Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion.

PURPOSE: Deficiency of stromal interaction molecule 1 (STIM1) results in combined immunodeficiency accompanied by extra-immunological findings like enamel defects and myopathy. We here studied a patient with a STIM1 loss-of-function mutation who presented with severe lymphoproliferation. We sought to explore the efficacy of the mTOR inhibitor rapamycin in controlling disease manifestations and reversing aberrant T-cell subsets and functions, which has never been used previously in this disorder. METHODS: Clinical findings of the patient were collected over time. We performed immunological evaluations before and after initiation of rapamycin treatment, including detailed lymphocyte subset analyses, alterations in frequencies of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes as well as T cell activation and proliferation capacities. RESULTS: A novel homozygous exon 2 deletion in STIM1 was detected in a 3-year-old girl with severe lymphoproliferation, recurrent infections, myopathy, iris hypoplasia, and enamel hypoplasia. Lymphoproliferation was associated with severe T-cell infiltrates. The deletion resulted in a complete loss of protein expression, associated with a lack of store-operated calcium entry response, defective T-cell activation, proliferation, and cytokine production. Interestingly, patient blood contained fewer cTFH and increased circulating follicular regulatory (cTFR) cells. Abnormal skewing towards TH2-like responses in certain T-cell subpopulations like cTFH, non-cTFH memory T-helper, and Treg cells was associated with increased eosinophil numbers and serum IgE levels. Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities, reversed T-cell responses, and repressed high IgE levels and eosinophilia. CONCLUSIONS: This study enhances our understanding of STIM1 deficiency by uncovering additional abnormal T-cell responses, and reveals for the first time the potential therapeutic utility of rapamycin for this disorder.

Visual Outcomes, Endothelial Loss, and Complications Following Iris-Claw Intraocular Lens Implantation and Trocar-Assisted Sutureless Scleral Fixation of Intraocular Lenses.

Objectives: Iris-claw intraocular lens (IC-IOL) implantation and sutureless scleral fixation of intraocular lenses (SSF-IOL) are two commonly preferred surgical approaches for the management of aphakic patients without sufficient capsular support. The aim of this study was to compare the outcomes of IC-IOL implantation and trocar-assisted SSF-IOL implantation. Methods: The medical records of secondary IOL implantation patients were retrospectively reviewed. All patients had a detailed ophthalmological examination, including LogMAR best-corrected distance visual acuity (CDVA), intraocular pressure (IOP), and endothelial cell density (ECD) preoperatively and postoperatively. SPSS 21.0 software was used for the statistical analysis. Results: There were 15 patients in the IC-IOL group and 12 patients in the SSF-IOL group. Age and gender distributions were similar between the groups (p=0.456 and p=0.398, respectively). Similarly, patients in both groups had similar CDVA preoperatively and postoperatively (p=0.51, p=0.48, respectively). Both IC-IOL and SSF-IOL implantation significantly increased CDVA (p=0.001 and p=0.005, respectively). IOP remained unchanged in both groups. However, ECD reduced significantly following both IC-IOL and SSF-IOL implantation (p=0.001 and p=0.005, respectively) and trocar-assisted SSF-IOL implantation resulted in significantly more endothelial loss compared to IC-IOL implantation (439.5±89 vs. 164.4±53, p=0.013). Conclusion: Both surgical approaches increased CDVA significantly and at similar levels. However, trocar-assisted SSF-IOL implantation resulted in significantly more endothelial loss compared to IC-IOL implantation. None of the patients developed bullous keratopathy, but this difference should be kept in mind, especially in patients with critically low ECD.

