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Purpose -- The patient journey from detection of an eye problem by optometrists to assessment and treatment by ophthalmologists can be streamlined by direct referral from optometrist to hospital eye service (HES). This requires locally agreed guidelines and training and feedback for optometrists to ensure high diagnostic competence. The purpose of this paper is to evaluate the quality of the West Suffolk Direct Referral Scheme, one of the first direct referral schemes in the UK to include all ophthalmic sub-specialties.Design/methodology/approach -- Two-cycle audit of existing practice, including all new patients referred by optometrists and seen at West Suffolk Hospital during a three-month period in 2003 and a seven-week period in 2006. Three interventions: direct referral clinics for urgent patients; introduced in 2003; six-monthly training sessions for optometrists; and regular, prompt feedback via letter about individual consultation outcome. Prospective data collection via proforma in both cycles; additional retrospective data collection in the second cycle. Diagnostic accuracy, perception of urgency and request of subspecialty clinic were evaluated.Findings -- The direct referral scheme streamlines the patient journey, and patients with acute problems have fast access to HES. In total, 99 per cent of referrals are appropriate. Diagnostic competence is high (87 per cent), and has improved with tighter communication between HES and optometrists. Agreement is less for referral urgency (75 per cent) and choice of subspecialty clinic (74 per cent).Originality/value -- The West Suffolk Direct Referral Scheme provides an efficient service of high quality. Good communications and continued feedback between community- and hospital-based eye care services improve standards and facilitate efficient use of resources. [ABSTRACT FROM AUTHOR]

Clinical and basic science applications using adipose-derived stem cells (ADSCs) are gaining popularity. The current adipose tissue harvesting procedures introduce nonphysiological conditions, which may affect the overall performance of the isolated ADSCs. In this study, we elucidate the differences between ADSCs isolated from adipose tissues harvested within the first 5 min of the initial surgical incision (well-vascularized, nonpremedicated condition) versus those isolated from adipose tissues subjected to medications and deprived of blood supply during elective free flap procedures (ischemic condition). ADSCs isolated from well-vascularized and ischemic tissues positively immunostained for several standard stem cell markers. Interestingly, the percent change in the CD36 expression for ADSCs isolated from ischemic versus well-vascularized tissue was significantly lower in males than females ( p < 0.05). Upon differentiation and maturation to adipocytes, spheroids formed using ADSCs isolated from ischemic adipose tissue had lower triglyceride content compared to those formed using ADSCs isolated from the well-vascularized tissue ( p < 0.05). These results indicate that ADSCs isolated from ischemic tissue either fail to uptake fatty acids or fail to efficiently convert those fatty acids into triglycerides. Therefore, more robust ADSCs suitable to establish in vitro adipose tissue models can be obtained by harvesting well-vascularized and nonpremedicated adipose tissues.

The generation of big data has enabled systems-level dissections into the mechanisms of cardiovascular pathology. Integration of genetic, proteomic, and pathophysiological variables across platforms and laboratories fosters discoveries through multidisciplinary investigations and minimizes unnecessary redundancy in research efforts. The Mouse Heart Attack Research Tool (mHART) consolidates a large data set of over 10 yr of experiments from a single laboratory for cardiovascular investigators to generate novel hypotheses and identify new predictive markers of progressive left ventricular remodeling after myocardial infarction (MI) in mice. We designed the mHART REDCap database using our own data to integrate cardiovascular community participation. We generated physiological, biochemical, cellular, and proteomic outputs from plasma and left ventricles obtained from post-MI and no-MI (naïve) control groups. We included both male and female mice ranging in age from 3 to 36 mo old. After variable collection, data underwent quality assessment for data curation (e.g., eliminate technical errors, check for completeness, remove duplicates, and define terms). Currently, mHART 1.0 contains >888,000 data points and includes results from >2,100 unique mice. Database performance was tested, and an example is provided to illustrate database utility. This report explains how the first version of the mHART database was established and provides researchers with a standard framework to aid in the integration of their data into our database or in the development of a similar database. NEW & NOTEWORTHY The Mouse Heart Attack Research Tool combines >888,000 cardiovascular data points from >2,100 mice. We provide this large data set as a REDCap database to generate novel hypotheses and identify new predictive markers of adverse left ventricular remodeling following myocardial infarction in mice and provide examples of use. The Mouse Heart Attack Research Tool is the first database of this size that integrates data sets across platforms that include genomic, proteomic, histological, and physiological data.

