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Purpose: To compare the visual outcomes and efficacy of opposite clear corneal incision (OCCI) and toric intraocular lens (IOL) implantation in correcting preexisting astigmatism (PEA) in patients undergoing phacoemulsification., Methods: This prospective interventional comparative study was conducted between June 2022 and January 2023 in patients having cataract with PEA undergoing phacoemulsification. Patients were divided into two groups - group A underwent phacoemulsification with OCCI and group B underwent phacoemulsification with toric IOL implantation. Uncorrected distance visual acuity (UDVA), manifest refractive cylinder, and corneal astigmatism using corneal tomography were measured preoperatively and at 6 weeks postoperatively. The eyes were categorized into three groups with PEA ranging from 1 to 1.5 D, 1.6 to 2 D, and 2.1 to 3 D. Depending upon the white-to-white corneal diameter, the eyes were also categorized into four groups with corneal diameter ranging from 10.5 to 10.9 mm, 11 to 11.4 mm, 11.5 to 11.9 mm, and 12 to 12.4 mm., Results: Sixty eyes of 60 patients were studied. At postoperative 6 weeks, 83.3% (25 eyes) in the OCCI group and 96.7% (29 eyes) in the toric IOL group achieved UDVA of 6/9 or better. No statistically significant difference was noted between the groups ( P = 0.37). The reduction in mean corneal astigmatism was 0.63 ± 0.37 D in the OCCI group and 0.15 ± 0.12 D in the toric IOL group ( P < 0.001). The residual mean refractive cylinder was 0.60 ± 0.38 D in the OCCI group and 0.05 ± 0.15 D in the toric IOL group at 6 weeks ( P = 0.007)., Conclusion: Both OCCI and toric IOL are effective in correcting PEA. However, in a resource-limited setting, OCCI is a better alternative surgical option for correcting astigmatism of 1-1.5 D during phacoemulsification without requiring additional skills or instruments., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Purpose: To evaluate the clinical outcomes with fibrin glue in comparison with vicryl sutures for limbal conjunctival wound closure in strabismus surgery., Methods: In this prospective interventional study, patients undergoing horizontal muscle strabismus surgery were randomized into two groups: the vicryl suture group and the fibrin glue group. The limbal conjunctival incisions were closed with 8-0 vicryl in the suture group and with fibrin glue in the other group. The outcomes measured were post-operative conjunctival inflammation and wound apposition, patient comfort with the help of a questionnaire, and conjunctival thickness using anterior segment optical coherence tomography (AS-OCT) for both groups at 6 weeks., Results: The study included 64 eyes of 64 patients (32 eyes in each group). The fibrin glue group performed better than the vicryl suture group for most of the symptoms like redness, irritation, watering, and foreign body sensation till 2 weeks post-operatively ( P < 0.001), after which both the groups performed similarly. As for clinical signs, no significant difference was noted between the two groups, except for conjunctival hyperemia, which was significantly lesser in the fibrin glue group at 2 weeks post-operatively ( P < 0.001). The conjunctival thickness measured at 6 weeks using AS-OCT revealed that the thickness increased significantly in the suture group compared to that in the glue group ( P < 0.001 medial site, P = 0.004 lateral site)., Conclusion: Because of greater patient comfort and reduced inflammation associated with fibrin glue, it may be considered as a procedure of choice for conjunctival wound closure in strabismus surgery in the absence of the cost constraints., (Copyright © 2023 Copyright: © 2023 Indian Journal of Ophthalmology.)

