Subconjunctival administration of low-dose murine allogeneic mesenchymal stromal cells promotes corneal allograft survival in mice.

BACKGROUND: Systemic administration of mesenchymal stromal cells (MSCs) has been efficacious in many inflammatory disease settings; however, little data are available on the potential immunomodulatory effects following local MSC administration in the context of corneal transplantation. The purpose of this study was to assess the potential of subconjunctival injection of MSCs to promote corneal allograft survival. METHODS: MSCs were isolated from female C57BL/6 (H-2k) or Balb/c (H-2d) mice and extensively characterized. An allogeneic mouse corneal transplant model was used with Balb/c mice as recipients of C57BL/6 grafts. A dose-finding study starting with 5 × 105 MSCs injected subconjunctivally at day - 7 was tested first followed by a more clinically translatable low-dose single or dual injection strategy on day - 1 and day + 1 before/after transplantation. Graft transparency served as the primary indicator of transplant rejection while neovascularization was also recorded. Lymphocytes (from draining lymph nodes) and splenocytes were isolated from treatment groups on day 2 post-transplantation and characterized by flow cytometry and qRT-PCR. RESULTS: Both high- and low-dose injection of allogeneic MSCs on day - 7 led to 100% graft survival over the observation period. Moreover, low-dose dual subconjunctival injection of 5 × 104 allogeneic MSCs on day - 1 or day + 1 led to 100% allograft survival in transplant recipients (n = 7). We also demonstrate that single administration of allogeneic MSCs on either day - 1 or day + 1 promotes rejection-free graft survival in 100% (n = 8) and 86% (n = 7) of transplanted mice, respectively. Early time point ex vivo analysis suggests modulation of innate immune responses towards anti-inflammatory, pro-repair responses by local MSC administration. CONCLUSION: This work demonstrates that low-dose subconjunctival injection of allogeneic MSCs successfully promotes corneal allograft survival and may contribute to refining future MSC immunotherapies for prevention of corneal allograft rejection.

Characterization of troponin I levels post synchronized direct current cardioversion of atrial arrhythmias in patients with and without cardiomyopathy.

BACKGROUND: Cardiac-specific markers of myocardial injury, such as troponin I (TnI), are often elevated following procedures that stimulate the myocardium. This study aimed to determine the effect of synchronized direct current (DC) cardioversion of atrial arrhythmias on myocardial injury 6-h post-procedure, as measured by cardiac TnI in patients with and without cardiomyopathy. METHODS: Seventy-three individuals (59 M:14 F) participated in this study. Inclusion criteria were subjects 18 and older undergoing DC cardioversion for an atrial arrhythmia, including elective and non-elective admissions. Exclusion criteria included MI or CABG within the past month, cardioversion for a ventricular arrhythmia, or recent shock by implantable internal cardioverter defibrillator. Patients underwent standard DC cardioversion procedure with blood work (TnI and CRP) prior to and 6-h post-cardioversion. Primary outcome was change in TnI. Secondary outcomes included changes in CRP, correlation of TnI with cumulative energy and LVM, and a sub-group analysis in patients with cardiomyopathy. RESULTS: There was no significant change in TnI following cardioversion (20.4 ± 7.9 vs. 17.5 ± 6.5 ng/L, F(1,72) = 2.651, p = 0.108). When stratified by cardiomyopathy status, there was a statistically significant reduction in TnI following cardioversion in the non-cardiomyopathy group (6.7 ± 3.7 ng/L vs. 6.2 ± 3.2 ng/L, F(1,58) = 6.481, p = 0.014) and a clinically significant reduction in the cardiomyopathy group (74.4 ± 136.7 ng/L vs. 54.6 ± 104.3 ng/L, F(1,13) = 3.676, p = 0.07). There was no significant relationship between change in TnI and cumulative energy or LVM (r = 0.137, p = 0.306 and r = 0.125, p = 0.412 respectively). CONCLUSIONS: Synchronized DC cardioversion of an atrial arrhythmia did not cause myocardial injury 6-h post-cardioversion. Sub-group analysis suggests that cardioversion of patients with cardiomyopathy may result in normalization of TnI levels.

