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Objectives: (i) To develop a prototype measure of co-production of health (CPH) in consultations for people with long-term conditions (LTCs); and (ii) to undertake initial validation of it, using a measure of patient-centred care, as defined by the Roter interaction analysis system (RIAS).Methods: Mixed methods were applied. A qualitative study gathered 11 experts' views on what comprised CPH behaviours. These were operationalised and a prototype measure applied to a convenience sample of 50 video-recorded consultations involving clinicians trained in self-management support and patients with LTCs at health services in six UK locations.Results: Twenty-two CPH behaviours were identified. High frequencies of CPH behaviours in consultations were associated with greater patient-centeredness, less clinician verbal dominance, and more patient communication control in comparison to consultations where CPH behaviours were less frequent.Conclusion: Although the CPH tool is promising, further testing is required in order to improve reliability and validity.Practical Implications: In the future, the measure could be used to test interventions to promote patient participation in decision making about self-management. [ABSTRACT FROM AUTHOR]

Slow Slip Events (SSEs) are a form of fault slip behaviour whose importance has only been recognised in the last decade at subduction zone plate boundaries worldwide. Here, we show one of the first examples of the use of Interferometric Synthetic Aperture Radar (InSAR) data to document deformation during an SSE on the Hikurangi subduction interface in New Zealand. Although much of the deformation that we observe is attributable to slow slip on the subduction interface, the InSAR data also reveals surface offsets of up to 1–2 cm across a major crustal fault during the period of the slow slip event. In order to fit the observations, we find that reverse aseismic slip is required along a portion of the Wellington fault where the Coulomb Failure Stress changes (ΔCFS), due to the SSE, are in excess of 0.01 MPa. This is the first-ever documented example of a subduction interface SSE triggering a transient slip event on a major upper plate fault, and it has wide-ranging implications for the role that SSEs can play in time-dependent seismic hazard. [ABSTRACT FROM AUTHOR]

Researchers in the field of health psychology have increasingly been involved in translating a body of knowledge about psychological factors associated with health-relevant behaviours, into the development and evaluation of interventions that seek to apply that knowledge. In this paper we argue that a changing economic and political climate, and the strong behavioural contribution to disease morbidity and mortality in developed nations, requires health psychologists to plan more rigorously for, and communicate more effectively, about how health promotion, social cognition and behaviour change interventions will have impact and be increasingly embedded into health services or health promotion activity. We explain academic and wider socio-economic uses of ‘impact’ in health services research. We describe the relationship between impact and dissemination, and impact as distinct from, but often used interchangeably with the terms ‘implementation’, ‘knowledge transfer’ and ‘knowledge translation’ (KT). The evidence for establishing impact is emergent. We therefore draw on a number of impact planning and KT frameworks, with reference to two self- management interventions, to describe a framework that we hope will support health psychologists in embedding impact planning and execution in research. We illustrate this further in an on-line annexe with reference to one of our own interventions,Mums-and-MS(see Supplemental Material). [ABSTRACT FROM PUBLISHER]

Interest in behaviour-change interventions targeting health professionals' adoption of clinical guidelines is growing. Recommendations have been made for interventions to have a theoretical base, explore the local context and to use mixed and multiple methods of evaluation to establish intervention effectiveness. This article presents a case study of a behaviour-change intervention delivered to community mental health professionals in one Primary Care Trust, aimed at raising adherence to a national suicide prevention guideline. A discussion of how the theory-base was selected, the local context explored, and how the intervention was developed and delivered is provided. Time series analysis, mediational analysis and qualitative process evaluation were used to evaluate and explore intervention effectiveness. The time series analysis revealed that the intervention was not effective at increasing adherence to the guideline. The mediational analysis indicates that the intervention failed to successfully target the key barrier to adoption of the guidance, and the qualitative process evaluation identified certain intervention components that were well received by the health professionals, and also identified weaknesses in the delivery of the intervention. It is recommended that future research should seek to further develop the evidence-base for linking specific intervention strategies to specific behavioural barriers, explore the potential of theories that take into account broader social and organisational factors that influence health professionals' practice and focus on the process of data synthesis for identifying key factors to target with tailored interventions. Multiple and mixed evaluation techniques are recommended not only to explore whether an intervention is effective or not but also why it is effective or not. [ABSTRACT FROM AUTHOR]

