Gender Diversity on Corporate Boards Associated with Ophthalmology.

PURPOSE: Enhancing diversity on boards has been linked to greater profitability and innovation. Unfortunately, there remains an underrepresentation of women in executive management and leadership positions in the ophthalmic corporate world. The purpose of these analyses was to examine the gender composition of directors for boards associated with the discipline of ophthalmology. DESIGN: Cross-sectional research design. METHODS: Using contemporary data, we examined a specific cohort, the American Academy of Ophthalmology (AAO) Foundation Ophthalmic Business Council corporate members as reported in the annual 2019 meeting program (N = 23). The board composition was analyzed using an online search of publicly available information in January and February 2020. The specific outcome measures included the number and percentage of women board members and their roles. RESULTS: There were a total of 23 Ophthalmic Business Council members with publicly available data; 37 of 195 total directorship seats (19%) were held by women, and 9 of 23 companies (39%) listed women as previous or current chairs of committees or outside corporations. Four of the 23 (17%) members of the Ophthalmic Business Council corporations had no women directors. CONCLUSIONS: The boards of directors of the AAO Foundation Ophthalmic Business Council corporate members remain predominately male. Despite the increasing number of women entering the specialty, women remain underrepresented in the corporate world of ophthalmology. Gender parity on boards is essential for the economic well-being of ophthalmic corporations as well as the relationship of the Ophthalmic Business Council with AAO members, health care systems, insurance carriers, government officials, and the public.

The impact of COVID-19 on rheumatology patients in a large UK centre using an innovative data collection technique: prevalence and effect of social shielding.

OBJECTIVES: We sought to gain insight into the prevalence of COVID-19 and the impact stringent social distancing (shielding) has had on a large cohort of rheumatology (RD) follow-up patients from a single large UK centre. METHODS: We linked COVID-19-related deaths, screening and infection rates to our RD population (1.2.20-1.5.20) and audited active rheumatology follow-up patients through survey data communicated via a linked mobile phone SMS message. We assessed epidemiology, effect of stringent social distancing (shielding) and quality of life (HRQoL) by Short Form 12 (SF12). RESULTS: There were 10,387 active follow-up patients, 7911 had linked mobile numbers. 12/10,387 RD patients died from COVID-19 (0.12%); local population 4131/7,415,149 (0.12%). For patients with mobile phones, 1693/7911 (21%) responded and of these, 1605 completed the SF12. Inflammatory arthritis predominated 1174/1693 (69%); 792/1693 (47%) were shielding. Advice on shielding/distancing was followed by 1372/1693(81%). 61/1693 (4%) reported COVID-19 (24/61 shielding); medication distribution was similar in COVID and non-COVID patients. Mental SF12 (MCS) but not physical (PCS) component scores were lower in COVID (60) vs. non-COVID (1545), mean differences: MCS, - 3.3; 95% CI - 5.2 to - 1.4, P < 0.001; PCS, - 0.4; 95% CI, - 2.1 to 1.3). In 1545 COVID-negative patients, those shielding had lower MCS (- 2.1; 95% CI - 2.8 to - 1.4) and PCS (- 3.1, 95% CI - 3.7 to - 2.5), both P < 0.001. CONCLUSIONS: Our full RD cohort had no excess of COVID deaths compared to the general local population. Our survey data suggest that shielding adversely affects both mental and physical health in RD. These data broaden our understanding of shielding, indicating need for further study.

Circadian time series proteomics reveals daily dynamics in cartilage physiology.

