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Bell's palsy is a common cranial neuropathy causing acute unilateral lower motor neuron facial paralysis. Immune, infective and ischaemic mechanisms are all potential contributors to the development of Bell's palsy, but the precise cause remains unclear. Advancements in the understanding of intra-axonal signal molecules and the molecular mechanisms underpinning Wallerian degeneration may further delineate its pathogenesis along with in vitro studies of virus-axon interactions. Recently published guidelines for the acute treatment of Bell's palsy advocate for steroid monotherapy, although controversy exists over whether combined corticosteroids and antivirals may possibly have a beneficial role in select cases of severe Bell's palsy. For those with longstanding sequaelae from incomplete recovery, aesthetic, functional (nasal patency, eye closure, speech and swallowing) and psychological considerations need to be addressed by the treating team. Increasingly, multidisciplinary collaboration between interested clinicians from a wide variety of subspecialties has proven effective. A patient centred approach utilising physiotherapy, targeted botulinum toxin injection and selective surgical intervention has reduced the burden of long-term disability in facial palsy.
By generating the second messenger cGMP in retinal rods and cones, ROS-GC plays a central role in visual transduction. Guanylate cyclase-activating proteins (GCAPs) link cGMP synthesis to the light-induced fall in [Ca(2+)]i to help set absolute sensitivity and assure prompt recovery of the response to light. The present report discloses a surprising feature of this system: ROS-GC is a sensor of bicarbonate. Recombinant ROS-GCs synthesized cGMP from GTP at faster rates in the presence of bicarbonate with an ED50 of 27 mm for ROS-GC1 and 39 mm for ROS-GC2. The effect required neither Ca(2+) nor use of the GCAPs domains; however, stimulation of ROS-GC1 was more powerful in the presence of GCAP1 or GCAP2 at low [Ca(2+)]. When applied to retinal photoreceptors, bicarbonate enhanced the circulating current, decreased sensitivity to flashes, and accelerated flash response kinetics. Bicarbonate was effective when applied either to the outer or inner segment of red-sensitive cones. In contrast, bicarbonate exerted an effect when applied to the inner segment of rods but had little efficacy when applied to the outer segment. The findings define a new regulatory mechanism of the ROS-GC system that affects visual transduction and is likely to affect the course of retinal diseases caused by cGMP toxicity.
A 63-year-old man presented with an asymptomatic papillary, sessile lesion of the juxtalimbal bulbar conjunctiva that was surgically excised with cryotherapy. Histopathologically, the lesion created some diagnostic confusion as it displayed an endophytic, or inverted, growth pattern-with squamous cells pushing into the substantia propria around fibrovascular cores, but without significant cytologic atypia, consistent with a conjunctival inverted papilloma (IP). Unlike previously reported cases of conjunctival IP, there were no goblet cells or cysts within the tumor. Immunostaining was diffusely positive for cytokeratin (CK) 7, and CK14 stained the basilar and suprabasilar cells, as in normal conjunctiva. CK17 weakly and non-uniformly stained the tumor, ruling out a dysplasia, which is usually strongly positive. The lesion's cytokeratin profile therefore paralleled that of normal conjunctiva. The proliferation index with Ki67 nuclear staining was extremely low (<1%), as was p53 nuclear staining (10-20%), both in contrast to squamous cell dysplasias or carcinomas that have a much higher percentage of positive cells. The lesion was negative for human papillomavirus subtypes associated with squamous neoplasias including carcinomas. We review the previous literature devoted to this comparatively rare condition and contrast its benign clinical course with that of inverted papillomas of the sinonasal, lacrimal drainage, and genitourinary systems and provide a set of criteria for establishing the diagnosis.