Within a national quality improvement programme for self-management of long-term conditions, we surveyed clinicians working with patients with diabetes, chronic obstructive pulmonary disease, musculoskeletal pain and depression. We applied the Self-Determination Theory framework to explore what factors can facilitate and impede the clinicians' engagement in clinical self-management support (SMS), patient centredness and organizational support for self-management. We also investigated whether attending professional training for clinicians in the practice of self-management (SM) increases motivation to support SM and reported use of SM practices. The study included 482 clinicians who were surveyed once (cross-sectional design) and 114 clinicians who were surveyed before and after training (longitudinal cohort). We found that the high level of satisfaction of competence need predicts practising SMS in all three areas (clinical SMS: β coefficient = 0.21; p < 0.0001; patient centredness: β coefficient = 0.50; p < 0.001; organizational SMS: coefficient = 0.20; p < 0.0001). Internalized regulation to support SMS increases engagement in clinical and organizational SMS. Upon comparing the two samples we explored the possible predictors of clinicians' self-referring to attend the training. Clinicians who volunteer to attend the training spend more time working directly with patients with long-term conditions (χ2 = 4.8; df = 1; p = 0.02), had less previous relevant training (χ2 = 4.77; df = 1; p = 0.02), and they have less autonomy to support SM (t = 5.0; df = 476; p < 0.0001). However, they report more engagement in patient-centred practices (t = 1.9; df = 585; p = 0.05). These factors are a good fit with the aims of the programme. We confirmed that attending the training had a significant, positive impact on clinicians' engagement in clinical SMS and patient centredness, as well as their overall confidence to support SM. We conclude that to facilitate clinicians to practice SMS it is very important to provide relevant professional training, professional support and incentives to foster clinicians' perceptions of their competence in relation to these practices. Organizations should develop a culture that values SMS, offer training to clinicians to enhance their sense of competence to effectively deliver SMS and support clinicians in finding their own way of supporting SM; in other words to create an optimal context to internalize regulation to support SM. [ABSTRACT FROM AUTHOR]

Abstract: We examine how well contemporary horizontal velocity fields from Global Positioning System (GPS) geodetic measurements describe long-term deformation rates. Million-year rates of extension, shortening, strike slip and vertical-axis rotations are compared with modelling of GPS velocities from the last 10–15 years in the Hikurangi subduction margin, New Zealand. Within measurement uncertainties of mainly ≤50%, the rates of deformation and vertical-axis rotations for each time interval are usually indistinguishable. The comparable deformation rates are consistent with the notion of near-constant rates since ∼1.5 Ma. During this time oblique relative plate motion was partitioned, with the majority (85%) of margin-normal motion accommodated on the plate interface, and most (≥60%) margin-parallel motion by strike-slip faulting and vertical-axis rotations in the upper plate. Prior to ∼1.5 Ma GPS velocities cannot be reliably used to describe deformation and rotations of the Hikurangi margin because, at this time, the Taupo Rift commenced opening, the boundary between Raukumara and Wairoa rotational domains was abandoned and the rates of upper-plate shortening increased. The broad compatibility of GPS and geological deformation and rotation rates since ∼1.5 Ma suggests that the build up of contemporary elastic strains in the North Island, measured by GPS, is largely uniform for much of the duration of each seismic cycle. The good agreement between the GPS and geological deformation rates in the North Island is consistent with the view that contemporary elastic strains will mainly be converted to permanent dip slip on the subduction thrust and to displacement on upper plate faults during future large-magnitude earthquakes. [Copyright &y& Elsevier]

: PurposeTo describe the features of atypical pigment dispersion in a child.: DesignObservational case report.: MethodsRetrospective chart review.: ResultsAn 8-year-old boy presented with midperipheral iris transillumination defects, iris backbowing, heavy pigmentation of the trabecular meshwork, and elevated intraocular pressure. He also had several atypical features including emmetropia, mild posterior subcapsular cataract, small pupils, and peripheral anterior synechiae.: ConclusionPigment dispersion in childhood is unusual and may have different features from those classically described in adults. [Copyright &y& Elsevier]