Chronic inflammatory diseases, such as periodontal disease, associate with adverse wound healing in response to myocardial infarction (MI). The goal of this study was to elucidate the molecular basis for impaired cardiac wound healing in the setting of periodontal-induced chronic inflammation. Causal network analysis of 168 inflammatory and extracellular matrix genes revealed that chronic inflammation induced by a subseptic dose of Porphyromonas gingivalis lipopolysaccharide (LPS) exacerbated infarct expression of the proinflammatory cytokine Ccl12. Ccl12 prevented initiation of the reparative response by prolonging inflammation and inhibiting fibroblast conversion to myofibroblasts, resulting in diminished scar formation. Macrophage secretion of Ccl12 directly impaired fibronectin and collagen deposition and indirectly stimulated collagen degradation through upregulation of matrix metalloproteinase-2. In post-MI patients, circulating LPS levels strongly associated with the Ccl12 homologue monocyte chemotactic protein 1 (MCP-1). Patients with LPS levels ≥ 1 endotoxin units (EU)/ml (subseptic endotoxemia) at the time of hospitalization had increased end diastolic and systolic dimensions compared with post-MI patients with < 1 EU/ml, indicating that low yet pathological concentrations of circulating LPS adversely impact post-MI left ventricle (LV) remodeling by increasing MCP-1. Our study provides the first evidence to our knowledge that chronic inflammation inhibits reparative fibroblast activation and generates an unfavorable cardiac-healing environment through Ccl12-dependent mechanisms.

PurposeThe aim of this report is to increase awareness of a possible association between cranial nerve paresis and the use of sumatriptan in migraine sufferers, particularly in patients who have additional vascular risk factors.Patients and methodsWe describe a series of three cases where third nerve paresis developed in patients who were treated with the oral form of sumatriptan. All of the patients had a clear history of repetitive migraine headache and none of them had previous third nerve paresis.ConclusionAmong a variety of medications for the treatment of migraine, there are some drugs with vasoconstrictive effects, particularly triptans. These drugs may be a contributing factor for microvascular damage of the cranial nerves and other organs.

Aims: Although macrophage phenotypes have been well studied in the myocardial infarction (MI) setting, this study investigated temporal neutrophil polarization and activation mechanisms., Methods and Results: Neutrophils isolated from the infarcted left ventricle (LV) of mice showed high expression of proinflammatory markers at Day 1 and anti-inflammatory markers at Days 5 and 7 post-MI, indicating distinct neutrophil phenotypes along the post-MI time continuum. Flow cytometry analysis revealed that although proinflammatory N1 neutrophils were always predominant (>80% of total neutrophils at each time point), the percentage of N2 neutrophils increased post-MI from 2.4 ± 0.6% at Day 1 to 18.1 ± 3.0% at Day 7. In vitro, peripheral blood neutrophils were polarized to proinflammatory N1 by lipopolysaccharide and interferon-γ or anti-inflammatory N2 by interleukin-4, indicating high plasticity potential. The in vivo post-MI relevant LV damage-associated molecular patterns (DAMPs) polarized neutrophils to a proinflammatory N1 phenotype by activating toll-like receptor-4. Transforming growth factor-β1 inhibited proinflammatory production in neutrophils. N1 neutrophils positively correlated with infarct wall thinning at Day 7 post-MI, possibly due to high production of matrix metalloproteinases-12 and -25., Conclusion: This study is the first to identify the existence of N1 and N2 neutrophils in the infarct region and reveals that N1 polarization could be mediated by DAMPs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling., Methods and Results: Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541 N-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all P<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP-9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post-myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression., Conclusions: Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis., (© 2015 American Heart Association, Inc.)