Mediastinal lymph node removal modulates natural killer cell exhaustion in patients with non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death globally. In this study, the effect of complete removal of mediastinal lymph nodes by video-assisted mediastinoscopic lymphadenectomy (VAMLA) on natural killer (NK) cell phenotype and functions in patients with NSCLC was evaluated. The study included 21 NSCLC patients (cIA-IVA) undergoing VAMLA staging and 33 healthy controls. Mononuclear cells were isolated from peripheral blood of all participants and mediastinal lymph nodes of the patients. NK cells were analyzed by flow cytometry to define NK subsets, expressions of PD-1, CTLA-4, activating/inhibitory receptors, granzyme A, and CD107a. The plasma levels of soluble PD-1, PDL-1, and CTLA-4 were measured by ELISA. Mediastinal lymph nodes of NSCLC patients had increased ratios of exhausted NK cells, increased expression of PD-1 and IL-10, and impaired cytotoxicity. Mediastinal lymph nodes removal increased CD56dimCD16bright cytotoxic effector phenotype and reduced exhausted NK cells. PD-1+ NK cells were significantly more abundant in patients' blood, and VAMLA significantly reduced their ratio as well. The ratio of IL-10 secreting regulatory NK cells was also reduced after VAMLA. Blood NK cells had increased cytotoxic functions and spontaneous IFN-γ secretion, and these NK cell functions were also recovered by VAMLA. Mediastinal lymph node removal reversed NK cell exhaustion, reduced regulatory NK cells, and improved antitumoral functions of NK cells. Tumor-draining lymph nodes may contribute to tumor evasion from antitumoral immune responses. The role of their removal needs to be further studied both to better understand this mechanism and as a potential immunotherapeutic approach.

Endothelial loss following postoperative intracameral triamcinolone acetonide and subconjunctival dexamethasone injections.

OBJECTIVES: To compare endothelial toxicity and efficacy of two local steroid injections (intracameral triamcinolone acetonide and subconjunctival dexamethasone) in controlling postoperative inflammation following pars plana vitrectomy (PPV) combined with phacoemulsification cataract surgery. METHODS: This cohort included 54 patients that underwent combined surgery and received either intracameral triamcinolone acetonide injections (n = 27, IC-TA group) or subconjunctival dexamethasone (n = 27, Sc-Dex group) injections at the end of the surgery. All participants had at least 4 months or longer follow-up. A detailed ophthalmologic examination including intraocular pressure (IOP) measurement and specular microscopy was performed at every visit. RESULTS: Endothelial cell density (ECD) reduced significantly in IC-TA group postoperatively (2418 vs. 2249, p = 0.019), while it did not change significantly in Sc-Dex group (2541 vs. 2492, p = 0.247). Postoperative ECD was also significantly lower in IC-TA group compared to Sc-Dex group (p = 0.011). Preoperative and postoperative IOP values remained unchanged both in IC-TA and Sc-Dex groups (p = 0.424 and p = 0.523, respectively). However, 4 patients in IC-TA group and 5 patients in the Sc-Dex group needed glaucoma medications. The postoperative need for glaucoma medications was similar between the groups (p = 0.347). Postoperative inflammation was well controlled in both groups and none of the patients developed fibrin membrane or synechiae postoperatively. CONCLUSION: Both treatments were effective in controlling postoperative inflammation, but patients in IC-TA group experienced significantly higher endothelial loss. Sc-Dex injections are safer in terms of endothelial loss and preferable to control postoperative inflammation following complex intraocular surgeries.

Optical coherence tomography and Scheimpflug imaging of the iridocorneal angle following intravitreal injection of different medications: A longitudinal analysis.

PURPOSE: Intravitreal injection of medications induces a sudden increase in posterior segment volume and pushes iris plane anteriorly to narrow iridocorneal angle. The aim of this study to follow and define longitudinal course of these changes following intravitreal injection of 3 different anti-vascular endothelial growth factor (VEGF) medications or dexamethasone implant. MATERIALS AND METHODS: This prospective, longitudinal study included 89 eyes of 89 patients that had an intravitreal injection of bevacizumab (n = 20) or ranibizumab (n = 26) or aflibercept (n = 22) or dexamethasone implant (n = 21). All the participants had a detailed ophthalmological examination including anterior segment optical coherence tomography (AS-OCT) and Scheimpflug imaging of the iridocorneal angle, evaluation of anterior chamber depth (ACD), axial length with optical biometry and endothelial cell counts with specular microscopy just before the injection, at post-injection day 1, and post-injection 1st month. RESULTS: Iridocorneal angle became significantly wider following intravitreal injection of dexamethasone implant at nasal and temporal quadrants at the post-injection 1st month both in AS-OCT (p = 0.006, p = 0.002, respectively) and Scheimpflug imaging (p = 0.003, p = 0.004, respectively). Small changes were observed in iridocorneal angle following anti-VEGF injections but these small could not be confirmed in both imaging techniques. There were also no changes in ACD, axial length and endothelial counts in all groups. CONCLUSION: Dexamethasone implants induced widening of iridocorneal angle that persisted at the post-injection 1st month both at nasal and temporal quadrants. However, intravitreal injection of anti-VEGF agents did not have a comparable effect on iridocorneal angle.

