CD4CD8 Double Positive T cell responses during Mycobacterium tuberculosis infection in cynomolgus macaques.

BACKGROUND: Tuberculosis (TB) kills millions of people every year. CD4 and CD8 T cells are critical in the immune response against TB. T cells expressing both CD4 and CD8 (CD4CD8 T cells) are functionally active and have not been examined in the context of TB. METHODS: We examine peripheral blood mononuclear cells (PBMC) and bronchoalveolar lavage cells (BAL) and lung granulomas from 28 cynomolgus macaques during Mycobacterium tuberculosis (Mtb) infection. RESULTS: CD4CD8 T cells increase in frequency during early Mtb infection in PBMC and BAL from pre-infection. Peripheral, airway, and lung granuloma CD4CD8 T cells have distinct patterns and greater cytokine production than CD4 or CD8 T cells. CONCLUSION: Our data suggest that CD4CD8 T cells transient the blood and airways early during infection to reach the granulomas where they are involved directly in the host response to Mtb.

Punctal Ectropion repair using the Raus-Garito clamp.

PURPOSE: To evaluate the results from the correction of ectropion of the punctum lacrimale in lower eyelids with a new surgical clamp. DESIGN: Prospective study. METHODS: Eighty eight eyelids in 55 patients with mild and moderate ectropion were included in the study. An excision of a diamond of tarso-conjunctiva with retractor reattachment and concomitant correction of horizontal lid laxity, if present, was performed. RESULTS: Resolution of tearing was obtained in 77 eyes. In 11 eyes, persistent tearing was reported. CONCLUSION: Conclusion:Conclusion: Repair of early to intermediate ectropion of the lacrimal punctum using the Raus-Garito clamp is associated with a good functional and cosmetic outcome.

Treatment strategies and long-term outcomes in patients with congenital microphthalmia-anophthalmia with cyst.

BACKGROUND/AIMS: Microphthalmia and anophthalmia are rare conditions, which represent ocular maldevelopment; both may be associated with orbital cysts. Current literature recommends retention to stimulate orbital growth during socket rehabilitation but does not illustrate their potential to deform the periocular tissues. This study aims to illustrate the long-term outcomes when other elements, such as forniceal and lid development, are also considered when formulating bespoke treatment plans for patients. METHODS: Retrospective case series of 78 patients attending a single prosthetics clinic between 1988 and 2020. Clinical and surgical notes, radiological imaging, clinical photographs and patient/doctor satisfaction questionnaires were used to report patient outcomes and natural history data. RESULTS: 89 sockets of 78 patients (11 bilateral) were included; average age of presentation being 2.8 years (9 days to 29.5 years). Cysts were clinically detected (48%) or were incidental findings (52%). The mean follow-up time was 7.2 years (6 months to 28 years). Cysts in 46% of sockets underwent surgical excision while the remainder were retained. Satisfaction surveys were obtained for 75 patients, with cosmetic outcomes rated as 'excellent' or 'good' in 90% of cases by physicians and 97% of cases by patients or guardians. CONCLUSION: The favourable long-term outcomes in this study have resulted from bespoke plans which considered periocular tissue development, regional orbital growth and orbital volume replacement. The authors contemplate cyst excision if the prosthetic fitting or retention is impeded by the cyst as this often heralds the increased risk of long-term periocular distortion.

The ophthalmology surgical competency assessment rubric for lateral tarsal strip surgery.

PURPOSE: To produce an internationally valid tool to assess skill in performing lateral tarsal strip surgery. METHODS: A panel of 7 content experts adapted a previously published tool for assessing lateral tarsal strip surgery by using a modified Dreyfus scale of skill acquisition and providing behavioral descriptors for each level of skill in each category. The tools were then reviewed by 11 international content experts for their constructive comments. RESULTS: Experts' comments were incorporated, establishing face and content validity. CONCLUSIONS: The tool International Council of Ophthalmology-Ophthalmology Surgical Competency Assessment Rubric for Lateral Tarsal Strip Surgery has face and content validity. It can be used globally to assess lateral tarsal strip surgical skill. Reliability and predictive validity still need to be determined.

Changes in tarsal plate fibrillar collagens and elastic fibre phenotype in floppy eyelid syndrome.