OBJECTIVE: Cartilage in joints such as the hip and knee experiences repeated phases of heavy loading and low load recovery during the 24-h day/night cycle. Our previous work has shown 24 h rhythmic changes in gene expression at transcript level between night and day in wild type mouse cartilage which is lost in a circadian clock knock-out mouse model. However, it remains unknown to what extent circadian rhythms also regulate protein level gene expression in this matrix rich tissue. METHODS: We investigated daily changes of protein abundance in mouse femoral head articular cartilage by performing a 48-h time-series LC-MS/MS analysis. RESULTS: Out of the 1,177 proteins we identified across all time points, 145 proteins showed rhythmic changes in their abundance within the femoral head cartilage. Among these were molecules that have been implicated in key cartilage functions, including CTGF, MATN1, PAI-1 and PLOD1 & 2. Pathway analysis revealed that protein synthesis, cytoskeleton and glucose metabolism exhibited time-of-day dependent functions. Analysis of published cartilage proteomics datasets revealed that a significant portion of rhythmic proteins were dysregulated in osteoarthritis and/or ageing. CONCLUSIONS: Our circadian proteomics study reveals that articular cartilage is a much more dynamic tissue than previously thought, with chondrocytes driving circadian rhythms not only in gene transcription but also in protein abundance. Our results clearly call for the consideration of circadian timing mechanisms not only in cartilage biology, but also in the pathogenesis, treatment strategies and biomarker detection in osteoarthritis.

A pragmatic proposal for triaging DXA testing during the COVID-19 global pandemic.

The COVID-19 pandemic has resulted in huge disruption to healthcare provision, including to dual-energy X-ray absorptiometry (DXA) imaging. Increased waiting lists for DXA from the pandemic mean potential long and uncertain delays in treatment for osteoporosis. To address these increased waiting lists, we propose a rapid, simple, one-stop algorithm incorporating medication use (aromatase inhibitor, corticosteroid) and clinical risk stratification supplementing a standard FRAX assessment. Our pragmatic algorithm produces a recommendation to treat empirically, image with DXA, or observe. If applied, we model a significant reduction in DXA scan requirements with a corresponding reduction in treatment delays for those awaiting DXA. We estimate this will reduce DXA scan numbers by about 50%, whilst pragmatically ensuring those with the highest clinical need correctly receive treatment without delay. This algorithm will help many clinicians including general practitioners/family physicians prioritise DXA when they may not always have the expertise to make this judgement based on clinical information alone. Although we have used UK guidelines as an example, this approach is flexible enough for adaptation by other countries based on their local guidelines, licensing, prescribing requirements, and DXA waiting list times. There are some limitations to our proposal. However, it represents one way of managing the uncertainty of the current COVID-19 pandemic.

Phosphorylation-deficient G-protein-biased µ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects.

Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the µ-opioid receptor and interaction with ß-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit ß-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that ß-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute µ-opioid receptor desensitization and long-term tolerance.

Histomorphological changes in endometriosis in a patient treated with ulipristal: A case report.

BACKGROUND: Selective progesterone receptor modulators have shown efficacy in the treatment of endometriosis, however they are not currently licensed in Canada for this purpose. Their histomorphological effects have been well documented in the endometrium, but not in endometriosis. CASE REPORT: The patient presented with uterine fibroids and heavy menstrual bleeding, and was treated with ulipristal acetate over three 90-day courses. She eventually elected to undergo definitive surgical management. On pathological examination, she was found to have a focus of endometriosis in the para-tubal soft tissue showing a morphology similar to progesterone receptor modulator associated endometrial changes (PAEC). CONCLUSIONS: To our knowledge this is the first reported case of PAEC involving a focus of endometriosis. This case demonstrates histomorphological evidence of the effects of ulipristal acetate on endometriosis, and thus provides evidence of a pharmacological effect.

Utility of circulating serum miRNAs as biomarkers of early cartilage degeneration in animal models of post-traumatic osteoarthritis and inflammatory arthritis.