Background: A substantial proportion of cases of glaucoma have a genetic basis. Mutations causing glaucoma have been identified in the chromosome 1 open-angle glaucoma gene (GLC1A), which encodes a 57-kd protein known as myocilin. The normal role of this protein and the mechanism by which mutations cause glaucoma are not known.Methods: We screened 716 patients with primary open-angle glaucoma and 596 control subjects for sequence changes in the GLC1A gene.Results: We identified 16 sequence variations that met the criteria for a probable disease-causing mutation because they altered the predicted amino acid sequence and they were found in one or more patients with glaucoma, in less than 1 percent of the control subjects. These 16 mutations were found in 33 patients (4.6 percent). Six of the mutations were found in more than 1 subject (total, 99). Clinical features associated with these six mutations included an age at diagnosis ranging from 8 to 77 years and maximal recorded intraocular pressures ranging from 12 to 77 mm Hg.Conclusions: A variety of mutations in the GLC1A gene are associated with glaucoma. The spectrum of disease can range from juvenile glaucoma to typical late-onset primary open-angle glaucoma. [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This article discusses the experience of progressing from a young ophthalmic resident to a full-time professional and, ultimately, to service on the American Board of Ophthalmology. [ABSTRACT FROM AUTHOR]

Focuses on the research in ocular development to find the more effective treatment of eye disease glaucoma. Population in the world affected by glaucoma as of March 7, 2003; Treatment of glaucoma by the regeneration of lost axons of eye; Need for the treatment of a modified risk factor for glaucoma intraocular pressure.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a 1 in 7500 incidence. Symptoms typically arise in young adulthood and most patients show clinical features before age 30. FSHD is characterized by progressive wasting and weakness of facial and shoulder-girdle muscles, although no consistent pattern of penetrance or severity exists. A hallmark characteristic of FSHD is asymmetrical muscle weakness. There are also non-muscular features including retinal vasculopathy and high frequency hearing loss. The current model of pathogenesis in FSHD involves mis-expression of the myotoxic DUX4 gene, but developing animal models has proven difficult. At previous meetings, we first described our transgenic reporter mice containing a putative DUX4 promoter cloned upstream of GFP. We generated three separate lines of DUX4 promoter-GFP mice to identify DUX4 expression patterns and the involvement of selected muscles in FSHD. In short, we found the DUX4 promoter directed GFP expression in the face and limbs of newborn and adult mice, as well as multiple cell types in the retina. Essentially all other organs were GFP negative with a few exceptions including the pancreas and brain. Closer analysis of GFP positive tissues has revealed extensive expression in both myogenic and neuronal cell types. Strikingly, all lines also showed variable penetrance and asymmetrical expression in all GFP-positive tissues, even within individual litters. We have recently created another transgenic line expressing a GFP-CRE fusion protein from the same DUX4 promoter. Importantly we see similar expression patterns to the original mice and are now using them to create an inducible DUX4 transgenic mouse. We have also created analogous AAV vectors to induce localized DUX4 expression at physiologically relevant levels. These models will aid in deciphering molecular mechanisms and developing therapeutic interventions for FSHD. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disorder that most commonly affects specific muscles of the face, shoulder girdle, and limbs. The molecular mechanisms underlying FSHD have recently emerged after several decades of study. Briefly, FSHD is associated with mis-expression of the DUX4 gene, which encodes a transcription factor that is toxic to mammalian muscle. We hypothesized that DUX4 may contribute to FSHD pathologies by initiating downstream gene expression changes that are incompatible with normal muscle homeostasis. In this study, our objective was to characterize prospective DUX4-controlled pathways with the goals of further defining the pathogenic events involved in FSHD, and potentially identifying therapeutic targets. Through expression profiling of DUX4-expressing mouse muscles, we found upregulation of several pro-apoptotic genes in the p53 pathway, suggesting that DUX4 myotoxicity may involve activation of p53-dependent programmed cell death. We are pursuing several p53-pathway candidates, but in this study we focused on one gene: the p53 homolog p63. Using multiple approaches, we found that DUX4 directly bound to both mouse and human p63 promoters and preferentially transactivated the cytotoxic isoform of p63 from each. Moreover, we showed that p63 co-localized with DUX4 in myofiber nuclei of DUX4-overexpressing mouse muscle and was elevated in primary muscle cells from FSHD patients compared to normal controls. Importantly, p63 inhibition mitigated the pro-apoptotic activity of over-expressed DUX4 in vitro and we are now confirming this genetically by investigating the effects of DUX4 expression in muscle-specific p63 knockout mice. Together, our results suggest that p63 is a downstream target of DUX4 and may play an important role in DUX4-mediated cell death. FSHD therapies may therefore involve disrupting the DUX4-p63 axis in FSHD-affected muscles. [Copyright &y& Elsevier]