Mediastinal lymph node removal ameliorates cytotoxic T-lymphocyte functions in patients with non-small cell lung cancer.

INTRODUCTION: Mediastinal lymph node (MLN) removal by video-assisted mediastinoscopic lymphadenectomy (VAMLA) for preoperative cancer staging was reported to be associated with increased survival. The aim of this study was to evaluate the immunologic effects of complete MLN removal by VAMLA on cytotoxic T lymphocyte (CTL) phenotype and function. METHODS: Seventeen patients with non-small cell lung cancer (NSCLC) (stage cT1-4N0-3M0-1A) and 20 healthy participants were included in this study. Blood samples were collected before and 4 weeks after the procedure. Lymphocytes were isolated from the removed MLNs. CTL phenotypes and functions were evaluated by flow cytometry. Plasma levels of soluble programmed cell death protein 1 (sPD-1), soluble programmed cell death protein 1 ligand, and soluble CTL antigen 4 (sCTLA-4) were measured with enzyme-linked immunosorbent assay. RESULTS: The ratio of the immunosenescent CTLs (CD3+CD8+CD28-) was increased in peripheral blood and MLNs of the patients with NSCLC compared to controls (p = 0.037), and MLN removal did not change this ratio. PD-1 and CTL antigen 4 expressions were significantly reduced in peripheral blood CTLs after MLN removal by VAMLA (p = 0.01 and p = 0.01, respectively). Granzyme A expression was significantly reduced in the peripheral blood CTLs of the patients compared to controls (p = 0.006) and MLN removal by VAMLA significantly improved Granzyme A expression in CTLs (p = 0.003). Plasma concentrations of sPD-1 and sCTLA-4 remained unchanged after VAMLA. CONCLUSION: CTLs in the MLNs and peripheral blood of the patients with NSCLC had an immunosenescent phenotype, increased immune checkpoint receptor expression, and impaired cytotoxicity. MLN removal by VAMLA improved these phenotypic and functional characteristics of CTLs. These changes may explain the potential contribution of VAMLA to improved survival.

Long-term follow-up of choroidal changes following COVID-19 infection: analysis of choroidal thickness and choroidal vascularity index.

OBJECTIVE: To investigate subclinical choroidal involvement in patients with systemic coronavirus disease 2019 (COVID-19) infection and evaluate its long-term course. MATERIALS AND METHODS: This prospective, longitudinal study included 32 eyes of 16 COVID-19 patients and 34 eyes of 17 age-matched healthy control subjects. All the participants had a detailed ophthalmologic assessment, including visual acuity assessment, slit-lamp examination, and indirect ophthalmoscopy. Enhanced depth optical coherence tomography imaging of the posterior pole and peripapillary region was performed in the early (days 15-40) and late (ninth month) postinfectious periods. Choroidal vascularity index (CVI) was calculated using ImageJ software (National Institutes of Health, Bethesda, Md.). RESULTS: None of the patients had any examination finding associated with the ocular involvement of COVID-19. Subfoveal choroidal thickness (SFCT) decreased significantly in the early postinfectious period compared with the healthy control individuals (p = 0.045). SFCT increased significantly in the late postinfectious period compared with the early period (p = 0.002), and the difference between patients and control individuals became statistically insignificant (p = 0.362). There was a similar trend for the peripapillary choroidal thickness measurements. CVI remained unchanged (p = 0.721) despite the significant decrease in SFCT and total choroidal area (p = 0.042), indicating that this decrease occurred both in choroidal stroma and in blood vessels. CVI remained unchanged in the late postinfectious period (p = 0.575) compared with the early period, indicating that recovery occurred in the entire choroidal tissue. CONCLUSION: This study demonstrates that choroidal thickness was reduced in all measured areas and that this decrease affected all choroidal layers. This choroidopathy was reversible and recovered in the ninth postinfectious month.

The influence of corneal incision size on endothelial cell loss and surgically induced astigmatism following phacoemulsification cataract surgery.