BACKGROUND: The aims of this study are to investigate the expression of the main structural components of the tarsal extracellular matrix (ECM) in floppy eyelid syndrome (FES) focusing on elastic fibres and collagen types I and III, and also to identify possible cell-mediated inflammatory mechanisms in the pathogenesis of this condition. METHODS: A histopathological case control study was conducted using 30 upper lid specimens from patients with FES and 15 undiseased upper lid control specimens. Structural ECM components were assessed using a combination of immunctorial ataining ohistochemical and techniques including antibodies to collagens I and III, Verhöeff's iron haematoxylin, Gomori's aldehyde fuchsin and Lillie's oxidised aldehyde fuchsin. The contribution of different cellular components of the inflammatory response was investigated by immunohistochemical techniques using antibodies to CD3, CD20, CD68. Slide scoring was performed using a semiquantitative technique on an ordinal scale. Statistical analysis was performed using matched ordinal regression analysis. RESULTS: FES tarsal plate tissue demonstrated a decreased abundance of mature elastic fibres (P ≤ 0.001) and an increased abundance of oxytalan fibres (P = 0.006). Intensity of staining for collagens I (P = 0.012) and III (P < 0.001) was increased. No significant difference in the abundance of CD3, CD20 and CD68 expressing cells was identified. CONCLUSIONS: The findings of altered elastic fibre phenotype and collagen accumulation are consistent with an adaptive response to cyclic mechanical loading of the tarsal plate, rather than an aetiological feature. These findings are important in understanding how the tarsal ECM responds to mechanical loading.

Subperiosteal midface lift: its role in static lower eyelid reconstruction after chronic facial nerve palsy.

PURPOSE: To describe the effect of subperiosteal midface lift on lower eyelid position of patients with chronic facial nerve palsy. METHODS: In an observational prospective study nine patients underwent subperiosteal midface lift. Indications for surgery were lower eyelid paralytic retraction, lagophthalmos, ocular surface disruption, reactive tearing, midface ptosis, and facial asymmetry. Exclusion criteria were previous rehabilitative oculofacial surgery, and facial nerve palsy onset less than a year. Preoperative and postoperative assessment included evaluation of lower eyelid position, lagophthalmos, midfacial ptosis and facial asymmetry. Follow-up was at 1 week, 1 month, 3, and 12 months, postoperatively. RESULTS: All patients referred improvement in their symptoms at 3 and 12 months, postoperatively: lower eyelid position (P=. 004), lagophthalmos (P=. 004), ocular surface symptoms, reactive tearing, and facial symmetry at rest. CONCLUSIONS: Subperiosteal midface lift has an effective role in the static lower eyelid malposition correction after chronic facial nerve palsy.

The associations of floppy eyelid syndrome: a case control study.

OBJECTIVE: To describe the demographic features of a large series of patients with floppy eyelid syndrome (FES) and to investigate the associations of the condition with keratoconus, obstructive sleep apnea-hypopnea syndrome (OSAHS), and a variety of upper and lower eyelid features. DESIGN: Case control study. PARTICIPANTS: The test group comprised 102 patients with FES. A control group of 102 patients were recruited from a diabetic retinopathy clinic and matched on a 1:1 basis on age, gender, and body mass index (BMI). METHODS: A full medical and ophthalmic history was taken. Patients also underwent a full ocular examination, including an assessment of upper and lower lid laxity and upper lid levator function. Keratoconus grading was made using the Oculus Instruments Pentacam imaging system (Oculus Optikgerate GmbH, Wetzlar, Germany). Patients were screened for OSAHS using the Epworth daytime somnolence score. Matched statistical analysis of dichotomous data was made using Mantel-Haenszel methods for odds ratios and McNemar's test. Analysis of continuous data was performed using a matched t test and tests for symmetry of larger tables were made using the McNemar-Bowker test. MAIN OUTCOME MEASURES: The significance of association of FES with keratoconus, OSAHS, smoking history, medial and lateral canthal laxity of the upper and lower lids, levator function, lash ptosis, and dermatochalasis. RESULTS: Significant associations were found between FES and OSAHS (P = 0.0008), keratoconus (P<0.0001), lash ptosis (P<0.0001), dermatochalasis (P = 0.02), upper lid medial canthal laxity (P = 0.02), upper lid distraction (P = 0.001), palpebral aperture (P = 0.004), and levator function (P = 0.005). CONCLUSIONS: Floppy eyelid syndrome seems to be a condition strongly associated with OSAHS and keratoconus. As well as providing a platform for an etiologic hypothesis for the condition, these findings should also encourage clinicians to be aware of these associations and to direct further treatment. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Long-term outcomes of surgical approaches to the treatment of floppy eyelid syndrome.