Purpose: Matrix metalloproteinases (MMPs) collectively degrade all extracellular matrix (ECM) proteins. Of the MMPs, MMP-9 has the strongest link to the development of cardiac dysfunction. Aging associates with increased MMP-9 expression in the left ventricle (LV) and reduced cardiac function. We investigated the effect of MMP-9 deletion on the cardiac ECM in aged animals., Experimental Design: We used male and female middle-aged (10- to16-month old) and old (20- to 24-month old) wild-type (WT) and MMP-9 null mice (n = 6/genotype/age). LVs were decellularized to remove highly abundant mitochondrial proteins that could mask identification of relative lower abundant components, analyzed by shotgun proteomics, and proteins of interest validated by immunoblot., Results: Elastin microfibril interface-located protein 1 (EMILIN-1) decreased with age in WT (p < 0.05), but not in MMP-9 null. EMILIN-1 promotes integrin-dependent cell adhesion and EMILIN-1 deficiency has been associated with vascular stiffening. Talin-2, a cytoskeletal protein, was elevated with age in WT (p < 0.05), and MMP-9 deficiency blunted this increase. Talin-2 is highly expressed in adult cardiac myocytes, transduces mechanical force to the ECM, and is activated by increases in substrate stiffness. Our results suggest that MMP-9 deletion may reduce age-related myocardial stiffness, which may explain improved cardiac function in MMP-9 null animals., Conclusions: We identified age-related changes in the cardiac proteome that are MMP-9 dependent, suggesting MMP-9 as a possible therapeutic target for the aging patient., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Matrix metalloproteinase-9 (MMP-9) deletion attenuates collagen accumulation and dilation of the left ventricle (LV) post-myocardial infarction (MI); however the biomechanical mechanisms underlying the improved outcome are poorly understood. The aim of this study was to determine the mechanisms whereby MMP-9 deletion alters collagen network composition and assembly in the LV post-MI to modulate the mechanical properties of myocardial scar tissue. Adult C57BL/6J wild-type (WT; n=88) and MMP-9 null (MMP-9(-/-); n=92) mice of both sexes underwent permanent coronary artery ligation and were compared to day 0 controls (n=42). At day 7 post-MI, WT LVs displayed a 3-fold increase in end-diastolic volume, while MMP-9(-/-) showed only a 2-fold increase (p<0.05). Biaxial mechanical testing revealed that MMP-9(-/-) infarcts were stiffer than WT infarcts, as indicated by a 1.3-fold reduction in predicted in vivo circumferential stretch (p<0.05). Paradoxically, MMP-9(-/-) infarcts had a 1.8-fold reduction in collagen deposition (p<0.05). This apparent contradiction was explained by a 3.1-fold increase in lysyl oxidase (p<0.05) in MMP-9(-/-) infarcts, indicating that MMP-9 deletion increased collagen cross-linking activity. Furthermore, MMP-9 deletion led to a 3.0-fold increase in bone morphogenetic protein-1, the metalloproteinase that cleaves pro-collagen and pro-lysyl oxidase (p<0.05) and reduced fibronectin fragmentation by 49% (p<0.05) to enhance lysyl oxidase activity. We conclude that MMP-9 deletion increases infarct stiffness and prevents LV dilation by reducing collagen degradation and facilitating collagen assembly and cross-linking through preservation of the fibronectin network and activation of lysyl oxidase., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the role of matrix metalloproteinase (MMP)-9 deletion on citrate synthase (CS) activity postmyocardial infarction (MI)., Results: We fractionated left ventricle (LV) samples using a differential solubility-based approach. The insoluble protein fraction was analyzed by mass spectrometry, and we identified CS as a potential intracellular substrate of MMP-9 in the MI setting. CS protein levels increased in the insoluble fraction at day 1 post-MI in both genotypes (p<0.05) but not in the noninfarcted remote region. The CS activity decreased in the infarcted tissue of wild-type (WT) mice at day 1 post-MI (p<0.05), but this was not observed in the MMP-9 null mice, suggesting that MMP-9 deletion helps to maintain the mitochondrial activity post-MI. Additionally, inflammatory gene transcription was increased post-MI in the WT mice and attenuated in the MMP-9 null mice. MMP-9 cleaved CS in vitro, generating an ∼20 kDa fragment., Innovation: By applying a sample fractionation and proteomics approach, we were able to identify a novel MMP-9-related altered mitochondrial metabolic activity early post-MI., Conclusion: Our data suggest that MMP-9 deletion improves mitochondrial function post-MI.