OBJECTIVE: To design and implement a teaching skills curriculum that addressed the needs of an ophthalmology residency training program, to assess the effect of the curriculum, and to present important lessons learned. DESIGN: A teaching skills curriculum was designed for the Harvard Medical School (HMS) Residency Training Program in Ophthalmology. Results of a needs assessment survey were used to guide curriculum objectives. Overall, 3 teaching workshops were conducted between October 2012 and March 2013 that addressed areas of need, including procedural teaching. A postcurriculum survey was used to assess the effect of the curriculum. SETTING: Massachusetts Eye and Ear Infirmary, a tertiary care institution in Boston, MA. PARTICIPANTS: Overall, 24 residents in the HMS Residency Training Program in Ophthalmology were included. RESULTS: The needs assessment survey demonstrated that although most residents anticipated that teaching would be important in their future career, only one-third had prior formal training in teaching. All residents reported they found the teaching workshops to be either very or extremely useful. All residents reported they would like further training in teaching, with most residents requesting additional training in best procedural teaching practices for future sessions. CONCLUSIONS: The pilot year of the resident-as-teacher curriculum for the HMS Residency Training Program in Ophthalmology demonstrated a need for this curriculum and was perceived as beneficial by the residents, who reported increased comfort in their teaching skills after attending the workshops.
Lymphedema is caused by defective drainage of the lymphatic system. In Melkersson-Rosenthal syndrome, involvement is predominantly of the lumens with blockage of lymphatic channels by histiocytic-epithelioid cell clusters accompanied by dermal granulomas and lymphocytes. It is a localized, painless, nonitching, and nonpitting form of lymphedema. Besides the eyelids, the disease can cause lip edema, facial palsy, and/or fissured tongue. It is rare and has received little attention in the ophthalmic literature, either in its complete triadic form, or more frequently, in its monosymptomatic forms. Pathogenesis is not well understood, and there is no effective therapy. The authors describe a case of Melkesson-Rosenthal syndrome in a 45-year-old Hispanic man with isolated unilateral upper eyelid edema. Histopathological and immunohistochemical evaluations of an eyelid biopsy specimen revealed intravascular and extravascular clusters of histiocytic-epithelioid cells that were CD68/163-positive. Variable numbers of mostly T-lymphocytes were found in the epidermis, dermis, and orbicularis muscle and by virtue of the associated granulomas established the diagnosis of Melkersson-Rosenthal syndrome. CD4 helper and CD8 suppressor T-lymphocytes were equally represented. CD20 B-lymphocytes were exceedingly sparse. Conspicuous CD1a-positive Langerhans' cells were present in the epidermis, sometimes formed subepithelial loose aggregates and were also incorporated in the granulomas. The differential diagnosis includes the far more common condition of acne rosacea. Management of Melkersson-Rosenthal syndrome, and of angioedema in general, is reviewed.
Importance: Little is known about the long-term risk of dying of uveal melanoma after treatment with radiotherapy. Objective: To determine the long-term risk of dying of this disease, we evaluated melanoma-related mortality rates up to 25 years after proton beam therapy in a large series of patients with uveal melanoma. Design, Setting, and Participants: In this analysis, we included 3088 patients with uveal melanoma, identified from a hospital-based cohort and treated with proton irradiation between January 1975 and December 2005. Vital status and cause of death were ascertained through active follow-up and searches of government databases (the Social Security Death Index and the National Death Index) through December 31, 2008. Cumulative rates of melanoma-related mortality were calculated using the Kaplan-Meier method. Patient and tumor characteristics of known prognostic significance for melanoma-associated death were evaluated, including patient age and tumor dimensions. Main Outcomes and Measures: The primary outcome measure was cumulative rates of melanoma-specific mortality, and secondary measures included annual melanoma-specific mortality hazard rates and cumulative all-cause mortality rates. Results: Of 1490 deceased patients, 620 (41.6%) died of ocular melanoma. In addition, 19 patients were alive, but their melanoma metastasized, by the end of the observation period (mean follow-up after diagnosis of metastasis, 5.3 years). All-cause mortality rates in this cohort were 49.0% (95% CI, 47.0-51.1) at 15 years, 58.6% (95% CI, 56.4%-60.8%) at 20 years, and 66.8% (95% CI, 64.2%-69.4%) at 25 years. Melanoma-related mortality rates were 24.6% (95% CI, 22.8-26.4) at 15 years after treatment, 25.8% (95% CI, 24.0-27.8) at 20 years after treatment, and 26.4% (95% CI, 24.5-28.5) at 25 years after treatment. The 20-year mortality rate was 8.6% (95% CI, 6.2-11.9) for younger patients (≤60 years) with small tumors (≤11 mm) and 40.1% (95% CI, 36.1-44.3) for older patients (>60 years) with large tumors (>11 mm). Conclusions and Relevance: In this large series of patients with ocular melanoma treated conservatively with proton beam irradiation, the cumulative melanoma-related mortality rates continued to increase up to 23 years after treatment. Annual rates decreased considerably (to <1%) 14 years after treatment. Information regarding the long-term risk of dying of uveal melanoma may be useful to clinicians when counseling patients.
Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.
Meibomian gland dysfunction is a leading cause of ocular surface disease. However, little is known about the regulatory processes that control the development and maintenance of this sebaceous gland. Here, we identify a novel function for CD147, a transmembrane protein that promotes tissue remodeling through induction of matrix metalloproteinases, in regulating meibocyte differentiation and activity. We found that CD147 localized along basal cells and within discrete membrane domains of differentiated meibocytes in glandular acini containing gelatinolytic activity. Induction of meibocyte differentiation in vitro promoted CD147 clustering and MMP9 secretion, whereas RNAi-mediated abrogation of CD147 impaired MMP9 secretion, concomitant with a reduction in the number of proliferative cells and cytoplasmic lipids. Meibomian glands of CD147 knockout mice had a lower number of acini in both the superior and inferior tarsal plates of the eyelids, and were characterized by loss of lipid-filled meibocytes compared with control mice. Together, our data provide evidence showing that gelatinolytic activity in meibocytes is dependent on CD147, and supports a role for CD147 in maintaining the normal development and function of the meibomian gland.
PURPOSE: Retinitis pigmentosa is a Mendelian disease with a very elevated genetic heterogeneity. Most mutations are responsible for less than 1% of cases, making molecular diagnosis a multigene screening procedure. In this study, we assessed whether direct testing of specific alleles could be a valuable screening approach in cases characterized by prevalent founder mutations. METHODS: We screened 275 North American patients with recessive/isolate retinitis pigmentosa for two mutations: an Alu insertion in the MAK gene and the p.Lys42Glu missense in the DHDDS gene. All patients were unrelated; 35 reported Jewish ancestry and the remainder reported mixed ethnicity. RESULTS: We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry. Haplotype analyses revealed that inheritance of the MAK mutation was attributable to a founder effect. CONCLUSION: In contrast to most mutations associated with retinitis pigmentosa-which are, in general, extremely rare-the two alleles investigated here cause disease in approximately one-third of North American patients reporting Jewish ancestry. Therefore, their screening constitutes an alternative procedure to large-scale tests for patients belonging to this ethnic group, especially in time-sensitive situations.Genet Med 17 4, 285-290.
BACKGROUND: Graft failure because of immune rejection remains a significant problem in organ transplantation, and lymphatic and blood vessels are important components of the afferent and efferent arms of the host alloimmune response, respectively. We compare the effect of antihemangiogenic and antilymphangiogenic therapies on alloimmunity and graft survival in a murine model of high-risk corneal transplantation. METHODS: Orthotopic corneal transplantation was performed in hemevascularized and lymph-vascularized high-risk host beds, and graft recipients received subconjunctival vascular endothelial growth factor (VEGF)-trap, anti-VEGF-C, sVEGFR-3, or no treatment, beginning at the time of surgery. Fourteen days after transplantation, graft hemeangiogenesis and lymphangiogenesis were evaluated by immunohistochemistry. The frequencies of Th1 cells in regional lymphoid tissue and graft-infiltrating immune cells were evaluated by flow cytometry. Long-term allograft survival was compared using Kaplan-Meier curves. RESULTS: VEGF-trap significantly decreased graft hemangiogenesis as compared to the control group and was most effective in reducing the frequency of graft-infiltrating immune cells. Anti-VEGF-C and sVEGFR3 significantly decreased graft lymphangiogenesis and lymphoid Th1 cell frequencies as compared to control. VEGF-trap (72%), anti-VEGF-C (25%), and sVEGFR-3 (11%) all significantly improved in the 8-week graft survival compared to control (0%), although VEGF-trap was significantly more effective than both anti-VEGF-C (P < 0.05) and sVEGFR-3 (P < 0.05). CONCLUSION: In a clinically relevant model of high-risk corneal transplantation in which blood and lymphatic vessels are present and treatment begins at the time of transplantation, VEGF-trap is significantly more effective in improving long-term graft survival as compared to anti-VEGF-C and sVEGFR-3, but all approaches improve survival when compared to untreated control.