OBJECTIVE: To identify and describe the different procedures used in the treatment of floppy eyelid syndrome (FES) at Moorfields Eye Hospital and to evaluate their effectiveness. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 71 patients who had undergone surgery for FES over a 13-year period since 1995 at Moorfields Eye Hospital were recruited. Retrospective data from 7 patients were also included, providing data for 78 patients. METHODS: Patients underwent a full ocular examination. A survival analysis was determined by plotting Kaplan-Meier curves for each type of procedure encountered. Comparison of survival trends was made using a log-rank test. The possible effects of bias arising from bilaterality of the condition were investigated using a sensitivity analysis and a Cox regression analysis allowing for clusters. Tests for surgeon bias were made using the Fisher exact test. MAIN OUTCOME MEASURES: Recurrence of the condition. An assessment of recurrence was made clinically by 2 independent observers who were masked to the type of surgery the patient had undergone. RESULTS: Four different forms of surgical treatment were encountered: (1) Full-thickness wedge excision (FTWE) (26 patients, 33 procedures); (2) Upper lid lateral tarsal strip (LTS) (31 patients, 43 procedures); (3) Medial canthal (MC) and lateral canthal (LC) plication (15 patients, 19 procedures); (4) Medial tarsal strip (6 patients, 6 procedures). A total of 44 of 101 procedures had failed. Superior long-term survival outcomes of both LC/MC plication (P = 0.003) and upper lid LTS (P = 0.001) procedures over FTWE was demonstrated. However, survival comparison between the LC/MC plication and LTS groups did not achieve significance (P = 0.37). No significant difference in outcome between surgeon groups of equivalent experience was demonstrated (P = 0.18). No bias arising from bilaterality of the condition was identified. CONCLUSIONS: These data provide strong evidence of better survival outcomes in FES using the MC/LC plication and LTS procedures in comparison with the FTWE procedure. On the basis of experience from our unit, we recommend that the FTWE procedure be avoided as a form of treatment for FES in favor of the MC/LC plication, LTS, or medial tarsal strip procedure. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Early cure rates with narrow-margin slow-Mohs surgery for periocular malignant melanoma.

BACKGROUND: Staged excision with rush-processed paraffin-embedded tissue sections (Slow-Mohs) is an effective treatment for periocular melanoma. Although there is no consensus on initial margins of excision, narrower margins in the eyelids have the functionally and cosmetically important consequence of smaller postoperative wounds. OBJECTIVES: To report early cure rates for periocular melanoma using Slow-Mohs surgery with en-face margin sectioning. METHODS: Retrospective, multicenter, noncomparative case series. Slow-Mohs surgery in 14 patients with periocular melanoma from 2000 to 2006. RESULTS: Fourteen patients underwent 14 Slow-Mohs procedures for eight lentigo maligna, one nodular, and one superficial spreading melanoma, and four lentigo maligna, 12 primary, and two recurrent tumors. The most common site was the lower eyelid (8/14, 57.1%). Breslow thickness ranged from 0.27 to 1.70 mm, with four cases less than 0.76 mm and one case greater than 1.5 mm. Five cases were a Clark level II or greater. Complete excision was achieved with one level (6 cases) or two or three levels (8 cases), with 2- to 3-mm margins at each level in all but one case. With median follow-up of 36 months, there were two local recurrences (2/14, 14.3%). CONCLUSION: Slow-Mohs with en-face sections achieves similar early cure rates to previously published margin-controlled excision techniques. Narrow margins of excision can optimize tissue preservation without compromising outcome.

Report on the incidence of squamous cell carcinomas affecting the eyelids in England over a 15-year period (2000-2014).

AIMS: The authors report on trends in the incidence of squamous cell carcinoma (SCC) affecting the eyelids in England over a 15-year period and identify associations between demographic factors and SCC risk. METHODS: The National Cancer Registration and Analysis Service identified all cases of eyelid SCC in England between 2000 and 2014. The crude and age-standardised rates of eyelid SCCs in England were calculated. The association of SCC with several known demographic risk factors was then examined to assess their importance in periocular cases. RESULTS: Over the 15 years studied, there were 4022 patients in England diagnosed with a first episode of SCC affecting the eyelids. The age-standardised number of reported cases rose between 2000 and 2014 by a mean of 0.0137 cases per 100 000 population per year (equivalent to a rise in SCC incidence of approximately 2% per year). The mean age-standardised incidence rate of SCC during the study period was 0.63 cases per 100 000 population per year.Age was exponentially correlated with incidence, with an approximate doubling of the risk for every decade over the age of 60. The relative risk of eyelid SCC in men compared with women was 1.9. Social deprivation quintile by income was not found to be associated with risk of SCC. CONCLUSION: The incidence of eyelid SCC in England is rising. In addition, the age-standardised and population-standardised rate of SCC is also rising. A higher risk of SCC is strongly correlated with age and male sex but not with deprivation.

