreased levels of pro-inflammatory cytokines (such as TNF-α and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF-α and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-α and IL-6 production after poly(I : C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.
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Nassi JJ, Gómez-Laberge C, Kreiman G, Born RT.
Corticocortical feedback increases the spatial extent of normalization. Front Syst Neurosci 2014;8:105.
AbstractNormalization has been proposed as a canonical computation operating across different brain regions, sensory modalities, and species. It provides a good phenomenological description of non-linear response properties in primary visual cortex (V1), including the contrast response function and surround suppression. Despite its widespread application throughout the visual system, the underlying neural mechanisms remain largely unknown. We recently observed that corticocortical feedback contributes to surround suppression in V1, raising the possibility that feedback acts through normalization. To test this idea, we characterized area summation and contrast response properties in V1 with and without feedback from V2 and V3 in alert macaques and applied a standard normalization model to the data. Area summation properties were well explained by a form of divisive normalization, which computes the ratio between a neuron's driving input and the spatially integrated activity of a "normalization pool." Feedback inactivation reduced surround suppression by shrinking the spatial extent of the normalization pool. This effect was independent of the gain modulation thought to mediate the influence of contrast on area summation, which remained intact during feedback inactivation. Contrast sensitivity within the receptive field center was also unaffected by feedback inactivation, providing further evidence that feedback participates in normalization independent of the circuit mechanisms involved in modulating contrast gain and saturation. These results suggest that corticocortical feedback contributes to surround suppression by increasing the visuotopic extent of normalization and, via this mechanism, feedback can play a critical role in contextual information processing.
Newman-Casey PA, Talwar N, Nan B, Musch DC, Pasquale LR, Stein JD.
The potential association between postmenopausal hormone use and primary open-angle glaucoma. JAMA Ophthalmol 2014;132(3):298-303.
AbstractIMPORTANCE: Retinal ganglion cells are known to express estrogen receptors and prior studies have suggested an association between postmenopausal hormone (PMH) use and decreased intraocular pressure, suggesting that PMH use may decrease the risk for primary open-angle glaucoma (POAG). OBJECTIVE: To determine whether the use of 3 different classes of PMH affects the risk for POAG. DESIGN, SETTING, AND PARTICIPANTS: Retrospective longitudinal cohort analysis of claims data from women 50 years or older enrolled in a US managed-care plan for at least 4 years in which enrollees had at least 2 visits to an eye care provider during the period 2001 through 2009. EXPOSURE: Postmenopausal hormone medications containing estrogen only, estrogen + progesterone, and estrogen + androgen, as captured from outpatient pharmacy claims over a 4-year period. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for developing incident POAG. RESULTS: Of 152,163 eligible enrollees, 2925 (1.9%) developed POAG. After adjustment for confounding factors, each additional month of use of PMH containing estrogen only was associated with a 0.4% reduced risk for POAG (HR, 0.996 [95% CI, 0.993-0.999]; P = .02). The risk for POAG did not differ with each additional month of use of estrogen + progesterone (HR, 0.994 [95% CI, 0.987-1.001]; P = .08) or estrogen + androgen (HR, 0.999 [95% CI, 0.988-1.011]; P = .89). CONCLUSIONS AND RELEVANCE: Use of PMH preparations containing estrogen may help reduce the risk for POAG. If prospective studies confirm the findings of this analysis, novel treatments for this sight-threatening condition may follow.
Nguyen J, Fay A, Yadav P, MacIntosh PW, Metson R.
Stereotactic microdebrider in deep lateral orbital decompression for patients with thyroid eye disease. Ophthalmic Plast Reconstr Surg 2014;30(3):262-6.
AbstractPURPOSE: Stereotactic navigation systems have been used in neurosurgery and otolaryngology with great success. The current investigation illustrates the novel use of a microdebrider with built-in stereotactic guidance in a series of thyroid orbitopathy patients who underwent deep lateral orbital wall decompression surgery. METHODS: A noncomparative, interventional, retrospective case series of patients who underwent deep lateral deep orbital wall decompression from 2006 to 2013 was conducted in accordance with Institutional Review Board policy and the Declaration of Helsinki. Patient demographics, indications for surgery, pre-, intra-, and postoperative findings along with complications were recorded. RESULTS: One hundred eight deep lateral orbital decompression surgeries were performed in 69 patients using the Straightshot M4 Microdebrider with built-in stereotactic guidance (Medtronics). Seventy-eight cases were in women and 30 cases were in men. The average age was 50.4 years (SD = 11.9 years). Indications for surgery included proptosis, exposure keratopathy, or compressive optic neuropathy. No patient experienced intraoperative complications. Specifically, cerebrospinal fluid leak, visual loss, infection, or unanticipated inflammation were not encountered. The average postoperative follow-up time was 5.35 months. Mean reduction in proptosis was 3.72 mm (SD = 2.1). Visual acuity improved in 32.4% (35/108) of cases. CONCLUSIONS: This surgical instrument combines a single handpiece locator, microdebrider, irrigator, retractor, and suction device into one. It enhances anatomical localization during orbital decompression and, with an integrated tissue guard, may decrease the risk of injury to orbital soft tissues. Stereotactic navigation enhances the surgeon's ability to determine the maximal limits of decompression in real time by confirming depth of bone removal and may potentially increase surgeons' confidence in orbital decompression surgery.