Purpose: To compare the visual outcomes and monocular defocus curve of a new monofocal Tecnis Eyhance IOL (Tecnis ICB00) with Tecnis 1 single piece (ZCB00)., Methods: Eighty patients diagnosed with cataract were divided into two groups: Tecnis ICB00 (n = 40) and ZCB00 (n = 40). The visual outcome was evaluated using the following parameters: uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), corrected distance visual acuity (CDVA), distance corrected intermediate visual acuity (DCIVA), corrected near visual acuity (CNVA), uncorrected visual acuity contrast sensitivity (UVACS), best-corrected visual acuity contrast sensitivity (BCVACS), manifest refraction, and defocus curve and was compared at the 6th week and 3 months after surgery., Results: The UIVA and UNVA were significantly (P < 0.05) better in ICB00 as compared with ZCB00 at 6 weeks and 3 months postoperative. The DCIVA was significantly better in ICB00 as compared with ZCB00 at 3 months postoperative (-0.015 ± 0.04 vs. 0.01 ± 0.020; P = 0.01). Regarding contrast sensitivity, UVACS and BCVACS were significantly better in ICB00 as compared with ZCB00 at 6 weeks and 3 months postoperative (P < 0.05). The defocus curves showed that the mean visual acuity of the ICB00 group was significantly better than that of the ZCB00 group at between - 0.5 D and - 2.50 D of defocus., Conclusion: In patients undergoing cataract surgery, Eyhance ICB00 provided better intermediate vision as compared with ZCB00., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Purpose: To compare different endophthalmitis prophylaxis methods adopted in cataract surgery (manual small-incision cataract surgery and phacoemulsification) between the years 2013 and 2021 in the community eye care section of a tertiary eye care hospital in South India and report their outcomes., Methods: All cataract surgeries performed from January 2013 to December 2021 (2,46,874 surgeries) at a single center were included in this retrospective study. The different endophthalmitis rates with each regimen were analyzed and evaluated., Results: 70,081 surgeries were performed from January 2013 to February 2015, where Tobramycin was added to Balanced Salt Solution (BSS) (Group A). From March 2015 to January 2017, 63,245 surgeries were performed when intracameral Moxifloxacin was given (Group B). From February 2017 to December 2021, 1,13,548 surgeries were performed were Amikacin was added to BSS (Group C). In total, 42 cases of postoperative endophthalmitis were reported during the study period (0.02%). There was no significant difference in the endophthalmitis rates between groups A and B (P = 0.4152); however, there was a significant decrease in endophthalmitis rates in group C when compared with group A (P = 0.04) and group B (P = 0.006)., Conclusion: There was a significant reduction in the rates of endophthalmitis following the addition of amikacin in irrigating BSS. Nocardia was one of the predominant organisms isolated from these endophthalmitis patients. This is the first single-center study to report a comparative analysis of different endophthalmitis prophylactic measures in a community eye care set up with a high incidence of Nocardia endophthalmitis prevented with amikacin in BSS irrigating solution., Competing Interests: None

Parkinson's disease (PD) is a neurodegenerative condition characterized by the dopamine (DA) neuronal loss in the substantia nigra. PD impairs motor controls symptoms such as tremor, rigidity, bradykinesia and postural imbalance gradually along with non-motor problems such as olfactory dysfunction, constipation, sleeping disorder. Though surplus of factors and mechanisms have been recognized, the precise PD etiopathogenesis is not yet implied. Reports suggest that various environmental factors play a crucial role in the causality of the PD cases. Epidemiological studies have reported that heavy metals has a role in causing defects in substantia nigra region of brain in PD. Though the reason is unknown, exposure to heavy metals is reported to be an underlying factor in PD development. Metals are classified as either essential or non-essential, and they have a role in physiological processes such protein modification, electron transport, oxygen transport, redox reactions, and cell adhesion. Excessive metal levels cause oxidative stress, protein misfolding, mitochondrial malfunction, autophagy dysregulation, and apoptosis, among other things. In this review, we check out the link between heavy metals like copper (Cu), arsenic (As), cadmium (Cd), iron (Fe), and lithium (Li) in neurodegeneration, and how it impacts the pathological conditions of PD. In conclusion, increase or decrease in heavy metals involve in regulation of neuronal functions that have an impact on neurodegeneration process. Through this review, we suggest that more research is needed in this stream to bring more novel approaches for either disease modelling or therapeutics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Type 2 diabetes is a metabolic disorder associated with abnormal glucose homeostasis and is characterized by intrinsic defects in β-cell function and mass. Trimethylguanosine synthase 1 (TGS1) is an evolutionarily conserved enzyme that methylates small nuclear and nucleolar RNAs and that is involved in pre-mRNA splicing, transcription, and ribosome production. However, the role of TGS1 in β-cells and glucose homeostasis had not been explored. Here, we show that TGS1 is upregulated by insulin and upregulated in islets of Langerhans from mice exposed to a high-fat diet and in human β-cells from type 2 diabetes donors. Using mice with conditional (βTGS1KO) and inducible (MIP-Cre ERT -TGS1KO) TGS1 deletion, we determined that TGS1 regulates β-cell mass and function. Using unbiased approaches, we identified a link between TGS1 and endoplasmic reticulum stress and cell cycle arrest, as well as and how TGS1 regulates β-cell apoptosis. We also found that deletion of TGS1 results in an increase in the unfolded protein response by increasing XBP-1, ATF-4, and the phosphorylation of eIF2α, in addition to promoting several changes in cell cycle inhibitors and activators such as p27 and Cyclin D2. This study establishes TGS1 as a key player regulating β-cell mass and function. We propose that these observations can be used as a stepping-stone for the design of novel strategies focused on TGS1 as a therapeutic target for the treatment of diabetes., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article, (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe a simple manual surgical technique for splitting a single-donor eye for performing both deep anterior lamellar keratoplasty (DALK) and Descemet membrane endothelial keratoplasty (DMEK) without using a microkeratome., Methods: Twenty-three eyes with anterior stromal pathology and 23 eyes with irreversible endothelial dysfunction were evaluated for keratoplasty at a tertiary eye care referral center. Twenty-three healthy donor corneas were split into two parts. The Descemet's membrane was stripped and used for DMEK. The stripped stroma was used for DALK. Best-corrected visual acuity (BCVA) of both DALK and DMEK, endothelial cell density, and endothelial cell loss in DMEK were noted at 1-year follow-up, along with any intraoperative or postoperative complications and failures., Results: In the DALK group, mean BCVA improved from 1.264 ± 0.25 log Mar preoperatively to 0.355 ± 0.27 log Mar at 12 months follow-up. There were no complications and failures. In the DMEK group, mean BCVA improved from 1.537 ± 0.61 log Mar preoperatively to 0.592 ± 0.67 log Mar and the mean donor ECD was 3071.66 (range, 2783-3487) cells/mm 2 preoperatively, which was reduced to 1989.33 (range, 1546-2543) cells/mm 2 at 12 months follow-up indicating a mean endothelial cell loss of 35%. The failure rate was 21.7%., Conclusion: This study demonstrates that with a single donor corneal tissue, both DALK and DMEK can be performed successfully without any complications. Our technique will help corneal surgeons in all developing countries to cost effectively perform more lamellar surgeries and help in reducing the magnitude of corneal blindness without the need for expensive microkeratomes., Competing Interests: None