Abstract: Limb-girdle muscular dystrophy refers to a group of 23 disorders characterized by progressive wasting and weakness of shoulder and hip girdle muscles. The onset and progression of LGMD varies among individuals and genetic subtypes. Pre-clinical studies support that gene therapy is a promising treatment approach for the LGMDs, and importantly one such strategy (for LGMD2D) was recently translated to human clinical trials. Despite the positive direction of LGMD-targeted gene therapies, all strategies to date focused on gene replacement approaches for recessive forms, while treatments for dominant LGMDs have been largely unexplored. This lack of focus on gene therapy for dominant LGMDs arose primarily because these disorders require disease gene knockdown, and the molecular tools to feasibly accomplish this did not exist until recently, with the emergence of RNA interference (RNAi). We hypothesized that patients with dominantly inherited LGMD would benefit from RNAi-mediated reduction of the pathogenic alleles underlying their disease. In this study, we developed the first RNAi-based, pre-clinical treatment for LGMD1A, caused by dominant mutation in one allele of the myotilin (MYOT) gene. To do this, we engineered and delivered MYOT-targeted artificial microRNA (miMYOT) vectors to knockdown mutant MYOT in muscles of an LGMD1A mouse model. Three months after treatment, miMYOT vectors significantly reduced soluble mutant MYOT protein to undetectable levels, and the protein aggregates that are characteristic of LGMD1A were either absent or very small in treated muscles. This reduction was associated with significantly improved muscle mass and whole muscle strength in LGMD1A mice. We are now assessing body wide improvements of miMYOT treatment following global vascular delivery. This work is an important first step toward translating targeted RNAi gene therapy approaches for LGMD1A, and our method could be adapted to impact a large class of dominant muscle disorders. [Copyright &y& Elsevier]

Discusses the nature and treatment of glaucoma. Leading cause of irreversible blindness; Number of people affected by the year 2000; The disease an optic neuropathy; Impact of axonal loss; Most forms painless; Diagnosis of the condition; Treatment with beta-adrenergic-antagonist drugs; Prostaglandin analogues; Adrenergic-agonist drugs; Carbonic anhydrase inhibitors; Cholinergic agonists; Cannabinoids.

Abstract: The processes by which crustal rocks are buried to tremendous depths and subsequently exhumed to Earth''s surface remain controversial. Rapid exhumation of Earth''s youngest (ultra-) high-pressure (UHP) rocks in the Woodlark Basin, Papua New Guinea, is occurring within an active rift, in contrast to more common scenarios of UHP exhumation during plate convergence. We use 2D and 3D thermo-mechanical models to demonstrate that UHP exhumation can result from feedback between rifting and the diapiric rise of a previously subducted continental fragment through the lithosphere. We infer that this feedback is responsible for the exhumation of the UHP rocks in gneiss domes in the Woodlark Basin. Our models successfully reproduce UHP exhumation paths and rates, and geological structures within the gneiss domes. We show that UHP exhumation by diapirism is mechanically consistent in post-collisional rifts. Our models highlight the complex feedback between diapiric ascent and extension. [Copyright &y& Elsevier]