Long-term outcomes after cosmetic customized prostheses and dermis fat graft in congenital anophthalmia: a retrospective multicentre study.

PURPOSE: To evaluate long-term outcomes of progressively enlarging cosmetic customized prostheses (CCP) early after birth followed by dermis fat graft (DFG), as a strategy of socket rehabilitation in children with clinical congenital anophthalmia (CCA). METHODS: Twenty patients with unilateral and two patients with bilateral CCA were enrolled. All patients were treated by inserting a CCP at the time of their first assessment which was then enlarged. Subsequently they underwent DFG. Differences in vertical palpebral aperture (VPA) and horizontal palpebral length (HPL), between affected and unaffected sides, were recorded at the first CCP fitting as well as before and after DFG. Satisfaction with cosmetic results, prosthetic retention, and complications rate were assessed. Magnetic resonance imaging of the orbit was performed in all patients before and after surgery. RESULTS: A significant decrease in the difference between the normal and the anophthalmic side of both PA and HPL was found over follow-up. Both VPA and HPL differences decreased by 47.6% (10.5 mm, range 1-28 mm) and by 7.1% (5.8 mm, range 0-18 mm), respectively. Satisfaction in terms of cosmetic outcomes proved to be very positive, being "very satisfied" for families and "satisfied" for physicians. Excellent retention of prostheses was observed in all cases. CONCLUSIONS: A rehabilitating strategy combining early CCP and further DFG proved to be a valuable approach in children with CCA, offering significant benefits in terms of socket expansion, prosthetic retention, psychological impact, and cosmetic outcomes.

Absence of SIX6 mutations in microphthalmia, anophthalmia, and coloboma.

PURPOSE: To investigate whether 173 patients with microphthalmia, anophthalmia, and coloboma have mutations in the eye-development gene SIX6. METHODS: The two exons of the SIX6 gene were amplified by PCR from patients' genomic DNA and directly sequenced to search for mutations. The PCR products of 75 patients were also analyzed by denaturing high-performance liquid chromatography (DHPLC). RESULTS: Six SIX6 polymorphisms were identified in the patient panel. Three of these polymorphisms change the encoded amino acid. However, all six polymorphisms were also identified in unaffected individuals. There was no statistically significant difference in genotypes between patients and control subjects. CONCLUSIONS: No evidence was found that SIX6 mutations underlie human congenital structural eye malformations.

Role of the lower lid retractors in involutional ectropion repair.

AIM. To outline the role of the lower lid retractors in correction of involutional ectropion. METHODS. Eight eyelids with a tarsal ectropion were included in the study. Clinical clues to help identify weakness of the lower lid retractors were documented. A transconjunctival lower lid retractor reattachment with concommitant correction of horizontal lid laxity and lamellar dissociation was performed. RESULTS. Stable eyelid position was obtained in 7 of the 8 cases. One case had a lateral ectropion due to a wound dehiscence. CONCLUSIONS. This small study helps better define the clinical presentations of retractor weakness and provides evidence of a systematic approach in correcting involutional ectropion.

Merkel cell carcinoma of the eyelid: management and prognosis.

IMPORTANCE: The literature on Merkel cell carcinoma (MCC) of the eyelid remains scarce, and there has yet to be a study using the most up-to-date TNM staging system for this rare but aggressive tumor. OBJECTIVE: To analyze the TNM stage, management, and outcomes of patients with MCC of the eyelid. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series of 21 patients from 5 tertiary referral centers in the United Kingdom and Australia with primary MCC of the eyelid presenting at a median age of 77 years, with median follow-up of 54 months. Tumors were staged according to the American Joint Committee on Cancer, 7th edition, TNM criteria for eyelid carcinoma and MCC. MAIN OUTCOMES AND MEASURES: TNM stage, treatment modalities, and clinical outcome. RESULTS: The eyelid carcinoma TNM stages were T2aN0M0 for 5 patients, T2bN0M0 for 7 patients, T3aN0M0 for 4 patients, T3bN0M0 for 3 patients, T2bN1M0 for 1 patient, and T3aN1M0 for 1 patient. The MCC TNM stages were T1N0M0 for 12 patients, T2N0M0 for 7 patients, T1N1M0 for 1 patient, and T2N1M0 for 1 patient. One patient had a sentinel lymph node biopsy, and 8 patients underwent head/neck imaging. Eighteen patients underwent a wide local excision, 12 with a paraffin section and 6 with a frozen section. Two patients underwent Mohs surgery, 1 of whom required an orbital exenteration. Twelve patients (57%) received adjuvant radiotherapy, and 2 patients received chemotherapy. The local recurrence rate was 10%, the regional nodal recurrence rate was 10%, and the distant metastatic recurrence rate was 19%. The lowest T category tumor metastasizing to both regional nodes and distant locations was a T2a (eyelid TNM)/T1 (Merkel TNM) tumor measuring 8 mm. Two patients with T3a (eyelid TNM)/T2 (Merkel TNM) tumors died of metastatic MCC. CONCLUSIONS AND RELEVANCE: The majority of patients with MCC of the eyelid present with localized eyelid disease of T category T2 (eyelid TNM)/T1 (Merkel TNM). A wide local excision with margin control remains the mainstay of treatment, whereas the use of radiotherapy is institution specific. Tumors with a low T category are associated with regional nodal and distant metastatic disease. It may therefore be reasonable to consider a sentinel lymph node biopsy or strict regional lymph node surveillance for all MCCs of the eyelid, regardless of T category or size.