PURPOSE: We explored whether risk factor associations differed by primary open-angle glaucoma (POAG) subtypes defined by visual field (VF) loss pattern (i.e., paracentral or peripheral). METHODS: We included 77,157 women in the Nurses Health Study and 42,773 men in the Health Professionals Follow-up Study (1986-2010) and incident medical-record confirmed cases of paracentral (n=440) and peripheral (n=865) POAG subtypes. We evaluated African-heritage, glaucoma family history, body mass index (BMI), mean arterial blood pressure, diabetes mellitus, physical activity, smoking, caffeine and alcohol intakes. We used competing risk Cox regression analyses modeling age as the metameter and stratified by age, cohort and event type. We sequentially identified factors with the least significant differences in associations with POAG subtypes ("stepwise down" approach with P for heterogeneity [P-het]<0.10 as threshold). RESULTS: BMI was more inversely associated with the POAG paracentral VF loss subtype than the peripheral VF loss subtype (per 10 kg/m2; hazard ratio [HR]=0.67 [95% Confidence Interval [CI]: 0.52, 0.86] vs. HR=0.93 [95% CI: 0.78, 1.10]; P-het=0.03) as was smoking (per 10 pack-years; HR=0.92 [95% CI: 0.87, 0.98] vs. HR=0.98 [95% CI: 0.94, 1.01]; P-het=0.09). These findings were robust in sensitivity analyses using a "stepwise up" approach (identify factors that showed the most significant differences). Non-heterogeneous (p-het>0.10) adverse associations with both POAG subtypes were observed with glaucoma family history, diabetes, African-heritage, greater caffeine intake and higher mean arterial pressure. CONCLUSIONS: These data indicate that POAG with early paracentral VF loss has distinct as well as common determinants compared to POAG with peripheral VF loss.
PURPOSE: Corneal wound healing is a highly regulated process that requires the proliferation and migration of epithelial cells and interactions between epithelial cells and stromal fibroblasts. Compounds that can be applied topically to the ocular surface and that have the capability of activating corneal epithelial cells to proliferate and/or migrate would be useful to promote corneal wound healing. We hypothesize that human growth hormone (HGH) will activate signal transducers and activators of transcription-5 (STAT5) signaling and promote corneal wound healing by enhancing corneal epithelial cell and fibroblast proliferation and/or migration in vitro. The purpose of this study was to test these hypotheses. METHODS: We studied cell signaling, proliferation, and migration using an immortalized human corneal epithelial cell line and primary human corneal fibroblasts in vitro. We also examined whether insulin-like growth factor-1 (IGF-1), a hormone known to mediate many of HGH's growth promoting actions, may play a role in this effect. RESULTS: We show that HGH activates STAT5 signaling and promotes corneal epithelial cell migration in vitro. The migratory effect requires an intact communication between corneal epithelia and fibroblasts and is not mediated by IGF-1. CONCLUSIONS: HGH may represent a topical therapeutic to promote corneal epithelial wound healing. This warrants further investigation.
Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs and through selective activation of these enhancers to regulate tissue-specific genes.
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