Purpose: To analyze the outcomes of phacoemulsification with high power customized toric intraocular lens implantation (IOL) in patients with high corneal astigmatism (6-10 D Cyl) post keratoplasty and keratoconus eyes with cataract., Methods: Five eyes post keratoplasty with clear graft, four eyes with stable keratoconus, one eye with pterygium excision scar with visually significant cataract were included in this retrospective study. Phacoemulsification was done followed by implantation of custom made high power toric IOL in all patients. Outcomes included uncorrected and best-corrected distance visual acuity (UDVA, BCVA), pre-operative astigmatism at the corneal plane and IOL plane, post-operative residual astigmatism, mean torus of all IOLs used were calculated., Results: The minimum follow-up time was 12 months. At the last follow-up visit, there was a significant improvement (pre-operative vs post-operative) of UDVA (1.5 ± 0.47 vs 0.28 ± 0.14 logMAR; P < 0.05), cylindrical refraction (-9.0 ± 1.80 D vs -1.1 ± 0.45 vs ; P < 0.05). Range of IOL powers used was 1.0-26.50 DSph and 9.0-15.5 DCyl. Post-operative mean residual spherical equivalent was 0.75 ± 0.5., Conclusion: This novel study describes the effectiveness of custom toric IOLs in high astigmatism in the range of 9.0-15.5 DCyl. Phacoemulsification with implantation of a customized high power toric IOL was effective in correcting high astigmatism in complex cases in our study., Competing Interests: None

Aim of the Study: The purpose of the study is to evaluate the occlusal relationship of the mesiobuccal cusp of a mandibular first molar with the marginal ridge of maxillary first molar and second premolar and to analyze the effect of the above occlusal relation on different direct and indirect restorations using finite element analysis (FEA)., Methodology: Four hundred volunteers studying in a dental college were screened, of which 100 volunteers were selected for studying occlusal relationships based on the inclusion and exclusion criteria. The two most common occlusal relationships were considered for analyzing two direct (amalgam and direct composite restorations) and two indirect restorations (composite and ceramic restorations). Three-dimensional (3D) scanning of the models was performed, and Class II tooth preparations specific for each restorative material were prepared digitally on 3D models. FEA was employed to study von Mises (VM) stress, principal stresses, and cuspal deflection for each restorative material, and failure of the tooth-restoration unit was calculated using the modified Mohr failure criterion., Results: Among all the analyzed materials, cuspal deformation, principal stresses, and VM stresses were high for direct composite restoration and least for ceramic inlay. According to modified Mohr criteria, except for direct composite, all other materials performed better., Conclusion: Silver amalgam and ceramic restorations presented with minimal stress concentration and cuspal deflection, and Type I occlusal relationship presented with higher stress concentration compared to Type II., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Conservative Dentistry.)

A donor corneo-scleral button was dissected into four parts using a simple manual technique. The anterior corneal lamellae was stripped from the Descemet's Membrane (DM) and Deep Anterior Lamellar Keratoplasty (DALK) was performed in a patient with advanced keratoconus after removing the recipient's stroma using the big bubble technique. Descemet's Membrane Endothelial Keratoplasty (DMEK) was done with the stripped donor DM in a patient with Fuch's endothelial dystroph (FECD). The cadaveric limbal stem cells from the tissue were used for simple limbal epithelial transplantation (SLET) in a Steven- Johnson Syndrome (SJS) with localized limbal stem deficiency and symblepharon. The sclera was used to revise a leaking hypotonus bleb in an advanced single-eyed glaucoma patient. No intraoperative or postoperative complications were observed. At 1 year, all the 4 cases retained healthy transplanted tissues with good visual outcomes. Shortage of donor eyes is a global problem and with the present COVID-19 scenario the situation is bound to worsen. The advent of customized component corneal transplantation using simple cost-effective techniques will be the future trend in the years to come., Competing Interests: None