OBJECTIVE: Corneal incision size has influence both on corneal biomechanics and intracameral fluid dynamics during phacoemulsification cataract surgery. The aim of this study was to evaluate the impact of corneal incision size on endothelial cell loss and surgically induced astigmatism (SIA) following phacoemulsification cataract surgery. METHODS: This prospective, randomized, and comparative study included 61 eyes with senile cataracts. The patients were randomly assigned to 2.2 mm and 2.8 mm corneal incision sizes and were operated with the same phacoemulsification system. Phacoemulsifcation energy parameters, pre-operative and post-operative endothelial cell counts and corneal astigmatism values were specifically recorded. SIA was calculated according to Alpins method and the results of both groups were compared. RESULTS: There were 31 eyes in the microincisional (2.2 mm) group and 30 eyes in the standard incision (2.8 mm) group. There was no significant difference between the groups for age and gender distribution (p=0.09 and p=0.18, respectively). Similar levels of cumulative dissipated energy was used during phacoemulsification in both groups (p=0.70). SIA was slightly higher in the standard incision group compared to microincisional group (0.47D at 64° vs. 0.37D at 61°, p=0.30). Pre-operative and post-operative uncorrected visual acuity (UCVA) was similar between the groups (p=0.45 and p=0.27).Endothelial cell loss tended to be slightly higher in the microincisional group compared to standard incision group (174.87±132.27 vs. 160.84±121.58, p=0.75), but this difference was not statistically significant. CONCLUSION: Smaller corneal incisions slightly reduced SIA, but tended to induce more endothelial cell loss. This small difference in SIA did not cause a significant change in the postoperative UCVA. Therefore, the trend in reducing corneal incision sizes below 2.8 mm might not be contributing the surgical outcomes of the patients, especially when we consider potential corneal endothelial changes.

Corneal Sensation and Nerve Fiber Changes in Patients With Interstitial Cystitis.

PURPOSE: Central sensitization syndromes are associated with ocular surface discomfort and certain changes in corneal sensation. The aim of this study was to evaluate corneal changes in patients with interstitial cystitis (IC). METHODS: Thirty patients with IC and 32 healthy control subjects were included in this study. All patients had a detailed ophthalmological examination including measurement of corneal sensation with Cochet-Bonnet esthesiometer, tear breakup time, Schirmer I test, and Ocular Surface Disease Index questionnaire. After these examinations, corneal subbasal nerve plexus of the patients was evaluated with in vivo corneal confocal microscopy (IVCM) and the images were analyzed using fully automated software (ACC Metrics Corneal Nerve Fiber Analyzer V.2). RESULTS: There was no significant difference between the groups regarding age and gender distribution. Corneal sensation was significantly higher in patients with IC (P = 0.03), whereas tear breakup time, Schirmer I test, and Ocular Surface Disease Index scores were similar between the patients and controls. IVCM demonstrated nerve fiber loss in patients with IC. Corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length were significantly reduced in patients with IC compared with healthy controls (P < 0.001, P = 0.04, and P < 0.001, respectively). CONCLUSIONS: Patients with IC had increased corneal sensation and decreased nerve fiber density in IVCM analysis. Corneal nerve fiber loss might decrease the induction threshold of the remaining fibers to induce peripheral sensitization, which may also trigger central sensitization in long term.

A Novel Use of Retinoscopy for the Evaluation of Binocular Balance of Spherical Refractive Errors.

PURPOSE: Binocular balancing is an important component of refractive correction to avoid asthenopic complaints. Polaroid filters are commonly used for binocular balancing; they rely on subjective examination and cannot represent daily visual activities. We describe a new examination approach to evaluate binocular balance with retinoscopy, which is an objective examination method and does not require strict patient cooperation. METHODS: Healthy young individuals with refractive errors (under the age of 40) were included in this study. Each patient was examined by three different ophthalmologists in the same room at 20-min intervals. The first ophthalmologist performed refractive examination separately for each eye, the second physician used binocular balance tests with polaroid glasses, and the third physician practiced binocular balance test with retinoscopy. After completion of clinical examinations, autorefractometry was repeated with cycloplegia. The difference between the spherical equivalents (SE) of the eyes was calculated for each method and compared with the SE difference obtained by cycloplegic autorefractometry. The SPSS 21.0 software was used for the statistical tests. RESULTS: The study included 30 patients (16 males, 14 females) and the mean age of the patients was 21 ± 8.5 years (range 10-37 years). There was no significant difference between the four groups for the interocular difference of SE (Greenhouse-Geisser F = 1.390, p = 0.257). The highest correlation was found between the retinoscopic binocular balance technique and cycloplegic autorefractometry (r = 0.878, p < 0.001). In addition, the intraclass correlation coefficient and the 95% limits of agreement supported strong agreement. CONCLUSION: Currently used binocular examination tests are subjective and some patients give inconsistent answers impairing the reliability of the outcome. These tests cannot be performed on patients with limited ability to cooperate. This study demonstrates that the use of retinoscopy in the evaluation of binocular balance delivers reliable results and is a low-cost, practical approach to address the above-mentioned problems.