OBJECTIVE: The purpose of this study was to determine if serum microRNA (miRNA) signatures were biomarkers of early cartilage degeneration in preclinical mouse models of post-traumatic osteoarthritis (OA) and inflammatory arthritis. METHODS: Cartilage degeneration was induced in 10-12 week old male C57BL6 mice by destabilization of the medial meniscus (DMM) or intra-articular injection of methylated-bovine-serum-albumin (AIA), with sham-operated or saline-injected control animals (n = 6/treatment/time). Total serum RNA and knee joints were isolated at 1, 4 and 16 weeks post-induction. Cartilage degeneration was scored histologically. Serum miRNA expression profiling was performed using Agilent microarrays and validated by qPCR. RESULTS: DMM-operated and AIA mice had characteristic cartilage degeneration (proteoglycan loss, chondrocyte hypertrophy, structural damage), that increased significantly with time compared with controls, and with distinct temporal differences between arthritis models. However, expression profiling revealed no statistically significant dysregulation of serum miRNAs between AIA vs saline-injected or DMM vs sham-operated control mice at the critical early disease stages. The inability to detect DMM or AIA serum miRNA signatures compared with controls was not due to the insensitivity of the expression profiling approach since significant changes were observed in miRNA expression between the arthritis models and between time points. CONCLUSION: While distinct patterns of progressive cartilage degradation were induced in the arthritis models, we were unable to identify any serum miRNAs that were significantly dysregulated in early stages of disease compared with controls. This suggests circulating serum miRNAs may not be useful as cartilage biomarkers in distinguishing the early or progressive stages of arthritis cartilage degeneration.

Free Nano-Object Ramsey Interferometry for Large Quantum Superpositions.

We propose an interferometric scheme based on an untrapped nano-object subjected to gravity. The motion of the center of mass (c.m.) of the free object is coupled to its internal spin system magnetically, and a free flight scheme is developed based on coherent spin control. The wave packet of the test object, under a spin-dependent force, may then be delocalized to a macroscopic scale. A gravity induced dynamical phase (accrued solely on the spin state, and measured through a Ramsey scheme) is used to reveal the above spatially delocalized superposition of the spin-nano-object composite system that arises during our scheme. We find a remarkable immunity to the motional noise in the c.m. (initially in a thermal state with moderate cooling), and also a dynamical decoupling nature of the scheme itself. Together they secure a high visibility of the resulting Ramsey fringes. The mass independence of our scheme makes it viable for a nano-object selected from an ensemble with a high mass variability. Given these advantages, a quantum superposition with a 100 nm spatial separation for a massive object of 10^{9} amu is achievable experimentally, providing a route to test postulated modifications of quantum theory such as continuous spontaneous localization.

The potential benefits of Zumba Gold(®) in people with mild-to-moderate Parkinson's: Feasibility and effects of dance styles and number of sessions.

OBJECTIVES: To assess the feasibility of Zumba Gold(®) in people with PD, and to investigate the effects of dance styles and number of sessions on activity levels and physiological load. DESIGN: Repeated measure uncontrolled (single group) feasibility study. SETTING: Eleven participants (age: 64.0±8.1years) with mild-to-moderate idiopathic PD (Hoehn & Yahr stage<3.0) took part in a screening session, followed by six Zumba Gold(®) workouts each separated by one week, and a follow-up interview six months later. MAIN OUTCOME MEASURES: The main feasibility parameters measured were retention, compliance, and adverse events. Furthermore, during each Zumba Gold(®) session, physical activity levels were measured using tri-axial accelerometers, while physiological load was assessed by average heart rate (HRmean). A two-way ANOVA with repeated measures assessed the effects of dance styles and session number on activity level and HR. RESULTS: 73% retention and 81% compliance were achieved, and no adverse events were recorded. Participants' enjoyment was high and 38% started Zumba Gold(®) classes in the community after intervention. HR values were similar between dance styles and within the American College of Sports Medicine (ACSM)'s recommendations in 50% of participants. Backwards steps reduced physiological load but improvements in activity levels between the first and last sessions show that steps could be learnt with time. CONCLUSIONS: Zumba Gold(®) is safe and enjoyable for people with PD. The excellent compliance and positive participants' feedback suggest the need for a larger-scale trial.

A dominant TRPV4 variant underlies osteochondrodysplasia in Scottish fold cats.