Purpose: To report a case of progressive axial myopia associated with traumatic glaucoma in a juvenile patient with no systemic disease.Design: Interventional case report.Methods: In a 15-year-old male, serial ocular examinations, including manifest refraction, tonometry, and axial eye length measurement, were performed over a 6-year period, beginning with blunt trauma, right eye, followed by a series of surgical procedures for traumatic cataract and glaucoma.Results: A 4-diopter myopic shift (from -1.25 to -5.25) with a 1.5 mm increase in the axial eye length occurred, whereas the intraocular pressure increased from 21 to 46 mm Hg, during a 2-year period. The refraction, axial eye length, and intraocular pressure remained stable during the same period in the fellow, normal eye.Conclusion: Progressive axial myopia associated with traumatic glaucoma is possible in a juvenile patient in his late teens. [ABSTRACT FROM AUTHOR]

Purpose: Aniridia is a rare congenital eye disease, characterized by a constellation of symptoms including hypoplastic irides, foveal hypoplasia, early cataract, corneal stem cell deficiency, and glaucoma. Large chromosomal deletions spanning the PAX6 gene cause WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability [formerly called mental retardation]). We describe clinical and genetic studies of a three-generation pedigree with aniridia along with additional systemic conditions (morbid obesity, diabetes) suggesting the possibility of a contiguous-gene syndrome like WAGR. Methods: Clinical records were obtained and DNA was prepared from blood samples from three of the four patients and tested for mutations in the coding sequences of the PAX6 gene. The index patient also had cardiomyopathy and was tested for known cardiomyopathy genetic mutations using a next-generation DNA sequencing assay. Results: We discovered a novel intragenic PAX6 mutation, a 16 bp heterozygous deletion c.203delCCAGGGCAATCGGTGG, with Sanger sequencing that is the likely cause of autosomal dominant aniridia in this pedigree. This PAX6 deletion causes a frameshift in predicted protein translation and a subsequent premature termination, p.Pro68Leufs*6. The PAX6 deletion was detected in all three available family members with aniridia, the index patient, his mother, and his maternal aunt but was not observed in the Exome Aggregation Consortium (ExAC) database. Targeted sequencing of known cardiomyopathy genes in the index patient identified a second mutation, a 1.7 Mp deletion that spans the MYBPC3 gene. Conclusions: We report a pedigree with aniridia and other systemic abnormalities that were initially suspicious for a contiguous-gene syndrome like WAGR. However, genetic analysis of the pedigree revealed two independent genetic abnormalities on chromosome 11p: 1) a novel PAX6 mutation, and 2) a large chromosome deletion spanning MYBPC3, a known cardiomyopathy gene. It is unclear if morbid obesity and type II diabetes mellitus have a related genetic cause. [ABSTRACT FROM AUTHOR]

Purpose: Copy number variations (duplications) of TANK binding kinase 1 (TBK1) have been associated with normal tension glaucoma (NTG), a common cause of blindness worldwide. Mutations in other genes involved in autophagy (TLR4 and OPTN) have been associated with NTG. Here we report searching for additional proteins involved in autophagy that may also have roles in NTG. Materials and methods: HEK-293T cells were transfected to produce synthetic TBK1 protein with FLAG and S tags. Proteins that associate with TBK1 were isolated from HEK-293T lysates using tandem affinity purification (TAP) and polyacrylamide gel electrophoresis (PAGE). Isolated proteins were identified with mass spectrometry. A cohort of 148 NTG patients and 77 controls from Iowa were tested for glaucoma-causing mutations in genes that encode identified proteins that interact with TBK1 using high resolution melt (HRM) analysis and DNA sequencing. Results: TAP studies show that three proteins expressed in HEK-293T cells (NAP1, TANK and TBKBP1) interact with TBK1. Testing cohorts of NTG and normal controls for disease-causing mutations in TANK, identified a total of nine unique variants including three non-synonymous changes, one synonymous changes and five intronic changes. When analyzed alone or as a group, the non-synonymous TBK1 coding sequence changes were not associated with either NTG or primary open angle glaucoma. Conclusion: TAP showed that NAP1, TANK and TBKBP1 interact with TBK1 and are good candidates for contributing to NTG. A mutation screen of TANK detected three non-synonymous variants. Although, it remains possible that one or more of these TANK mutations may have a role in NTG, the data in this report do not provide statistical support for an association between TANK variants and NTG. [ABSTRACT FROM AUTHOR]

The article discusses the clinical features of primary open-angle glaucoma and mechanisms of elevated intraocular pressure and optic-nerve damage. Mutations in the myocilin (MYOC) gene are examined to illustrate the mechanisms of intraocular pressure. The authors explain that primary open-angle glaucoma is the second leading cause of blindness in the U.S. Risk factors including older age and black race are discussed. The effect of intraocular pressure on retinal ganglion cells and the structural changes of the optic-nerve head are also discussed.