PD-1, CTLA-4, LAG-3, and TIGIT: The roles of immune checkpoint receptors on the regulation of human NK cell phenotype and functions.

The roles of immune checkpoint receptors were defined in many cancers and autoimmune diseases, while there is limited information on their functional roles in the NK cells of healthy individuals. Immune checkpoint receptor expression of NK cell subsets and their association with NK cell functions (cytotoxic capacity and cytokine production) in healthy population were investigated. PD-1, CTLA-4, LAG-3 and TIGIT expression of peripheral blood NK cells, cytokine levels (TNF-α, IFN-γ, IL-10) and cytotoxic functions (granzyme A, perforin, CD107a; with/without K562 target cell stimulation) were evaluated by flow cytometry. CD56dimCD16dim NK cells had the highest expression of TIGIT, while CD56dimCD16- NK cells had highest expression of PD-1, CTLA-4 and LAG-3. PD-1+ NK cells, CTLA-4+ NK cells and LAG-3+ NK cells had increased amount of IL-10 however, reduced IFN-γ and TNF-α levels. Cytotoxic granule expressions (perforin and granzyme A) were reduced in PD-1+ NK cells, CTLA-4+ NK cells and LAG-3+ NK cells. However, TIGIT expression did not alter perforin and granzyme A expressions. Degranulation capacity was reduced in three groups of NK cells (PD-1+ or LAG-3+ or TIGIT+). TIGIT+ NK cells responded strongly to target cell stimulation, while NK cells in the other groups (PD-1+ or CTLA-4+ or LAG-3+) were resistant. PD-1+ NK cells, CTLA-4+ NK cells and LAG-3+ NK cells had a regulatory phenotype, impaired cytotoxic functions, and response to target cell stimulation. In contrast, TIGIT+ NK cells had strong baseline cytotoxic activity that further increased in response to target cell stimulation.

Clinical outcome and endothelial loss following prepupillary and retropupillary implantation of iris claw intraocular lenses.

PURPOSE: Iris claw intraocular lenses (IOLs) were successfully used for the management of aphakia in patients that lack capsular support. The aim of this study was to compare the clinical outcome of prepupillary and retropupillary implantation of these IOLs. METHODS: The files of the 26 patients that had an iris claw IOL implantation between 2010 and 2020 were retrospectively reviewed. Detailed ophthalmological examination findings including corrected distance visual acuity (CDVA), intraocular pressure, endothelial cell counts, slit lamp and dilated fundus examination findings were specifically tabulated. Intraoperative and postoperative complications were also specifically recorded. RESULTS: There were 18 patients in the prepupillary implantation group and eight patients in the retropupillary implantation group. Age and gender distribution were similar between the groups. CDVA significantly increased in prepupillary and retropupillary implantation groups (p = 0.001 and p = 0.012, respectively). Median endothelial cell loss was 6.7% in prepupillary group and 7.2% in retropupillary group. The only intraoperative complication was iridodialysis (n = 1). Postoperative complications included retinal detachment (n = 1), cystoid macular edema (n = 2) and IOL tilt (n = 1). All of these complications occurred in the prepupillary implantation group. CONCLUSION: Prepupillary and retropupillary implantation of iris claw IOLs resulted with similar visual gain and endothelial loss rates in a follow-up time of 6 months. There was an insignificant trend toward a reduced complication rate following retropupillary implantation.

Corneal neuropathic pain in irritable bowel syndrome: clinical findings and in vivo corneal confocal microscopy.