Purpose: The purpose of this study is to evaluate 2-year clinical outcome after Descemet membrane endothelial keratoplasty (DMEK) in a variety of endothelial dysfunctions using a standardized protocol., Methods: : From a group of 230 eyes which underwent DMEK for Fuchs' endothelial corneal dystrophy (FECD), aphakic and pseudophakic bullous keratopathy, failed full thickness corneal transplants, ICE syndrome, failed DSEK, and TASS the clinical outcomes [best spectacle-corrected visual acuity (BSCVA), central endothelial cell density (ECD)] were evaluated before, and at 6, 12, and 24 months and the success rate, failure rate and postoperative complications were also analyzed., Results: Out of 230 eyes, 144 eyes (70%) had BSCVA 6/9 or better 2 years postoperatively. Mean donor ECD was 2692.23 (range, 2300-3436) cells/mm 2 preoperatively, which was reduced to 1433.64 (range, 619.0-2272.0) cells/mm 2 2 years after DMEK surgery, indicating a mean reduction of 1258 cells/mm 2 (46%) in ECD., Conclusion: DMEK is a highly successful surgical procedure when following a standard protocol for treating diseases of the corneal endothelium providing a near perfect anatomic restoration and a high degree of visual rehabilitation., Competing Interests: None

Autism spectrum disorder is a neurodevelopmental disorder and the cause of autism is still unclear. The aim of this study was to investigate the association of socioeconomic, environmental, pregnancy and newborn-related risk factors among children with autism spectrum disorders. This was a population-based case-control study. The study included 55 children with autism spectrum disorder and 55 age and sex matched typically developing normal children (TD) between 3 and 12 years. Several socio-economic factors, environmental factors, pregnancy related, natal, post-natal factors and the first noticed signs by the parents were analyzed. Chi-square test was used to compare nominal variables. For multivariate analysis, forward stepwise logistic regression model was employed to examine the association between autism and the chances that the child develops ASD to assess the odds ratios. Male predominance was observed in the study. Logistic regression model showed statistical significance of the following factors: paternal age greater than 40 years, family history of autism, nutrition during pregnancy, mode of labor, fetal hypoxia, NICU stay and history of breast feeding. In this epidemiological study of autism in Coimbatore city, we found correlation between several environmental factors during fetal development and can be transmitted to succeeding generations, causing atypical behavior phenotypes. The exact exposure magnitude, exposure time in relation to vital developmental periods need to be studied to understand the influence of socioeconomic and environmental factors, which can be improved to prevent ASD-related challenges.

Purpose: The aim was to study the visual performance of a new refractive extended depth of focus (EDOF) intraocular lens (IOL)., Design: Prospective, comparative study., Methods: Consenting patients with age-related cataract willing for bilateral cataract surgery within 2 weeks were implanted with the Supraphob EDOF IOL and those willing for 1 eye surgery were implanted with a monofocal IOL. The uncorrected and best-corrected distance, intermediate and near visual acuity, and contrast sensitivity were evaluated at 1 and 3 months postoperatively. We also inquired about glare, halos, difficulties in night driving, requirement for spectacles, and overall satisfaction with vision., Results: The Supraphob EDOF group (n = 72 eyes) and the monofocal IOL group (n = 54 eyes) were comparable with respect to all preoperative parameters including biometry, visual acuity, and cataract status. The mean age of participants was 58.4 ± 10.6 years. Both groups had similar distance vision but the EDOF group had significantly better intermediate (0.2 ± 0.2 logMAR vs 0.75 ± 0.19 logMAR, P < 0.001) and near vision (median = N6 vs N12, P < 0.001) compared to the monofocal group at 3 months. The contrast sensitivity was similar in both groups. Patients in the EDOF IOL group had much greater satisfaction for intermediate and near vision. Less than 10% patients reported glare, halos, and difficulty in driving at night in the EDOF group., Conclusions: The Supraphob EDOF IOL was effective in improving the distance, intermediate and near vision in majority of patients, and retained good contrast sensitivity with most patients reporting excellent satisfaction.

Aim: To do a randomized prospective interventional study for comparing the effects of a single subconjunctival triamcinolone acetonide (SCTA) injection to tapering topical loteprednol in patients undergoing phacoemulsification surgery under topical anesthesia., Methods: A total of 400 patients were randomized into 2 groups; Group A (200 patients) received 5 mg SCTA at the end of surgery and topical ketorolac tromethamine (0.5%) with ofloxacin (0.3%) combination for 3wk. Group B (200 patients) received tapering topical loteprednol etabonate (0.5%) along with ofloxacin (0.3%) and ketorolac tromethamine (0.5%) for 3wk. Outcomes evaluated were intraocular pressure (IOP), anterior chamber cells/flare and macular oedema postoperatively at 1, 6 and 12wk., Results: Baseline parameters were almost similar in both the groups. No statistical difference was seen between the preoperative and postoperative IOP values for Group A ( P =0.82) and Group B ( P =0.61) and postoperative IOP values in between both groups ( P =0.14) at 1wk. Incidence of cells/flare postoperative was statistically not significant ( P =0.82) in both groups at all follow up visits. Postoperative macular oedema was not observed at any follow up visit., Conclusion: SCTA appears to be an effective alternative to prolong postoperative topical steroid use.