Purpose: To study the concordance of diurnal intraocular pressure (IOP) between fellow eyes in primary open-angle glaucoma (POAG). Design: Retrospective chart review. Participants: Ninety-three POAG patients. Methods: Patients who met the definition of POAG and underwent diurnal curve measurement were included. Subjects were excluded if there was a history of surgery, trauma, ocular vascular disease, incomplete diurnal curve, or asymmetric ocular medication use. Patients on symmetric ocular medication were included and analyzed separately. Goldmann applanation tonometry was performed at 10 am, 1 pm, 4 pm, 7 pm, 10 pm, and 7 am (the next day). The following statistical analyses were performed: (1) average Pearson correlation coefficient (r) from individual correlations of right and left eye IOP over the 6 time points for each subject; (2) linear mixed model analysis for repeated measures, with eye (right and left) and time as the within-subject fixed effects, and (3) absolute difference in change in IOP between fellow eyes over each time interval and probability that the difference was within 2 or 3 mmHg. Main Outcome Measure: The concordance of the IOP between fellow eyes as measured by absolute difference in change in IOP between fellow eyes and probability of the difference being within 2 or 3 mmHg. Results: Thirty-seven patients were untreated and 56 were treated on symmetric IOP-lowering medications. The diurnal curves of fellow eyes exhibited parallel profiles according to the linear mixed model. The average difference in the change of IOP between fellow eyes over given time intervals ranged from 1.6 to 2.0 mmHg. The estimated probability that the absolute change in IOP between fellow eyes was within 2 mmHg was 68% to 90%, and within 3 mmHg was 78% to 95% for all time intervals. Conclusion: The diurnal variation of IOP in POAG is largely concordant between fellow eyes. For any given time interval, the fellow eye IOPs may fluctuate asymmetrically a minority of the time. Clinicians who utilize the uniocular trial should be aware of the limit of the IOP concordance. [Copyright &y& Elsevier]

Purpose: To identify the chromosomal location of the gene involved in the pathogenesis of cavitary optic disk anomalies in a large pedigree with autosomal dominant inheritance of disease.Design: Linkage analysis of a pedigree affected with cavitary optic disk anomalies.Methods: Optic disk photographs were examined for the presence of cavitary optic disk anomalies. Sixteen affected family members and one obligate carrier were identified and studied with linkage analysis using both microarrays of single nucleotide polymorphisms (SNPs) and short tandem repeat polymorphism (STRP) markers.Results: Multipoint linkage analysis of SNP genotypes yielded a maximum nonparametric logarithm of the odds (LOD) score of 21.7 with markers located on chromosome 12q. Linkage was confirmed with 16 STRP markers in the 12q region. A maximum two-point LOD score of 4.06 (theta = 0) was obtained with marker D12S1700. The disease interval defined by observed recombinants is 9.1 cM, which corresponds to 13.5 Mbp. Three candidate genes (GDF-11, NEUROD4, and WIF1) in the chromosome 12q locus were evaluated as possible disease-causing genes. No mutations were detected in the coding sequence of these genes.Conclusions: The discovery of the chromosomal location of a gene responsible for cavitary optic disk anomalies is a key step in identifying the genetic basis of this condition and ultimately may provide important insight into the pathogenesis of more common optic nerve diseases such as normal-tension glaucoma and primary open-angle glaucoma (POAG). [ABSTRACT FROM AUTHOR]