Inferolateral T wave inversion in athletes: phenotype-genotype correlation.

AIMS: Significant T wave inversion in young asymptomatic athletes is rare but poses a significant clinical challenge. Pre-participation sports screening programs identify such subjects. Clinical concern that such ECG changes represent an occult cardiomyopathy or forme fruste hypertrophic cardiomyopathy leads to diagnostic and therapeutic dilemma. We sought to genotype a cohort of such subjects with a normal cardiac phenotype identified in our unit over a 3-year period. METHODS: Ten athletes were referred from external screening. All exhibited deep T wave inversion inferolaterally. All had negative family history for sudden death and had a normal phenotype. A panel of 133 cardiac genes were screened. RESULTS: Ten male subjects with mean age of 39 years were screened. Seven had no evidence of mutations. Three subjects demonstrated variants of uncertain significance in 5 different genes: alpha-2-actinin (ACTN2), myopalladin (MYPN), the calcium channel genes CACNA1C and TRPM4 and potassium channel gene KCNQ1. The variants found have not been described in cardiomyopathies or channelopathies. At 3-year follow-up, one patient had undergone detraining, and his ECG showed complete resolution of all T wave changes. He did not have any demonstrated variants. CONCLUSIONS: The absence of mutations in target genes and heterogeneous sequence variations identified in this study suggest that inferolateral T wave inversion in athletes without a phenotype may potentially represent a benign repolarization syndrome related to athletic adaptation. This was the first study to assess a phenotype-genotype correlation in this population. Further genetic studies need to be undertaken in this area.

A 24-month review of globe rupture in a tertiary referral hospital.

BACKGROUND: Globe rupture is a full thickness penetration of the ocular wall. It is a sight-threatening injury and requires emergent ophthalmic management. Prognosis for vision is dependent on the nature of the rupture, as well as clinical and intraoperative exam findings. AIMS: To identify the outcomes of globe rupture in the University Hospital Galway, a tertiary ophthalmic surgery referral unit, over a 24-month period. METHODS: A retrospective review in all cases of globe rupture was undertaken. The nature of the injury, vision, and exam findings at presentation, and intraoperative findings were recorded. Outcomes included vision at most recent follow-up, the development of complications, and the need for further surgery. RESULTS: A total of 12 cases were identified: 9 blunt injuries (assault, mechanical fall, workplace accident, self-inflicted) and 3 due to penetration with a sharp object (glass fragment, hammering). Globe rupture was almost twice as common in males under 40 years of age, compared with all patients over 40. All eyes with perception of light vision or less at presentation developed phthisis. Further surgery was required in a minority of cases. CONCLUSIONS: Globe rupture after a mechanical fall was most common in the over-75 age group. Globe rupture from assault, followed by workplace injury, was the most common injury in young males under 40. In an Irish setting, this represents a change in the aetiology of globe ruptures in young males compared with rates reported 20 years ago when workplace injuries were more common. The preventable nature of these injuries is highlighted.

Refractive error and vision problems in children: association with increased sedentary behavior and reduced exercise in 9-year-old children in Ireland.

PURPOSE: To investigate whether refractive error and vision problems in children are associated with increased sedentary behavior and reduced participation in physical activity and sport and, secondarily, to examine the relationship between vision problems and body mass index. METHODS: This was a cross-sectional study of the first wave of the Growing Up in Ireland (GUI) Study, a nationally representative study of children in Ireland. Data was collected between August 2007 and May 2008. Body mass index (BMI) was calculated at the time of the interview. The presence of a vision problem requiring treatment, including refractive error, was detected by report of the primary care giver, usually the mother. Association between vision problems and sedentary behavior, physical activity, and level of participation in sports was investigated in adjusted regression analysis. RESULTS: A total of 8,568 children (mean age, 9 ± 0.13 years; 4,024 [48.68%] males) were included. The presence of refractive error or a vision problem was reported for 1,000 (11.68%) children. The majority of children had normal weight, but 1,497 (17.5%) were overweight, and 446 (5.2%) were obese. A positive association between vision problems and sedentary behavior (P = 0.00089) and an inverse association with exercise (P = 0.01) were found. Overall, vision problems were not associated with BMI. CONCLUSIONS: In this study cohort, refractive error and vision problems were associated with increased sedentary behavior and decreased physical activity, although no causal relationship was established.