Umbilical cord blood (UCB) is an important source of stem cells, the heart of regenerative medicine. As the globalization and population of the world continues to increase, we are faced with an inundation of new diseases, affecting millions of people. Research work considering stem cells is essential for developing therapy for various conditions. Reduced availability of UCB serves as a hindrance to promote further research. Hence, India being one of the most densely populated countries in the world, can be considered a potential UCB repository. In this study 428 mothers of children born in the period from 2012 to 2017 were asked to fill questionnaires that evaluated their awareness regarding stem cell banking. This investigation deliberates if expectant mothers in this region are aware of stem cell banking and if there is a significant pattern regarding awareness based on parameters like age, educational qualification, locality, annual income and consulted hospitals. Although, majority of the women were unaware of this facility, knowledge was heightened in wealthy, educated, women from urban areas who consulted private hospitals. Hence, great efforts need to be made to further the awareness of expectant mothers in South India regarding UCB storage and donation.

Purpose: To generate virtual models using different hinge locations and to investigate the advantages of a temporal hinge to a superior in LASIK., Methods: The study design was cross sectional. An image processing software was used to construct virtual LASIK models of 56 slit lamp photos of eyes. For a given hinge location and width, the largest flap diameter and maximum treatable stromal bed area were calculated, comparing temporal hinge to superior., Results: Temporal hinge allowed a greater flap diameter than superior and thus a greater treatment zone area for a given hinge width. A temporal hinge allowed a greater hinge width than a superior hinge for a given treatment zone area., Conclusion: We provide a rational basis for a mechanically stable temporal hinge. Moreover, we provide a method to pre-operative model flap size and hinge location, using a slit lamp camera and an image editing software.

Phosphodiesterase 1C (PDE1C) is expressed in mammalian heart and regulates cardiac functions by controlling levels of second messenger cyclic AMP and cyclic GMP (cAMP and cGMP, respectively). However, molecular mechanisms of cardiac Pde1c regulation are currently unknown. In this study, we demonstrate that treatment of wild type mice and H9c2 myoblasts with Wy-14,643, a potent ligand of nuclear receptor peroxisome-proliferator activated receptor alpha (PPARα), leads to elevated cardiac Pde1C mRNA and cardiac PDE1C protein, which correlate with reduced levels of cAMP. Furthermore, using mice lacking either Pparα or cardiomyocyte-specific Med1 , the major subunit of Mediator complex, we show that Wy-14,643-mediated Pde1C induction fails to occur in the absence of Pparα and Med1 in the heart. Finally, using chromatin immunoprecipitation assays we demonstrate that PPARα binds to the upstream Pde1C promoter sequence on two sites, one of which is a palindrome sequence (agcTAGGttatcttaacctagc) that shows a robust binding. Based on these observations, we conclude that cardiac Pde1C is a direct transcriptional target of PPARα and that Med1 may be required for the PPARα mediated transcriptional activation of cardiac Pde1C .

PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT -/- ) in adult mice. These mice manifest enlargement of heart, with nearly 100% mortality by 7.5 months of age due to dilated cardiomyopathy. Significant reductions in the expression of genes (i) pertaining to mitochondrial respiratory chain complexes I to IV; (ii) calcium cycling cardiac muscle contraction ( Atp2a1 , Atp2a2 , Ryr2 ); and (iii) nuclear receptor PPAR- regulated genes involved in glucose and fatty acid energy metabolism were found in csPIMT -/- mouse heart. Elevated levels of Nppa and Nppb mRNAs were noted in csPIMT -/- heart indicative of myocardial damage. These hearts revealed increased reparative fibrosis associated with enhanced expression of Tgfβ2 and Ctgf . Furthermore, cardiac-specific deletion of PIMT in adult mice, using tamoxifen-inducible Cre-approach (TmcsPIMT -/- ), results in the development of cardiomyopathy. Thus, cumulative evidence suggests that PIMT functions in cardiac energy metabolism by interacting with nuclear receptor coactivators and this property could be useful in the management of heart failure.