OBJECTIVE: Scottish fold cats, named for their unique ear shape, have a dominantly inherited osteochondrodysplasia involving malformation in the distal forelimbs, distal hindlimbs and tail, and progressive joint destruction. This study aimed to identify the gene and the underlying variant responsible for the osteochondrodysplasia. DESIGN: DNA samples from 44 Scottish fold and 54 control cats were genotyped using a feline DNA array and a case-control genome-wide association analysis conducted. The gene encoding a calcium permeable ion channel, transient receptor potential cation channel, subfamily V, member 4 (TRPV4) was identified as a candidate within the associated region and sequenced. Stably transfected HEK293 cells were used to compare wild-type and mutant TRPV4 expression, cell surface localisation and responses to activation with a synthetic agonist GSK1016709A, hypo-osmolarity, and protease-activated receptor 2 stimulation. RESULTS: The dominantly inherited folded ear and osteochondrodysplasia in Scottish fold cats is associated with a p.V342F substitution (c.1024G>T) in TRPV4. The change was not found in 648 unaffected cats. Functional analysis in HEK293 cells showed V342F mutant TRPV4 was poorly expressed at the cell surface compared to wild-type TRPV4 and as a consequence the maximum response to a synthetic agonist was reduced. Mutant TRPV4 channels had a higher basal activity and an increased response to hypotonic conditions. CONCLUSIONS: Access to a naturally-occurring TRPV4 mutation in the Scottish fold cat will allow further functional studies to identify how and why the mutations affect cartilage and bone development.

Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFкB-dependent pathway.

OBJECTIVE: To define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFα)) affect the circadian clock mechanism and the expression of clock-controlled catabolic genes within cartilage, and to identify the downstream pathways linking the cytokines to the molecular clock within chondrocytes. METHODS: Ex vivo cartilage explants were isolated from the Cry1-luc or PER2::LUC clock reporter mice. Clock gene dynamics were monitored in real-time by bioluminescence photon counting. Gene expression changes were studied by qRT-PCR. Functional luc assays were used to study the function of the core Clock/BMAL1 complex in SW-1353 cells. NFкB pathway inhibitor and fluorescence live-imaging of cartilage were performed to study the underlying mechanisms. RESULTS: Exposure to IL-1ß severely disrupted circadian gene expression rhythms in cartilage. This effect was reversed by an anti-inflammatory drug dexamethasone, but not by other clock synchronizing agents. Circadian disruption mediated by IL-1ß was accompanied by disregulated expression of endogenous clock genes and clock-controlled catabolic pathways. Mechanistically, NFкB signalling was involved in the effect of IL-1ß on the cartilage clock in part through functional interference with the core Clock/BMAL1 complex. In contrast, TNFα had little impact on the circadian rhythm and clock gene expression in cartilage. CONCLUSION: In our experimental system (young healthy mouse cartilage), we demonstrate that IL-1ß (but not TNFα) abolishes circadian rhythms in Cry1-luc and PER2::LUC gene expression. These data implicate disruption of the chondrocyte clock as a novel aspect of the catabolic responses of cartilage to pro-inflammatory cytokines, and provide an additional mechanism for how chronic joint inflammation may contribute to osteoarthritis (OA).

Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization.