TNF-α/IL-1ß-licensed mesenchymal stromal cells promote corneal allograft survival via myeloid cell-mediated induction of Foxp3+ regulatory T cells in the lung.

Mesenchymal stromal cells (MSCs) have shown promise as a therapy for immune-mediated disorders, including transplant rejection. Our group previously demonstrated the efficacy of pretransplant, systemic administration of allogeneic but not syngeneic MSCs in a rat cornea transplant model. The aim of this study was to enhance the immunomodulatory capacity of syngeneic MSCs. In vitro, MSCs licensed with TNF-α/IL-1ß (MSCsTNF-α/IL-1ß) suppress syngeneic lymphocyte proliferation via NO production. In vivo, when administered post-transplantation, nonlicensed syngeneic MSCs improved graft survival from 0 to 50% and MSCsTNF-α/IL-1ß, in an NO-dependent manner, improved survival to 70%. Improved survival was associated with increased CD4+CD25+forkhead box P3+ regulatory T (Treg) cells and decreased proinflammatory cytokine expression in the draining lymph node. MSCsTNF-α/IL-1ß demonstrated a more potent immunomodulatory capacity compared with nonlicensed MSCs, promoting an immune-regulatory CD11b+B220+ monocyte/macrophage population and significantly expanding Treg cells in the lungs and spleen. Ex vivo, we observed that lung-derived myeloid cells act as intermediaries of MSC immunomodulatory function. MSC-conditioned myeloid cells suppressed stimulated lymphocyte proliferation and promoted expansion of Treg cells from naive lymphocytes. This work illustrates how syngeneic MSC therapy can be enhanced by licensing and optimization of timing strategies and further highlights the important role of myeloid cells in mediating MSC immunomodulatory capacity.-Murphy, N., Treacy, O., Lynch, K., Morcos, M., Lohan, P., Howard, L., Fahy, G., Griffin, M. D., Ryan, A. E., Ritter, T. TNF-α/IL-1ß-licensed mesenchymal stromal cells promote corneal allograft survival via myeloid cell-mediated induction of Foxp3+ regulatory T cells in the lung.

Corneal perforation in undiagnosed Sjögren's syndrome following topical NSAID and steroid drops post routine cataract extraction.

A 74-year-old man presented with a progressive decrease in visual acuity and foreign body sensation in his right eye 8 days post uncomplicated phacoemulsification cataract surgery and intraocular lens insertion. The patient had been placed on a perioperative cataract regimen which consisted of G. Maxitrol (dexamethasone, polymyxin B sulfate, neomycin sulfate) four times a day and G. Yellox twice daily (bromfenac, a non-steroidal anti-inflammatory) for 2 weeks. On examination, he had a corneal ulcer and stromal thinning in his right eye which progressed to a full thickness perforation 12 hours later. The patient required a full thickness tectonic corneal transplant. Direct questioning revealed that this patient had both dry mouth and eyes. Serology revealed that the patient was positive for rheumatoid factor and for anti-Ro and anti-La antibodies. A parotid gland biopsy revealed significant lymphocytic infiltrate consistent with Sjögren's syndrome.

Corneal Immunosuppressive Mechanisms, Anterior Chamber-Associated Immune Deviation (ACAID) and Their Role in Allograft Rejection.