Objective: MED1 (mediator 1) interacts with transcription factors to regulate transcriptional machinery. The role of MED1 in macrophage biology and the relevant disease state remains to be investigated., Approach and Results: To study the molecular mechanism by which MED1 regulates the M1/M2 phenotype switch of macrophage and the effect on atherosclerosis, we generated MED1/apolipoprotein E (ApoE) double-deficient (MED1 ΔMac /ApoE - /- ) mice and found that atherosclerosis was greater in MED1 ΔMac /ApoE -/- mice than in MED1 fl/fl /ApoE -/- littermates. The gene expression of M1 markers was increased and that of M2 markers decreased in both aortic wall and peritoneal macrophages from MED1 ΔMac /ApoE -/- mice, whereas MED1 overexpression rectified the changes in M1/M2 expression. Moreover, LDLR (low-density lipoprotein receptor)-deficient mice received bone marrow from MED1 ΔMac mice showed greater atherosclerosis. Mechanistically, MED1 ablation decreased the binding of PPARγ (peroxisome proliferator-activated receptor γ) and enrichment of H3K4me1 and H3K27ac to upstream region of M2 marker genes. Furthermore, interleukin 4 induction of PPARγ and MED1 increased the binding of PPARγ or MED1 to the PPAR response elements of M2 marker genes., Conclusions: Our data suggest that MED1 is required for the PPARγ-mediated M2 phenotype switch, with M2 marker genes induced but M1 marker genes suppressed. MED1 in macrophages has an antiatherosclerotic role via PPARγ-regulated transactivation., (© 2017 American Heart Association, Inc.)

The aim of the study is to investigate the applicability of a newly developed corneal topographer in assessing tear film stability in Indian subjects. A prospective comparative study of 25 Indian subjects with dry eyes attending a tertiary eye care clinic in South India and 25 normal control subjects was conducted. The diagnosis of dry eye was made based on ocular surface disease index questionnaire. Non-invasive tear film break-up time (NI-TBUT) was measured using a new method based on a corneal topographer equipped with modified scan software. The correlations between the NI-TBUT and the traditional fluorescein tear film break-up time (F-TBUT), Schirmer I test values were determined. A total of 50 patients (100 eyes) were included. The values of NI-TBUT were significantly lower than the values of F-TBUT in both the cases (NI-TBUT 5.78 ± 0.8 s and F-TBUT 7.56 ± 0.5 s; p < 0.02) and controls (NI-TBUT 11.66 ± 1 s and F-TBUT 12.92 ± 1.2 s; p < 0.01). NI-TBUT values were significantly lower than the corresponding F-TBUT values in the varying grades of dry eyes. The mean NI-TBUT values in mild dry eyes was 6.42 ± 0.2 s, moderate dry eyes was 4.70 ± 0.3 s and in severe dry eyes was 2.32 ± 1.2 s. There was a significant difference in the NI-TBUT values for cases and controls (p < 0.001). There was a good correlation seen between the NI-TBUT values and the F-TBUT values, Schirmer I values and the ODSI scores. NI-TBUT was found to have a sensitivity of 86.1 % and a specificity of 81.1 % when the cut-off value was kept at 6.2 s. We investigated the performance of a non-invasive technique for measuring tear film stability to aid in the diagnosis of dry eye disease. It is a useful non-invasive objective method for the detection of dry eye, and its varying grades and may be useful in monitoring the efficacy of therapies for dry eye.

Purpose: To evaluate visual outcomes, endothelial cell density and complications following Descemet's membrane endothelial keratoplasty (DMEK)., Methods: This study included 40 consecutive eyes that underwent DMEK for various pathologies involving the corneal endothelium. Best corrected visual acuity (BCVA) and endothelial cell density (ECD) were measured and compared before and 6 months after surgery., Results: Out of 40 eyes, 34 eyes (85%) had BCVA ranging from 0.5 to 0.7 LogMAR 6 months postoperatively. Mean donor ECD was 2367.96 ± 47.87 (range, 2314.0-2472.0) cells/mm 2 preoperatively, which was reduced to 1798.42 ± 45.79 (range, 1736.0-1902.0) cells/mm 2 6 months after DMEK surgery, indicating a mean reduction of 569.54 cells/mm 2 (24%) in ECD., Conclusion: DMEK is an emerging and a more advanced alternative to penetrating keratoplasty (PKP) and Descemet's stripping endothelial keratoplasty (DSEK) for corneal pathologies involving the corneal endothelium. Compared to PK and DSEK, however, DMEK has a longer learning curve, and its safety and efficacy need to be confirmed through more experience on a large volume of cases., Competing Interests: There are no conflicts of interest.

[This corrects the article DOI: 10.1371/journal.pone.0160755.].

Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1-/-) during late gestational and early postnatal development by intercrossing Med1fl/fl mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1-/- mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1-/- heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1-/-), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1-/- studies described above are highly reproducible in TmcsMed1-/- mouse heart. Collectively, these observations suggest that Med1 plays a critical role in the maintenance of heart function impacting on multiple metabolic, compensatory and reparative pathways with a likely therapeutic potential in the management of heart failure., Competing Interests: The authors have declared that no competing interests exist.

