Upper eyelid motility in blepharoptosis and in the aging eyelid

PURPOSE. To study the metrics of lid saccades in blepharoptosis and to distinguish any differences in the dynamics of eyelid movements that are related to the cause of blepharoptosis and to aging. METHODS. The lid and vertical eye saccades of 7 patients with congenital blepharoptosis and those of 18 patients with aponeurogenic blepharoptosis, either involutional or rigid-contact-lens-induced, were recorded with electromagnetic search coils. For each saccade, two parameters were assessed: amplitude and peak velocity. Two age-matched control groups were assessed in the same manner. Repeated measures analysis of variance was used to investigate any observed differences between the included groups. RESULTS. Congenital and rigid-contact-lens-induced blepharoptosis were readily distinguishable from one another, as well as from the age-matched control group, in both lid saccadic amplitude and peak velocity. For example, 40 degrees downward lid saccades in the congenital blepharoptosis group averaged 22.9 degrees +/- 4.0 degrees (SD), whereas 30.0 degrees +/- 4.7 degrees lid saccades were made by the age-matched control group. The subjects in the two groups with aponeurogenic blepharoptosis also made lid saccades that were distinctive for their group (P: < 0.02), in both amplitude and peak velocity. For 40 degrees downward saccades in involutional and rigid-contact-lens-induced blepharoptosis, lid saccadic amplitude averaged 32.7 degrees +/- 4.3 degrees and 40.3 degrees +/- 3.5 degrees, respectively. Lid saccadic peak velocity declined significantly with age. Lid saccadic peak velocity for 40 degrees upward saccades in the younger control group averaged 401.7 +/- 11.4 deg/sec, whereas the older control group achieved an average peak velocity of 360.7 +/- 60.4 deg/sec. The lid saccadic dynamics in the involutional blepharoptosis group proved to be similar (P: > 0.05) in saccadic amplitude and peak velocity to those of age-matched controls. CONCLUSIONS. In diffe

State of the art of the Fontan strategy for treatment of univentricular heart disease [version 1; referees: 2 approved]

In patients with a functionally univentricular heart, the Fontan strategy achieves separation of the systemic and pulmonary circulation and reduction of ventricular volume overload. Contemporary modifications of surgical techniques have significantly improved survival. However, the resulting Fontan physiology is associated with high morbidity. In this review, we discuss the state of the art of the Fontan strategy by assessing survival and risk factors for mortality. Complications of the Fontan circulation, such as cardiac arrhythmia, thromboembolism, and protein-losing enteropathy, are discussed. Common surgical and catheter-based interventions following Fontan completion are outlined. We describe functional status measurements such as quality of life and developmental outcomes in the contemporary Fontan patient. The current role of drug therapy in the Fontan patient is explored. Furthermore, we assess the current use and outcomes of mechanical circulatory support in the Fontan circulation and novel surgical innovations. Despite large improvements in outcomes for contemporary Fontan patients, a large burden of disease exists in this patient population. Continued efforts to improve outcomes are warranted. Several remaining challenges in the Fontan field are outlined

Quantitative assessment of systolic left ventricular function with speckle-tracking echocardiography in adult patients with repaired aortic coarctation

Despite successful aortic coarctation (CoA) repair, systemic hypertension often recurs which may influence left ventricular (LV) function. We aimed to detect early LV dysfunction using LV global longitudinal strain (GLS) in adults with repaired CoA, and to identify associations with patient and echocardiographic characteristics. In this cross-sectional study, patients with repaired CoA and healthy controls were recruited prospectively. All subjects underwent echocardiography, ECG and blood sampling within 1 day. With speckle-tracking echocardiography, we assessed LV GLS on the apical four-, three- and two-chamber views. We included 150 subjects: 75 patients (57 % male, age 33.4 ± 12.8 years, age at repair 2.5 [IQR: 0.1–11.1] years) and 75 healthy controls of similar sex and age. LV GLS was lowe

Atrial function in Fontan patients assessed by CMR: Relation with exercise capacity and long-term outcomes