Floppy eyelid syndrome: stretching the limits.

Floppy eyelid syndrome is a distressing condition that can cause significant morbidity and vision loss. Many systemic and ocular associations have been proposed, most notably keratoconus and obstructive sleep apnea-hypopnea syndrome. Although conservative treatments can sometimes be effective, a wide variety of surgical treatments to tighten the upper eyelid have been described. The underlying pathogenesis remains elusive, although progress has been made in the identification of extracellular matrix changes in the tarsal plate. This systematic review discusses the issues surrounding ambiguities in the definition of floppy eyelid syndrome as well as what is currently known about its clinical features, ocular and systemic associations, pathological changes, and proposed theories of pathogenesis. In addition a critical discussion of the proposed surgical treatments and their reported success rates and follow-up times is provided.

Changes in fibroblast mechanostat set point and mechanosensitivity: an adaptive response to mechanical stress in floppy eyelid syndrome.

PURPOSE: Floppy eyelid syndrome (FES) is an acquired hyperelasticity disorder affecting the upper eyelid. The tarsal plate becomes hyperelastic with a loss of intrinsic rigidity. As a result, the eyelid is subjected to cyclic mechanical stress. This condition was used as a model to investigate changes in dynamic fibroblast contractility in the context of chronic cyclic mechanical stress. METHODS: Contractile efficiency was investigated in a free-floating, three-dimensional collagen matrix model. Intrinsic cellular force measurements and responses to changes in gel tension were explored using a tensioning culture force monitor (t-CFM). Gene expression differences between cell lines exhibiting differences in contractile phenotype were explored with a genome level microarray platform and RT-PCR. RESULTS: FES tarsal plate fibroblasts (TFs) showed an increased contractile efficiency compared with the control, and t-CFM measurements confirmed a higher intrinsic cellular force at plateau levels. Cyclic stretch/relaxation experiments determined that TFs in FES maintained a functional tensional homeostasis response but with an altered sensitivity, operating around a higher mechanostat set point. Gene expression array and RT-PCR analysis identified V-CAM1 and PPP1R3C as being upregulated in FES TFs. CONCLUSIONS: These changes may represent an adaptive response that allows tensional homeostasis to be maintained at the high levels of tissue stress experienced in FES. Gene expression studies point to a role for V-CAM1 and PPP1R3C in mediating changes in the dynamic range of mechanosensitivity of TFs. This work identifies FES as a useful model for the study of adaptive physiological responses to mechanical stress.

Ionic radii for Group 1 halide crystals and ion-pairs.

Internuclear separations calculated from empirical soft-sphere radii for seventeen crystalline Group 1 halides with rock-salt structures and from empirical hovering-sphere radii for fourteen gaseous Group 1 halide ion-pairs agree well with experimental measurements. Two lithium and four fluoride ion-pairs appear to be anomalous. Soft-sphere ionic radii are compared with atomic radii of noble gases.

Lax eyelid syndrome or 'progeria' of eyelid tissues.

PURPOSE: The lax eyelid syndrome was described by Van den Bosch and Lemij as an uncommon disorder seen in non-obese elderly people and characterised by chronic ocular surface irritation symptoms and a "floppy upper eyelid". The authors present some new features of the lax eyelid syndrome. METHODS: The authors report five patients, belonging to a younger age group, who presented with premature laxity of all the eyelid tissues. This caused medial and lateral canthal dystopia and eyelid malposition including ptosis, entropion and ectropion. Initial surgical correction was often followed by recurrence after some time. CONCLUSIONS: The authors highlight the differences between lax eyelid syndrome, cutis laxa, floppy eyelid syndrome and the blepharochalasis syndrome and suggest that lax eyelid syndrome can be thought of as "progeria" or premature ageing of the eyelid tissues to distinguish it clearly from these other conditions.