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Omoto M, Katikireddy KR, Rezazadeh A, Dohlman TH, Chauhan S.
Mesenchymal stem cells home to inflamed ocular surface and suppress allosensitization in corneal transplantation. Invest Ophthalmol Vis Sci 2014;
AbstractPurpose: To investigate whether systemically-injected syngeneic mesenchymal stem cells (MSCs) can home to the inflamed transplanted cornea, suppress induction of alloimmunity, and promote allograft survival. Methods: MSCs were generated from bone marrow of wild-type BALB/c or GFP+ C57BL/6 mice, and 1x106 cells were intravenously injected to allografted recipients 3 hours after surgery. MSCs homing to the cornea were examined at day 3 post-transplantation by immunohistochemistry. CD11c+MHC II+ cells were detected in the cornea and lymph nodes (LNs) 14 days post-transplantation using flow cytometry. Cytokine expression of bone marrow-derived dendritic cells (BMDCs) was determined using real-time PCR. ELISPOT assay was used to assess indirect and direct host T cell allosensitization, and graft survival was evaluated by slit-lamp biomicroscopy weekly up to 8 weeks. Results: Intravenously injected GFP+ MSCs were found in abundance in the transplanted cornea, conjunctiva, and lymph nodes, but not in the ungrafted (contralateral) tissue. The frequencies of mature CD11c+MHC II+ APCs were substantially decreased in the corneas and draining LNs of MSC-injected allograft recipients compared to control recipients. Maturation and function of in vitro cultured BMDCs was decreased when cocultured with MSCs. Draining LNs of MSC-injected allograft recipients showed significantly lower frequencies of IFNγ-secreting Th1 cells compared to the control group. Allograft survival rate was significantly higher in MSC-injected recipients compared to non-MSC injected recipients. Conclusions: Our data demonstrate that systemically-administered MSCs specifically home to transplanted corneas and promote allograft survival by inhibiting APC maturation and induction of alloreactive T cells.
Ousler GW, Abelson MB, Johnston PR, Rodriguez J, Lane K, Smith LM.
Blink patterns and lid-contact times in dry-eye and normal subjects. Clin Ophthalmol 2014;8:869-74.
AbstractPURPOSE: To classify blinks in dry eye and normal subjects into six subtypes, and to define the blink rate and duration within each type of blink, as well as the total lid-contact time/minute. MATERIALS AND METHODS: This was a single-centered, prospective, double-blind study of eleven dry-eye and ten normal subjects. Predefined subjects watched a video while blinks were recorded for 10 minutes. Partial blinks were classified by percentage closure of maximal palpebral fissure opening: 25%, 50%, 75%. Complete blinks were characterized as full (>0 seconds), extended (>0.1 seconds), or superextended (>0.5 seconds). The mean duration of each type of blink was determined and standardized per minute as total lid-contact time. RESULTS: Total blinks observed were 4,990 (1,414 normal, 3,756 dry eye): 1,809 (50.59%) partial and 1,767 (49.41%) complete blinks among dry-eye subjects versus 741 (52.90%) partial and 673 (47.60%) complete blinks among normal subjects. Only superextended blinks of ≥0.5-second duration were significantly more frequent in dry-eye subjects than normals (2.3% versus 0.2%, respectively; P=0.023). Total contact time was seven times higher in dry-eye subjects than normals (0.565 versus 0.080 seconds, respectively; P<0.001). Isolating only extended blinks (>0.1 second), the average contact time (seconds) was four times longer in dry-eye versus normal subjects (2.459 in dry eye, 0.575 in normals; P=0.003). Isolating only superextended blinks (>0.5 seconds), average contact time was also significantly different (7.134 in dry eye, 1.589 in normals; P<0.001). The contact rate for all full closures was 6.4 times longer in dry-eye (0.045 versus 0.007, P<0.001) than normal subjects. CONCLUSION: Dry-eye subjects spent 4.5% of a minute with their eyes closed, while normal subjects spent 0.7% of a minute with their eyes closed. Contact time might play a role in the visual function decay associated with increased blink rates.
Owen LA, Morrison MA, Ahn J, Woo SJ, Sato H, Robinson R, Morgan DJ, Zacharaki F, Simeonova M, Uehara H, Chakravarthy U, Hogg RE, Ambati BK, Kotoula M, Baehr W, Haider NB, Silvestri G, Miller JW, Tsironi EE, Farrer LA, Kim IK, Park KH, Deangelis MM.
FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression. Invest Ophthalmol Vis Sci 2014;55(6):3543-54.
AbstractPURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.