Objective: To assess the role of atrial function on exercise capacity and clinical events in Fontan patients. Design: We included 96 Fontan patients from 6 tertiary centers, aged 12.8 (IQR 10.1–15.6) years, who underwent cardiac magnetic resonance imaging and cardiopulmonary exercise testing within 12 months of each other from 2004 to 2017. Intra-atrial lateral tunnel (ILT) and extracardiac conduit (ECC) patients were matched 1:1 with regard to age, gender and dominant ventricle. The pulmonary venous atrium was manually segmented in all phases and slices. Atrial function was assessed by volume-time curves. Furthermore, atrial longitudinal and circumferential feature tracking strain was assessed. We determined the relation between atrial function and exercise capacity, assessed by peak oxygen uptake and VE/VCO2 slope, and events (mortality, listing for transplant, re-intervention, arrhythmia) during follow-up. Results: Atrial maximal and minimal volumes did not differ between ILT and ECC patients. ECC patients had higher reservoir function (21.1 [16.4–28.0]% vs 18.2 [10.9–22.2]%, p = .03), lower conduit function and lower total circumferential strain (13.8 ± 5.1% vs 18.0 ± 8.7%, p = .01), compared to ILT patients. Only for ECC patients, a better late peak circumferential strain rate predicted better VE/VCO2 slope. No other parameter of atrial function predicted peak oxygen uptake or VE/VCO2 slope. During a median follow-up of 6.2 years,

PDGF enhances orbital fibroblast responses to TSHR stimulating autoantibodies in Graves' ophthalmopathy patients

Purpose: Thyroid-stimulating hormone receptor (TSHR) stimulating autoantibodies are associated with Graves' ophthalmopathy (GO), the orbital manifestation of Graves' disease (GD). TSHR autoantibody levels and orbital TSHR expression levels correlate positively with GO disease activity. Platelet-derived growth factors (PDGF) are increased in GO and potently activate orbital fibroblast effector functions. We investigated the possible relationship between PDGF and TSHR expression on orbital fibroblasts and how that influences the immunopathological effects of TSHR autoantibodies on orbital fibroblast activity. Methods: Orbital fibroblasts were stimulated with PDGF-AA, PDGF-AB, and PDGF-BB, and TSHR expression was determined by flow cytometry. Stimulatory effects of bovine TSH and GD immunoglobulins on orbital fibroblasts (with or without PDGF-BB preincubation) were determined by IL-6, IL-8, chemokine (C-C motif) ligand (CCL)-2, CCL5, CCL7, and hyaluronan ELISA. The TSHR blocking antibody K1-70 and the cAMP inhibitor H89 were used to determine involvement of TSHR signaling. Results: PDGF-AB and PDGF-BB stimulation increased TSHR expression on orbital fibroblasts, whereas PDGF-AA did not. Furthermore, stimulation with bovine TSH and immunoglobulins from GD patients induced IL-6, IL-8, CCL2, and hyaluronan production by orbital fibroblasts, and PDGF-BB preincubation enhanced this response of orbital fibroblasts. Blocking studies with a TSHR blocking antibody and a cAMP inhibitor inhibited these effects, indicating the involvement of TSHR signaling and thus of TSHR stimulating autoantibodies herein. Conclusions: These findings indicate that PDGF-B containing PDGF isoforms amplify the immunopathological effects of TSHR-stimulating autoantibodies in GO patients by stimulating TSHR expression on orbital fibroblasts. Copyrigh

Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in graves' ophthalmopathy

Purpose: Platelet-derived growth factors (PDGF) are regulators of fibroblast activity that may be involved in the pathophysiology of Graves' ophthalmopathy (GO). We unraveled the expression and origin of PDGF family members in GO orbital tissue and investigated the effect of PDGF isoforms on IL-6 and hyaluronan production and proliferation by orbital fibroblasts. Methods: PDGF-A, PDGF-B, PDGF-C, PDGF-D, PDGF-Rα, and PDGF-Rβ expression was determined by real-time quantitative PCR and PDGF-A and PDGF-B protein expression was determined by Western blot in orbital tissues. Orbital tissues were immunohistochemically stained for PDGF-A and PDGF-B expression, together with stainings for T cells, monocytes, B cells, macrophages, and mast cells. Effects of PDGF-AA, PDGF-AB, and PDGF-BB on orbital fibroblast proliferation and IL-6 and hyaluronan production were examined. Finally, effects of PDGF-BB- and PDGF-AA-neutralizing antibodies on IL-6 and hyaluronan production in GO whole orbital tissue cultures were tested. Results: GO orbital tissue showed increased PDGF-A and PDGF-B mRNA and protein levels. Increased numbers of PDGF-A- and PDGF-B-positive monocytes, macrophages, and mast cells were present in GO orbital tissue. PDGF-BB stimulated proliferation and hyaluronan and IL-6 production by orbital fibroblasts the most, followed by PDGF-AB and PDGF-AA. Finally, in particular imatinib mesylate and PDGF-BB-neutralizing antibodies reduced IL-6 and hyaluronan production by whole orbital tis