PURPOSE: Ocular discomfort is a common symptom in central sensitization syndromes. The aim of this study was to evaluate ocular surface discomfort and related corneal changes in patients with irritable bowel syndrome. METHODS: Twenty-nine patients with IBS (20 female, 9 male, mean age: 45.3 ± 10.1 years) and 37 healthy control subjects (25 female, 12 male, mean age: 44.95 ± 9.76 years) were included. A detailed ophthalmological examination was performed to all participants including tear break-up time (TBUT) and Schirmer test I with anesthetic (SIT). Ocular discomfort was evaluated using the ocular surface disease index (OSDI) questionnaire and corneal sensation was evaluated with Cochet-Bonnet esthesiometer. Corneal subbasal nerve plexus was evaluated with in vivo corneal confocal microscopy (IVCM). RESULTS: There was no significant difference between the groups for age, gender distribution, and visual acuity. OSDI scores were significantly higher (p = 0.008) and TBUT was significantly reduced in patients with IBS compared to controls (p = 0.001 for right eye, p = 0.014 for left eye). However, there was no significant difference in corneal touch sensation and SIT results between the groups. IVCM revealed that corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length were significantly reduced in patients with IBS (p < 0.001, p < 0.001, and p = 0.023, respectively). CONCLUSION: Patients with IBS have increased dry eye-associated ocular surface complaints and nerve fiber loss in corneal subbasal nerve plexus. IBS should be remembered in the differential diagnosis, when there is discordance between the level of ocular surface discomfort and dry eye disease associated corneal findings.

Refractive outcome of trocar-assisted sutureless scleral fixation with 3-piece intraocular lenses.

PURPOSE: Intraocular lens (IOL) implantation with a trocar-assisted sutureless scleral fixation technique is a relatively new IOL implantation approach for aphakic eyes. During this surgery, the intrascleral position of the haptics can change the location of the IOL optic and may alter the refractive outcome. This study aimed to evaluate the refractive outcome of this surgery. METHODS: The files of 22 patients who had undergone IOL implantation with the trocar-assisted sutureless scleral fixation technique were retrospectively reviewed, and the patients were invited for final examination. IOL power was calculated with optical biometry (Lenstar LS900). IOL power calculations were performed according to formulas designed for in-the-bag IOL implantation. The final refractive error was determined with an autorefractometer (Topcon KR-1/RM-1). RESULTS: This study included 14 patients (8 male, 6 female, mean age: 62.7 ± 18.7). There were no significant differences between the preoperative and postoperative corneal astigmatism values (p = 0.16). There were also no significant differences between the postoperative corneal and total astigmatism values (p = 0.44), confirming the absence of significant IOL tilt. The difference between the implanted IOLs and the calculated IOL power for emmetropia was 0.09 D ± 0.49 D (p = 0.52). Although emmetropia was targeted, the refractive outcome shifted to hyperopia (+ 0.85 D ± 1.15 D) and was significantly different from the refractive status calculated with optical biometry (p = 0.034). CONCLUSIONS: The intrascleral fixation of IOLs results in increased posterior positioning of the IOL optic and can induce approximately 0.85 D of hyperopia if proper adjustments are not performed during IOL power calculations.

The Role of Natural Killer Cells in Autoimmune Diseases.

Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970's. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don't express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet's disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and "bridge" them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

Effects of Ab Interno XEN Gel Implantation on Postural Intraocular Pressure Elevations.

Purpose: The aim of this study was to analyze the postural intraocular pressure (IOP) changes in open-angle glaucoma after ab interno XEN gel implant surgery and to compare them with the changes observed with trabeculectomy and medical treatment.Patients and Methods: The study sample included 18 patients with XEN gel implants, 30 patients who had trabeculectomy, and 30 medically managed glaucoma patients. All patients in XEN gel implant and trabeculectomy groups had at least 11 months of follow-up and had successful surgeries that resulted in medication-free control of IOP. A rebound tonometer (Icare, Finland Oy, Helsinki, Finland) was used to measure the IOP levels at the sitting, supine, and dependent lateral decubitus (DLDP) positions after a 5-minute rest at each position.Results: In all the groups, the mean IOP values in the DLDP and supine positions were significantly higher than the sitting position. The IOP elevation after moving from sitting to supine position was significantly reduced in XEN gel implant and trabeculectomy groups compared to medical treatment group (p = .001 and p = .002, respectively). The IOP elevation after a moving from sitting to DLDP was also significantly reduced in XEN gel implant and trabeculectomy groups compared to the medical treatment group (p = .003 and p = .01, respectively). However, there was no significant difference in IOP change after moving from sitting to supine or DLDP positions between XEN gel implant and trabeculectomy groups (p = .74 and p = .98, respectively).Conclusion: This study demonstrated that XEN gel implant could reduce postural elevations in IOP to the same degree as trabeculectomy and provide significantly better postural IOP control than medical treatment. This surgery can be an effective minimally invasive alternative for patients with significant positional IOP elevations.