OBJECTIVE: To investigate the in vivo role of the IRE1/XBP1 unfolded protein response (UPR) signaling pathway in cartilage. DESIGN: Xbp1(flox/flox).Col2a1-Cre mice (Xbp1(CartΔEx2)), in which XBP1 activity is ablated specifically from cartilage, were analyzed histomorphometrically by Alizarin red/Alcian blue skeletal preparations and X-rays to examine overall bone growth, histological stains to measure growth plate zone length, chondrocyte organization, and mineralization, and immunofluorescence for collagen II, collagen X, and IHH. Bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were used to measure chondrocyte proliferation and cell death, respectively. Chondrocyte cultures and microdissected growth plate zones were analyzed for expression profiling of chondrocyte proliferation or endoplasmic reticulum (ER) stress markers by Quantitative PCR (qPCR), and of Xbp1 mRNA splicing by RT-PCR to monitor IRE1 activation. RESULTS: Xbp1(CartΔEx2) displayed a chondrodysplasia involving dysregulated chondrocyte proliferation, growth plate hypertrophic zone shortening, and IRE1 hyperactivation in chondrocytes. Deposition of collagens II and X in the Xbp1(CartΔEx2) growth plate cartilage indicated that XBP1 is not required for matrix protein deposition or chondrocyte hypertrophy. Analyses of mid-gestation long bones revealed delayed ossification in Xbp1(CartΔEx2) embryos. The rate of chondrocyte cell death was not significantly altered, and only minimal alterations in the expression of key markers of chondrocyte proliferation were observed in the Xbp1(CartΔEx2) growth plate. IRE1 hyperactivation occurred in Xbp1(CartΔEx2) chondrocytes but was not sufficient to induce regulated IRE1-dependent decay (RIDD) or a classical UPR. CONCLUSION: Our work suggests roles for XBP1 in regulating chondrocyte proliferation and the timing of mineralization during endochondral ossification, findings which have implications for both skeletal development and disease.

Voltage transfer function as an optical method to characterize electrical properties of liquid crystal devices.

The voltage transfer function is a rapid and visually effective method to determine the electrical response of liquid crystal (LC) systems using optical measurements. This method relies on crosspolarized intensity measurements as a function of the frequency and amplitude of the voltage applied to the device. Coupled with a mathematical model of the device it can be used to determine the device time constants and electrical properties. We validate the method using photorefractive LC cells and determine the main time constants and the voltage dropped across the layers using a simple nonlinear filter model.

Distinct ocular expression in infants and children with Down syndrome in Cairo, Egypt: myopia and heart disease.

IMPORTANCE: The study establishes the importance of genetic background for the expression of Down syndrome phenotype. OBJECTIVE: To define the ocular manifestations of Down syndrome in infants and children in Cairo, Egypt, a historically isolated region, and compare them with systemic features and with findings in other geographic groups. DESIGN AND PARTICIPANTS: We prospectively studied the ocular status and systemic features of 90 infants and children with Down syndrome and monitored all patients for 3 years. The complete ophthalmic examinations were performed along with ultrasonography, if media opacities were evident. Thyroid and cardiac status were assessed. An extensive literature search for comparison was performed. SETTING: Outpatient clinical genetics department at the National Research Centre in Cairo, Egypt. MAIN OUTCOMES AND MEASURES: Ocular and systemic manifestations of Down syndrome in infants and children in Cairo, and comparison of these features with patients with this anomaly from other geographic regions and ethnic populations. RESULTS: Fifty-two infants or children (58%) had at least 1 abnormal ocular finding identified at the first visit. Significant refractive errors (in 37 [41%] patients) were the most common. Nasolacrimal duct obstruction, blepharoconjuctivitis, or conjunctivitis was found in 18 (20%), strabismus in 13 (14%), cataract in 5 (6%), nystagmus in 3 (3%), and optic nerve dysplasia in 2 (2%). Brushfield spots were not found. Additional ocular features developed over time. Thirty-six patients (40%) had congenital heart defects, and many (31 [86%]) had associated ocular disorders; a statistically significant correlation with myopia was established. Chromosomal translocations were high. The phenotype in Cairo was distinct. CONCLUSIONS AND RELEVANCE: More than half of infants and children with Down syndrome in Cairo had ophthalmic abnormalities; myopia was correlated with congenital heart defects. Comparison of the specific ocular features in our population with those in previous worldwide studies shows differences that may be related to overexpression or polymorphisms of key, modifying genes or other mutations in this historically isolated region along the Nile River. Down syndrome is more common in the highly consanguineous and multiparous Middle Eastern populations, and our Cairo findings underscore regional differences.

Exploratory study on the effect of osteoactivin on bone formation in the rat critical-size calvarial defect model.