To evaluate the efficacy of combined procedure of Descemet's membrane endothelial keratoplasty (DMEK) and posterior iris-claw-fixated intra ocular lens (IOL) implantation in the management of aphakic bullous keratopathy (ABK). Sankara eye centre, a tertiary eye care centre. A prospective case series analysis. A prospective study comprised ten eyes of ten patients who underwent DMEK and posterior iris-claw-fixated IOL. Mean follow-up period was 12-36 months. Pre-operative and post-operative best corrected visual acuity (BCVA), endothelial cell density (ECD) and complications were noted. A total ten eyes of ten patients underwent DMEK. Out of ten patients BCVA improved from 1.00 to 1.60 LogMAR with mean and SD of 1.40 ± 0.20 to +0.20-0.40 LogMAR with mean and SD of 0.30 ± 0.07, with a significant p value of <0.001, Mean ECD of the donor tissue pre-operatively was 2367 cells, whereas 24 months post-operatively it was reduced to 1798 cells. Mean reduction in ECD pre procedure and post procedure was 569 (24 %). Iris-fixated IOL appears to offer simplicity in implantation and may be combined with DMEK in ABK. This procedure provides a faster visual recovery than other endothelial keratoplasties with iris-fixated IOL.

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to Ig switch regions (S regions). During CSR, the IgH locus undergoes dynamic three-dimensional structural changes in which promoters, enhancers, and S regions are brought to close proximity. Nevertheless, little is known about the underlying mechanisms. In this study, we show that Med1 and Med12, two subunits of the mediator complex implicated in transcription initiation and long-range enhancer/promoter loop formation, are dynamically recruited to the IgH locus enhancers and the acceptor regions during CSR and that their knockdown in CH12 cells results in impaired CSR. Furthermore, we show that conditional inactivation of Med1 in B cells results in defective CSR and reduced acceptor S region transcription. Finally, we show that in B cells undergoing CSR, the dynamic long-range contacts between the IgH enhancers and the acceptor regions correlate with Med1 and Med12 binding and that they happen at a reduced frequency in Med1-deficient B cells. Our results implicate the mediator complex in the mechanism of CSR and are consistent with a model in which mediator facilitates the long-range contacts between S regions and the IgH locus enhancers during CSR and their transcriptional activation., (© 2016 Thomas-Claudepierre et al.)

Purpose: To evaluate the visual outcome and intraocular pressure changes after Visian Implantable Collamer Lens (ICL) implantation V4b and V4c (with central hole) for correction of high myopia., Methods: A prospective, consecutive, interventional comparative case series of V4b and V4c ICL implantation was done in high myopic patients who were unsuitable for laser vision. The main outcome measures studied were uncorrected and corrected distant visual acuity (UDVA, CDVA), ICL vault, intraocular pressure (IOP), endothelial cell count (ECC), and development of subcapsular lens opacities. The patients were evaluated at postoperative 1,3,6, and 9 months., Results: A total of 62 eyes of 32 patients (24.56 ± 4.8 years) underwent V4b ICL implantation (21 non-toric, 41 toric ICL-TICL) with intraoperative peripheral iridectomy (PI), and 10 eyes of 5 patients (26.13 ± 3.8 years) had implantation of V4c ICL (4 non-toric, 6 TICL). The mean preoperative manifest spherical equivalent (MSE) was -9.98 ± 2.8 D and -9.14 ± 2.4 D in the V4b and V4c groups, respectively, which reduced to postoperative values of -0.24 ± 1.3 D and -0.2 ± 1.18 D, respectively. At the end of 9 months follow-up, mean ECC loss was 6.4% and 6.1%, mean vault was 573.13 ± 241.13 μ, and 612 ± 251.14 μ, respectively, in the V4b and V4c groups. Anterior subcapsular opacities were present in 6.9% and 3.14% of eyes with V4b and V4c groups, respectively. Four eyes from V4b (9.75%) and 1 eye from V4c (16.66%) had rotation of more than 30° and required realignment surgery, which was done successfully. Two eyes (3.22%) with V4b ICL implantation had high postoperative IOP (>35 mm Hg) due to blocked PI and required Nd:Yag laser iridotomy, which was done with successful control of IOP. The safety indices were 1.11 and 1.14, and efficacy indices were 1.4 and 1.5 in the V4b and V4c groups, respectively, at the end of 9 months., Conclusion: ICL implantation is a safe and effective surgery for correction of high myopia. Implantation of ICL with a central hole showed negligible postoperative IOP fluctuations without a peripheral iridectomy.