Purpose: To describe a multigenerational family with autosomal dominant inheritance of cavitary optic nerve head (ONH) anomalies and abnormal ONH vasculature. Design: Description of a single family with inherited eye disease. Methods: A four-generation pedigree was investigated. Examination included visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP) measurement, and ophthalmoscopy. Visual fields and fundus photography were obtained when possible. Results: Seventeen clinically affected individuals and two obligate carriers were identified. Most (64.7%) affected persons had bilateral involvement. Visual acuity in affected eyes ranged from 20/20 to no light perception. Although the appearance of affected nerves varied greatly, most lacked a well-formed central retinal artery and instead had multiple radial cilioretinal arteries. Prominent cupping was seen in most affected nerves. Four individuals for whom information was available were treated for glaucoma, but none had documented elevated IOP. Four eyes of two patients demonstrated progressive ONH cupping at normal IOPs. Nine (56.3%) of the 16 individuals for whom we had data had evidence of serous macular detachments; five of these had bilateral macular disease. Conclusions: A large family with autosomal dominant inheritance of cavitary ONH anomalies and abnormal vasculature is presented. Clinical phenotypes varied markedly. Progressive ONH cupping was documented in four eyes of two patients. Genetic linkage analysis of this family has identified the chromosomal location of a gene responsible for ONH development. This may provide insight into the pathogenesis of glaucomatous ONH damage. [Copyright &y& Elsevier]

Abstract: Inappropriate activity of the complement cascade contributes to the pathophysiology of several neurodegenerative conditions. This study sought to determine if components of the complement cascade are synthesized in the retina following the development of ocular hypertension (OHT) and if complement accumulates in association with retinal ganglion cells. Toward this goal the gene expression levels of complement components 1qb (C1qb) and 3 (C3) were determined in the retina by quantitative polymerase chain reaction in human eyes with elevated intraocular pressure (IOP) and healthy retinal tissue as well as in a rat model of OHT induced by laser cauterization of the trabecular meshwork and episcleral veins. Immunohistochemical methods were employed to determine the sites of complement deposition in the retina and optic nerve head. Our data demonstrate that transcript levels for C1q and C3 are significantly elevated in retinae subjected to OHT, both in the animal model as well as in human eyes. Immunohistochemical analyses indicate that C1q and C3 accumulate specifically in the retinal ganglion cell layer and the nerve fiber layer. In addition, we demonstrate that the terminal complement complex, or membrane attack complex, is formed both in the human and rat model as a consequence of OHT. Complement activation, particularly formation of membrane attack complexes, has the potential to exacerbate ganglion cell death through bystander lysis or glial cell activation. The results show that complement activation occurs in the retina that has been subjected to elevated IOP, and may have implications in pathophysiology of glaucoma. [Copyright &y& Elsevier]

: PurposeMutations of the forkhead transcription factor gene FOXC1 result in anterior segment anomalies. No description of the spectrum of defects resulting from a single point mutation of this gene exists in the ophthalmology literature. We have screened all available patients with Axenfeld–Rieger genes (PITX2 and FOXC1). In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1.: DesignObservational case series.: MethodsTen members of a multigenerational family were examined for signs of glaucoma, anterior segment abnormalities, and systemic features of Axenfeld–Rieger syndrome. The examinations were performed in an ophthalmology examination room or in the patients’ homes. Blood was obtained from 10 members and screened for mutations in FOXC1 using direct DNA sequencing.: ResultsA single mutation causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six members of the family. Five of these six patients were examined and all demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one had Rieger syndrome, and one had both Axenfeld anomaly and Peters anomaly. Additionally, some members demonstrated cardiac abnormalities, which may be secondary to their FOXC1 mutation.: ConclusionsA wide spectrum of clinical phenotypes can result from a single point mutation of FOXC1. This report confirms that Rieger syndrome (with dental and facial abnormalities) can be caused by a mutation in FOXC1. It is also the first report of Peters anomaly being caused by a FOXC1 mutation. [Copyright &y& Elsevier]