BACKGROUND AND OBJECTIVE: Osteoactivin is a novel glycoprotein shown to exhibit an important role in regulating osteoblast differentiation and function. The aim of the present study was to evaluate the potential of osteoactivin to support bone regeneration using an established defect model. MATERIAL AND METHODS: Critical-size, 8-mm-diameter through-and-through calvarial osteotomy defects were created in 60 adult male Sprague-Dawley rats. Test animals received 0.1 mL of osteoactivin in phosphate-buffered saline (50 µg/mL) soak-loaded onto an absorbable collagen sponge. Controls received 0.1 mL of phosphate-buffered saline soak-loaded onto the absorbable collagen sponge or no further intervention (sham-surgery). The animals were euthanized 2 and 4 wk after treatment and histometric analyses were performed. RESULTS: The absorbable collagen sponge control (mean ± standard deviation: 40.9 ± 26.9%) showed borderline significant greater bone fill compared with sham-surgery (22.9 ± 15.8%; p = 0.10) and osteoactivin (20.2 ± 11.8%; p = 0.07) treatments at 2 wk. In contrast, osteoactivin (84.7 ± 15.8%) showed significantly greater bone fill than sham-surgery (28.4 ± 9.6%; p < 0.001) and absorbable collagen sponge (41.8 ± 22.1%; p < 0.001) at 4 wk. No animals receiving sham-surgery or absorbable collagen sponge exhibited complete bone fill at 4 wk while 70% of the animals receiving osteoactivin showed complete bone fill. CONCLUSION: Osteoactivin demonstrates a significant potential to support bone regeneration/formation. Studies using discriminating large animal models are necessary to explore clinical application for periodontal and craniofacial indications.

Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis.

OBJECTIVES: To investigate the regulation of sclerostin (SOST) in osteoarthritis (OA) and its potential effects on articular cartilage degradation. METHODS: SOST and other Wnt-ß-catenin components were immuno-localised in osteochondral sections of surgically-induced OA in knees of sheep and mice, and human OA samples obtained at arthroplasty. Regulation of SOST mRNA and protein expression by ovine chondrocytes in response to interleukin-1α (IL-1α) or tumour necrosis factor-α (TNFα) was examined in explant cultures. The effect of 25 or 250 ng/ml recombinant SOST alone or in combination with IL-1α, on ovine articular cartilage explant aggrecan degradation, and chondrocyte gene expression of Wnt-ß-catenin pathway proteins, metalloproteinases and their inhibitors, and cartilage matrix proteins was quantified. RESULTS: Contrary to being an osteocyte-specific protein, SOST was expressed by articular chondrocytes, and mRNA levels were upregulated in vitro by IL-1α but not TNFα. Chondrocyte SOST staining was significantly increased only in the focal area of cartilage damage in surgically-induced OA in sheep and mice, as well as end-stage human OA. In contrast, osteocyte SOST was focally decreased in the subchondral bone in sheep OA in association with bone sclerosis. SOST was biologically active in chondrocytes, inhibiting Wnt-ß-catenin signalling and catabolic metalloproteinase [matrix metalloproteinases (MMP) and distintegrin and metalloproteinase with thrombospndin repeats (ADAMTS)] expression, but also decreasing mRNA levels of aggrecan, collagen II and tissue inhibitors of metalloproteinaes (TIMPs). Despite this mixed effect, SOST dose-dependently inhibited IL-1α-stimulated cartilage aggrecanolysis in vitro. CONCLUSIONS: These results implicate SOST in regulating the OA disease processes, but suggest opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of cartilage.

Duane retraction syndrome, nystagmus, retinal pigment epitheliopathy and epiretinal membrane with micro- and pachygyria, developmental delay, hearing loss and craniopharyngioma.