Basic FGF and PDGF-BB synergistically stimulate hyaluronan and IL-6 production by orbital fibroblasts

Orbital fibroblast activation is a central pathologic feature of Graves' Ophthalmopathy (GO). Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been proposed to contribute to GO, but their effects on orbital fibroblasts are largely unknown.We found that bFGF stimulated proliferation and hyaluronan production, but not IL-6 production by orbital fibroblasts, while VEGF hardly affected orbital fibroblast activity. Remarkably, co-stimulation of orbital fibroblasts with bFGF and PDGF-BB synergistically enhanced IL-6 and hyaluronan production and displayed an additive effect on proliferation compared to either bFGF or PDGF-BB stimulation. Nintedanib, a FGF- and PDGF-receptor targeting drug, more efficiently blocked bFGF + PDGF-BB-induced IL-6 and hyaluronan production than dasatinib that only targets PDGF-receptor.In conclusion, bFGF may contribute to orbital inflammation and tissue remodeling in GO, especially through synergistic interaction with PDGF-BB. Multi-target therapy directed at the bFGF and PDGF pathways may potentially be of interest for the treatment of GO

Platelet-derived growth factor-BB: A stimulus for cytokine production by orbital fibroblasts in graves' ophthalmopathy

Purpose. Graves' ophthalmopathy (GO) is characterized by the infiltration of immune cells into the orbit, a process in which cytokines play a central role. Orbital fibroblasts are potent producers of cytokines on different stimuli. Recently, the authors showed increased expression of the PDGF-B chain in GO orbital tissue. The dimeric PDGF-BB molecule has been described to activate the NF-κB pathway, which is well recognized for its role in regulating cytokine production. This study was conducted to determine the role of PDGF-BB in the production of proinflammatory cytokines by orbital fibroblasts in GO. Methods. Orbital, lung, and skin fibroblasts were stimulated with PDGF-BB, and cytokine (IL-1β, IL-6, IL-8, IL-16, CCL2, CCL5, CCL7, TNF-α) production was measured by ELISA. Involvement of NF-κB activation through PDGF signaling was investigated by electrophoretic mobility shift assay, specific NF-κB inhibitors, and the PDGF-receptor kinase inhibitor imatinib mesylate. Results. IL-6, IL-8, CCL2, CCL5, and CCL7 production by orbital fibroblasts was increased by PDGF-BB stimulation, whereas IL-16, IL-1β, and TNF-α production was not affected. PDGF-BB induced NF-κB activity in orbital fibroblasts, and both NF-κB inhibitors and imatinib mesylate reduced PDGF-BB-induced cytokine production. Similar, but less vigorous, effects of PDGF-BB on cytokine production were observed in lung and skin fibroblasts. Conclusions. PDGF-BB is a potent inducer of proinflammatory cytokines via the NF-κB pathway in orbital fibroblasts, whereas cytokine production by fibroblasts from other anatomic locations showed a moderate response. These data suggest a possible role for PDGF-BB in regulating orbital inflammation in GO and identify the PDGF signaling cascade as a therapeutic target in GO

Not only hard contact lens wear but also soft contact lens wear may be associated with blepharoptosis

Objective: The authors attempt to establish an association between prolonged hard and soft contact lens wear and ptosis. Design: Single-center retrospective consecutive series. Participants: All patients between 18 and 50 years of age who were diagnosed with unilateral or bilateral ptosis between January 2002 and December 2005 (35 patients). Methods: In a retrospective consecutive series, we included all patients between 18 and 50 years of age, with unilateral or bilateral ptosis between January 2002 and December 2005. Patients with congenital ptosis, ophthalmic surgery or disease, trauma, giant papillary conjunctivitis, unknown duration of contact lens wear, or muscular or neurologic disorders were excluded. We compared this study group to a Dutch reference population (the total underlying population from which the ptosis cases derive). Results: The group included 35 patients: 20 (57%) (ages 18 to 50 years, average 37 years) had been wearing hard contact lenses for, on average, 17.6 years (range 6 to 27 years); 9 (26%) (ages 18 to 45 years, average 30 years) had been wearing soft contact lenses for, on average, 9 years (range 1.5 to 20 years); and 6 (17%) (ages 23 to 39 years, average 33 years) had no history of contact lens wear. The odds ratio for soft contact lenses was 14.7 (4.2 to 50.7; CI = 95) and for hard contact lenses 97.8 (22.5 to 424). Conclusions: This study suggests that not only hard contact lens wear but also soft contact lens wear may be associated with ptosis