Double-Organ Bias in Controlled Trials on Eyelid Ptosis.

PURPOSE: Proper statistical analysis is an essential element in the evaluation of clinical trial outcomes. We had the informal observation that double-organ bias was a neglected issue during the statistical analyses of clinical trials on eyelid ptosis. The aim of this study was to formally document the prevalence of this bias in these studies. METHODS: Clinical trials on eyelid ptosis, published in the last 20 years, were searched in PubMed with the terms; "((blepharoptosis) OR upper eyelid ptosis) OR eyelid ptosis" and with the filters "Randomized Controlled Trial (RCT), Clinical Trial, Humans." Two independent observers evaluated the articles for eligibility, field of the journal, field of the authors, presence of randomization, type of the study (surgical, medical), and statistical approach to double organ bias. RESULTS: The PubMed search yielded 101 articles and 23 of them met the above-mentioned criteria. In 3 articles, primary outcome measure was not related with the eyes. Among the remaining 20 articles, 14 (70%) had double-organ bias in the statistics. The bias was slightly less common in randomized trials (60% vs. 80%), but the difference was not statistically significant. Its prevalence was similar between ophthalmology journals and the rest (p = 0.64). Interestingly, the bias tended to be more in Q1 journals (87.5%) compared to Q2 and Q3 journals (58.3%) and median impact factor was higher in biased articles (1.82 vs. 1.29), but the differences weren't statistically significant (p = 0.32, p = 0.24). There was no difference between the last 2 decades (66.6% vs. 75%, p = 0.64). CONCLUSIONS: The prevalence of the double-organ bias was very high in published clinical trials on eyelid ptosis (70%) and even among RCTs (60%). The prevalence of the bias didn't prevent publication in higher impact factor journals and didn't change between journals from different disciplines or over time.

SARS-CoV-2 Presence in the Saliva, Tears, and Cerumen of COVID-19 Patients.

OBJECTIVES/HYPOTHESIS: The emergence of a new coronavirus strain (SARS-CoV-2) in December 2019 from China led to a global pandemic. The lack of herd immunity against this virus and the possibility of viral spread from asymptomatic individuals is still a major challenge for the prevention of viral transmission. The aim of this study was to evaluate the presence of the virus in different bodily secretions as a potential source of viral spread among patients infected with SARS-CoV-2. STUDY DESIGN: Cross Sectional Study. METHODS: The study included 38 COVID-19 patients with a positive real-time polymerase chain reaction (RT-PCR) test result for SARS-CoV-2, obtained from the combined nasopharyngeal-oropharyngeal swab samples. Saliva, tear, and cerumen samples were taken from the patients within 72 hours of the first RT-PCR test. SARS-CoV-2 N1 and N2 gene regions were studied with single-step RT-PCR in all samples. RESULTS: Among the studied samples, the highest positivity rate was in saliva (76.3%) followed by tears (55.3%) and cerumen (39.5%). Viral load in saliva was also significantly higher compared to tears and cerumen (P < .001), while there was no significant difference between tears and cerumen. Higher viral load in combined nasopharyngeal-oropharyngeal swab samples was associated with higher viral load in tears, but not in saliva or cerumen. Half of the saliva, tear, and cerumen samples obtained from asymptomatic patients contained SARS-CoV-2 genome. CONCLUSIONS: The virus was detected in the saliva, tears, and cerumen samples of both symptomatic and asymptomatic patients. The potential role of these bodily fluids on viral spread needs to be studied. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1677-E1682, 2021.

SARS-CoV-2 Presence in Cerumen.

The emergence of a new coronavirus strain (SARS-CoV-2) in December 2019 from China led to a global pandemic. The lack of herd immunity against this virus and the possibility of viral spread from asymptomatic individuals is still a major challenge for the prevention of viral transmission. The studies of Islamoglu and Hanege evaluated the presence of the virus in different bodily secretions (Cerumen) as a potential source of viral spread among patients infected with SARS-CoV-2. We would like to comment on these 2 studies.