: PurposeTo study the rate and pattern of visual field decline in primary open-angle glaucoma.: DesignRetrospective observational case series.: ParticipantsForty eyes of 40 patients with primary open-angle glaucoma that were followed longitudinally with serial Goldmann visual fields for a minimum period of 8 years in an academic institution. Eyes with any other ocular disease except for mild cataract were excluded.: MethodsVisual fields obtained with worse than 20/50 Snellen visual acuity from cataract were excluded from analysis. In the remainder (671 Goldmann visual fields), the I4e isopter was quantified manually using a grid template previously described by Esterman. The visual field was divided into central and peripheral, superior and inferior, and nasal and temporal regions, all centered at the blind spot. The rate of visual field decline was estimated for each visual field region (including the four quadrants: superonasal [SN], superotemporal [ST], inferotemporal [IT], and inferonasal [IN]) using linear regression. Asymmetry of visual field progression was determined by comparing the rates of progression among the four quadrants. Pertinent clinical factors were evaluated for association with the asymmetry of visual field progression.: Main outcome measuresRates of visual field decline for the entire visual field and each region. Long-term clinical outcome measures, including visual acuity, cataract and cup-to-disc ratio progression, intraocular pressures, and medical and surgical interventions were also studied.: ResultsThe rate of visual field change was −1.3% per year for the entire visual field. The rates of visual field section change (in % per year) were −1.3 (central), −1.4 (peripheral), −1.5 (superior), −1.2 (inferior), −1.4 (nasal), −1.2 (temporal), −1.8 (SN), −1.3 (IT), −1.2 (IN), and −1.1 (ST). About half the patients showed symmetric visual field decline, whereas others showed a more asymmetric pattern. Asymmetric visual field progression was associated with the presence of disc hemorrhage, overall rate of visual field progression, and surgical intervention for glaucoma.: ConclusionsIn this group of selected patients with primary open-angle glaucoma with a long-term follow-up, all sections of the visual field declined over time. Disc hemorrhage was associated with more asymmetric visual field progression, implicating focal damage to the optic disc. [Copyright &y& Elsevier]

Purpose: To determine whether primary open-angle glaucoma (POAG) and ocular hypertensive (OHT) patients who harbor the myocilin Gln368Stop mutation differ in phenotype or clinical course from patients without the mutation.Design: Case-control study.Methods: A retrospective case-control study compared all known POAG patients (n = 18) and OHT patients (n = 4) harboring the Gln368Stop mutation evaluated by the University of Iowa Glaucoma Service with control patients from the same population. Patients and control subjects were matched for diagnosis, age, sex, and race and were compared for phenotype and clinical course.Results: Mean age of disease onset and mean peak intraocular pressures (IOPs) of cases were similar to those reported by other studies. There was no statistically significant difference between cases and controls for the following variables: age at onset, peak intraocular pressure, Snellen visual acuity, number of medications, Humphrey visual field (HVF) mean deviation, HVF pattern deviation, number of filtering surgeries performed, time intervals from diagnosis to argon laser trabeculoplasty (ALT), diagnosis to first filtering surgery, ALT to first filtering surgery, and percent change in IOP after ALT and after first filtering surgery.Conclusions: There is no statistically significant difference between the onset and clinical course of POAG and OHT caused by the Gln368Stop mutation and POAG and OHT not associated with the mutation. [ABSTRACT FROM AUTHOR]

Genetic factors have long been implicated in the pathophysiology of primary open-angle glaucoma (POAG). Recently, myocilin, a gene of unknown function, was associated with both juvenile open-angle glaucoma (JOAG) and POAG. Forty-three different myocilin mutations have been reported in open-angle glaucoma patients, and several large studies have suggested that as a group these mutations are associated with 3–4% of POAG in patient populations worldwide. Support for the pathogenicity of the individual myocilin mutations has been obtained from in vitro assays, statistical methods, and conservation of gene sequence arguments. Several of these myocilin mutations were observed in multiple patients allowing the identification of mutation-specific glaucoma phenotypes (maximum intraocular pressure and age at diagnosis). Associations between myocilin and other forms of open-angle glaucoma have been explored. At present there is no evidence to link myocilin mutations and steroid-induced ocular hypertension or normal-tension glaucoma. Clinical vignettes of POAG patients from four generations of a family harboring the TYR437HIS myocilin mutation are presented, highlighting the benefits of elucidating the genetics of glaucoma. [Copyright &y& Elsevier]