PURPOSE: To report the association of Duane syndrome with nystagmus and a patterned hyperpigmentation of the retinal pigment epithelium, developmental delay, micro- and pachygyria and craniopharyngioma. CASE REPORT: We describe a 12-year old girl with developmental delay, hearing loss, cortical micro- and pachygyria, and a cystic craniopharyngioma; her ocular features include unilateral Duane syndrome, monocular nystagmus under binocular conditions, and a patterned hyperpigmentation of the retinal pigment epithelium. Her mother had similar retinal pigment epithelial abnormalities. CONCLUSIONS: The combination of two neuronal migrational disorders, the unusual retinal pigment epithelial abnormalities in the proband and her mother, and evidence that each feature may be genetic and are suggestive of a genetic basis for this constellation of features.

Regional review of patients with psoriatic arthritis in secondary care in the West Midlands: prevalence, disease activity and eligibility for anti-tumour necrosis factor therapy.

OBJECTIVES: Tumour necrosis factor alpha-blockers (TNF-alpha) are licensed for the treatment of psoriatic arthritis (PsA) and their use has been approved by the National Institute for Health and Clinical Excellence (NICE) for use in the United Kingdom under a set of defined clinical criteria. METHODS: In this out-patient study we evaluated PsA in rheumatology secondary care clinics in units across the West Midlands over a 2-week period, assessing prevalence, disease activity and eligibility for anti TNF-alpha treatment as defined by the NICE criteria. RESULTS: Of the 1718 forms returned from the 2000 sent (86% response rate), 175 patients had PsA (10.2%). Of those, 22 (12.6%) were already on anti TNF-alpha treatment. 12 patients were noted to have purely axial disease and as per the NICE guidelines should not be assessed under the PsA criteria. A further 5 patients fulfilled the criteria for treatment with anti TNF-alpha with no contraindications. In the region 22 out of 27 patients (81%) with active disease were correctly on Anti TNF therapy. In total 27 (15.4%) patients with PsA met the NICE criteria for treatment of PsA with anti TNF-alpha therapy. 3 patients had previously failed anti TNF-alpha treatment. No patient fulfilling criteria for treatment were found to have any contraindications to treatment. CONCLUSION: We note the relatively high proportion of PsA patients eligible for treatment with anti TNF-alpha blockers in the region (15.4%) compared to the NICE estimate (2.4%). This may be in part explained by a selection bias. However, the results may have significant implications for healthcare provision given the relatively high cost of anti-TNF-alpha agents. We comment on the limitations of such criteria and the effective use of regional collaboration for both training and audit purposes.

Clinical variability of autosomal dominant cataract, microcornea and corneal opacity and novel mutation in the alpha A crystallin gene (CRYAA).

We studied 28 individuals from a four-generation Chilean family (ADC54) including 13 affected individuals with cataracts, microcornea and/or corneal opacity. All individuals underwent a complete ophthalmologic exam. We screened with a panel of polymorphic DNA markers for known loci that cause autosomal dominant cataracts, if mutated, and refined the locus using the ABI Prism Linkage Mapping Set Version 2.5, and calculated two-point lod scores. Novel PCR primers were designed for the three coding exons, including intron-exon borders, of the candidate gene alpha A crystallin (CRYAA). Clinically, affected individuals had diverse and novel cataracts with variable morphology (anterior polar, cortical, embryonal, fan-shaped, anterior subcapsular). Microcornea and corneal opacity was evident in some. Marker D21S171 gave a lod score of 4.89 (theta(m) = theta(f) = 0). CRYAA had a G414A transition that segregated with the disease and resulted in an amino acid alteration (R116H). The phenotypic variability within this family was significant with novel features of the cataracts and a corneal opacity. With the exception of iris coloboma, the clinical features in all six previously reported families with mutations in the CRYAA gene were found in this family. We identified a novel G414A transition in exon 3 of CRYAA that co-segregated with an autosomal dominant phenotype. The resulting amino acid change R116H is in a highly conserved region and represents a change in charge. The genotype-phenotype correlation of this previously unreported mutation provides evidence that other factors, genetic and/or environmental, may influence the development of cataract as a result of this alteration.