Aim: The purpose of the study was to examine the results of frontalis brow suspension after levator excision in patients with ptosis, and to determine whether satisfactory cosmetic results can be achieved with this procedure., Methods: A retrospective case notes review of 13 patients (21 lids) undergoing levator weakening and frontalis brow suspension using autogenous fascia lata was performed. Seven patients (14 lids) were affected by the Marcus Gunn jaw-winking phenomenon. These had bilateral levator muscle excision. Five patients (5 lids) had unilateral congenital levator dystrophy (isolated congenital ptosis) with poor levator function. These had levator muscle excision on the normal side only. One patient (2 lids) had congenital aberrant regeneration of the third nerve. This patient had bilateral levator muscle excision. A successful result in terms of lid height was defined as a lid height within 1 mm of the desired height., Results: During the first post-operative month, 11 out of 21 lids were undercorrected by more than 1 mm, whilst 10 achieved a satisfactory lid height. At subsequent follow-up visits, 18 lids were within 1 mm of the desired height and only 3 lids of 2 patients remained undercorrected by more than 1 mm and required further surgery. There were no overcorrections., Conclusions: Excision of the levator muscle followed by brow suspension ptosis correction can reliably produce satisfactory cosmetic results with good symmetry of lid movement and position. It is used selectively in the normal upper lid in congenital ptosis with poor levator function and in both upper lids in synkinetic ptosis.

A novel phenotype in a 3-generation family with early-onset aponeurotic ptosis and corneal limbal vascularization is described. Karyotype analysis was normal in the proband, and autosomal dominant transmission is demonstrated.

A spectrum of retinal features has been recognised in association with incontinentia pigmenti. The majority of reported cases describe a rapidly progressive proliferative retinopathy, often leading to retinal detachment, emphasizing the potentially blinding nature of the disease. In some instances, the retinopathy has been noted to be less severe but follow-up has been short. We describe a young girl with incontinentia pigmenti in whom the retinopathy has shown a fluctuating but stable course over 13 years without treatment.

Purpose: To identify any consistent factors which may predict over- or undercorrection of congenital blepharoptosis treated by anterior levator resection., Methods: A retrospective case note review of 100 consecutive patients undergoing anterior levator resection for congenital blepharoptosis was performed to identify: (1) the amount of ptosis and degree of levator function present pre-operatively and (2) the surgical outcome. For unilateral ptosis, a successful result was defined as a lid level within 1 mm of the fellow lid following a single operation., Results: Seventy-six per cent of all unilateral cases had a successful outcome at 6 weeks following surgery, falling slightly to 74% by 6 months. The most common complications at 6 months were undercorrection (19%) and overcorrection (7%). All patients undercorrected at 6 months had a pre-operative levator function in the range of 4-10 mm with a mean of 6.4 mm, whereas all those overcorrected at 6 months had a levator function in the range 9-15 mm with a mean of 12.2 mm. In the whole population, the degree of levator function was a predictor of increased risk of overcorrection, with a trend towards predicting undercorrection as well., Conclusions: In this series of patients, pre-operative levator function was found to be the most significant predictor of surgical outcome for anterior levator resection.

Purpose: To evaluate the use of the MTI photoscreener (Medical Technology Inc, Iowa City, Iowa) in assessing and documenting lens abnormalities in the pediatric ophthalmology clinic., Methods: MTI photoscreener photographs of pediatric patients with lens abnormalities were taken to assess and document lens opacities and subluxation, to assist with explanations to parents, and to monitor progression of abnormalities. Postoperative photographs were taken to assess opacification of the posterior capsule and contact lens fit., Results: Nineteen children with lens abnormalities were examined. Twelve patients underwent surgery and 9 patients had postoperative photoscreener pictures. Illustrative cases are reported., Conclusion: The MTI photoscreener is a useful adjunct to clinical examination in the assessment and documentation of pediatric lens abnormalities.

Uveitis-glaucoma-hyphaema (UGH) syndrome is an unusual cause of transient monocular visual loss which may follow cataract extraction and intraocular lens implantation. If misdiagnosed as amaurosis fugax, patients may undergo unnecessary investigations and inappropriate treatment with aspirin.

Many isoprenylated proteins are known to participate in signal transduction, but not all have been identified. Using an in vitro prenylation screen, two human cDNAs (PTP(CAAXI) and PTP(CAAX2)) homologous to the rat PRL-1 and human OV-1 protein tyrosine phosphatase genes were identified. PTP(CAAXI) and PTP(CAAX2) were farnesylated in vitro by mammalian farnesyl:protein transferase, and epitope-tagged PTP(CAAX2) was prenylated in epithelial cells. Overexpression of PTP(CAAXI) and PTP(CAAX2) in epithelial cells caused a transformed phenotype in culture and tumor growth in nude mice. Thus, PTP(CAAXI) and PTP(CAAX2) represent a novel class of isoprenylated, oncogenic protein tyrosine phosphatases.