Corneal transplantation is the most frequently performed transplant procedure in humans. Human leukocyte antigen matching, while imperative for other types of organ transplants, is usually not performed before cornea transplantation. With the use of topical steroid immunosuppressants, which are subsequently tailed off to almost zero, most corneal transplants will not be rejected in recipients with low risk of graft rejection. This phenomenon has been described as immune privilege by Medawar many years ago. However, this immune privilege is relative and can be easily eroded, e.g. by postoperative nonspecific inflammation or other causes of corneal or ocular inflammation. Interestingly, corneas that are at high risk of rejection have a higher failure rate than other organs. Considerable progress has been made in recent years to provide a better understanding of corneal immune privilege. This chapter will review current knowledge on ocular immunosuppressive mechanisms including anterior chamber-associated immune deviation and discuss their role(s) in corneal allograft rejection. Ultimately, this evolving information will be of benefit in developing therapeutic strategies to prevent corneal transplant rejection.

Resolution of idiopathic granulomatous orbital inflammation with intraorbital triamcinolone.

A 77-year-old man presented with a right lower eyelid swelling. Biopsy and histopathology of the lesion identified idiopathic granulomatous orbital inflammation. Clinical resolution of this patient's orbital mass was achieved with injection of 40 mg triamcinolone acetonide, perilesionally, at three sites in the right orbit. Such treatment may thus form an alternative to oral corticosteroid therapy in the management of granulomatous orbital inflammation.

Simultaneous isolated bilateral superior orbital vein thrombosis as a presenting feature of antiphospholipid syndrome.

PURPOSE: To report a rare case of isolated bilateral simultaneous superior ophthalmic vein occlusions secondary to antiphospholipid syndrome. CASE REPORT: We report the case of a 77-year-old female who presented with a one week history of right relative proptosis, conjunctival injection and optic disc swelling. Magnetic resonance imaging revealed bilateral orbital masses which were diagnosed as superior ophthalmic vein occlusion. The patient was anticoagulated and the lesions resolved completely. System cardiovascular and haematological work-up revealed the patient was suffering from anti-phospholipid syndrome. CONCLUSION: Although superior ophthalmic vein occlusion is rare, it is an important differential as orbital biopsy is to be avoided. This is only the second reported case secondary to antiphospholipid syndrome and the first such case with bilateral occlusions.

Multiple accessory pathways, dual AV nodal physiology, non-compacted myocardium and patent foramen ovale in a patient with Ebstein's anomaly: report of a case.

Ebstein's anomaly is a rare congenital cardiac disease initially described by Wilhelm Ebstein in 1866. The primary pathology involves significant apical displacement of the septal tricuspid valve leaflet and the presence of a redundant, elongated, anterior tricuspid valve leaflet. This congenital malformation has multiple known associated morphological and electrophysiological cardiac pathologies. In the present article, we report, to the best of our knowledge for the first time in the literature, a case of Ebstein's anomaly with multiple accessory bypass tracts, dual AV nodal physiology, non-compacted left ventricular myocardium and a patent foramen ovale. Indeed, complete evaluation of the left heart is required in cases of Ebstein's anomaly to accurately assess left ventricular myocardial structure.

Endophthalmitis secondary to corneal sutures: series of delayed-onset keratitis requiring intravitreal antibiotics.

PURPOSE: To describe 5 cases of endophthalmitis secondary to corneal sutures. SETTING: Department of Ophthalmology, University College Hospital, Galway, Ireland. METHODS: A retrospective review was done of 5 patients who presented over a period of 19 months with suture-related bacterial keratitis that progressed to endophthalmitis. Intravitreal antibiotics were used to control the infection. RESULTS: Despite intensive topical broad-spectrum antibiotic treatment for suture-related infective keratitis, the infection progressed to endophthalmitis in all 5 patients. Intravitreal antibiotics resolved the infection. CONCLUSIONS: Corneal sutures are a risk factor for infective keratitis irrespective of their site. Suture-related keratitis may progress rapidly to endophthalmitis despite intensive topical antibiotics. Intravitreal antibiotics are indicated when endophthalmitis is present.