The kidney is one of the target organs for various metabolic diseases, including diabetes, metabolic syndrome, and obesity. Most of the metabolic studies underscore glomerular pathobiology, although the tubulo-interstitial compartment has been underemphasized. This study highlights mechanisms concerning the pathobiology of tubular injury in the context of myo-inositol oxygenase (Miox), a tubular enzyme. The kidneys of mice fed a high fat diet (HFD) had increased Miox expression and activity, and the latter was related to phosphorylation of serine/threonine residues. Also, expression of sterol regulatory element-binding protein1 (Srebp1) and markers of cellular/nuclear damage was increased along with accentuated apoptosis and loss of tubular brush border. Similar results were observed in cells treated with palmitate/BSA. Multiple sterol-response elements and E-box motifs were found in the miox promoter, and its activity was modulated by palmitate/BSA. Electrophoretic mobility and ChIP assays confirmed binding of Srebp to consensus sequences of the miox promoter. Exposure of palmitate/BSA-treated cells to rapamycin normalized Miox expression and prevented Srebp1 nuclear translocation. In addition, rapamycin treatment reduced p53 expression and apoptosis. Like rapamycin, srebp siRNA reduced Miox expression. Increased expression of Miox was associated with the generation of reactive oxygen species (ROS) in kidney tubules of mice fed an HFD and cell exposed to palmitate/BSA. Both miox and srebp1 siRNAs reduced generation of ROS. Collectively, these findings suggest that HFD or fatty acids modulate transcriptional, translational, and post-translational regulation of Miox expression/activity and underscore Miox being a novel target of the transcription factor Srebp1. Conceivably, activation of the mTORC1/Srebp1/Miox pathway leads to the generation of ROS culminating into tubulo-interstitial injury in states of obesity., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background and Purpose: To assess the diagnostic performance of conventional and diffusion weighted (DWI) magnetic resonance imaging (MRI) in predicting response in locally advanced cervical cancer., Materials and Methods: Total 24 patients with stage IIB-IIIB squamous cell carcinoma cervix were treated with initial two cycles of paclitaxel and carboplatin and concurrent low dose radiotherapy prior to standard chemoradiation. Response was assessed clinically and radiologically after 3 weeks of initial treatment. Volumetric and functional parameters derived from conventional and diffusion weighted MRI, due to treatment were measured., Results: Significant reduction of GTV was noted in MRI (54 cm(3) vs. 11 cm(3), p < 0.01) and DWI (44 cm(3) vs. 6 cm(3), p < 0.01, ΔADC = 0.49 × 10(-3)mm(2)/sec, p < 0.01) after treatment. Tumor volume reduction rate (TVRR) in DWI was significantly higher in pathological good responders (p = 0.03). In this group both mean post treatment apparent diffusion coefficient (ADC) value and ΔADC were significantly higher (p = 0.01 and p = 0.03). ADC was a good predictor for pathological response (area under receiver operating characteristic curve (ROC) 0.814)., Conclusion: TVRR (DWI) and ΔADC can be used as a predictor of early pathological response. Complete response based on DWI, could be a useful predictor of long term disease control., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The mechanisms underlying inflammation induced insulin resistance are poorly understood. Here, we report that the expression of PIMT, a transcriptional co-activator binding protein, was up-regulated in the soleus muscle of high sucrose diet (HSD) induced insulin resistant rats and TNF-α exposed cultured myoblasts. Moreover, TNF-α induced phosphorylation of PIMT at the ERK1/2 target site Ser(298). Wild type (WT) PIMT or phospho-mimic Ser298Asp mutant but not phospho-deficient Ser298Ala PIMT mutant abrogated insulin stimulated glucose uptake by L6 myotubes and neonatal rat skeletal myoblasts. Whereas, PIMT knock down relieved TNF-α inhibited insulin signaling. Mechanistic analysis revealed that PIMT differentially regulated the expression of GLUT4, MEF2A, PGC-1α and HDAC5 in cultured cells and skeletal muscle of Wistar rats. Further characterization showed that PIMT was recruited to GLUT4, MEF2A and HDAC5 promoters and overexpression of PIMT abolished the activity of WT but not MEF2A binding defective mutant GLUT4 promoter. Collectively, we conclude that PIMT mediates TNF-α induced insulin resistance at the skeletal muscle via the transcriptional modulation of GLUT4, MEF2A, PGC-1α and HDAC5 genes.

Background: We investigated the feasibility of neoadjuvant low-dose radiation and chemotherapy with paclitaxel and carboplatin (LDCRT) before radical chemoradiation (CRT) and assessed the feasibility, efficacy, and response rate to such a regimen., Methods: This is a single-arm phase II trial of 24 patients, with locally advanced squamous cell carcinoma of the cervix (stage IIB-IIIB). Patients received low-dose fractionated radiotherapy, carboplatin (AUC×5) and paclitaxel (175 mg/m(2)), three weekly for two cycles followed by CRT. The primary end point was overall and disease-free survival., Results: Mean age of the patients at diagnosis was 50 years; Radiological complete or partial response rate was 40% and 60%, respectively, post-LDCRT. The median follow-up was 30 months (24-36 months). Both overall and progression-free survivals at 2.5 years were 84%. Grade 3/4 toxicities were 24% hematological toxicity during LDCRT and 46% during CRT (hematological: 42%, non-hematological: 4%)., Conclusion: A good response rate is achieved by low-dose radiation and chemotherapy with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible and effective as evidenced by the acceptable toxicity and 84% local control at 2.5 years., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Spermatogenesis is a highly coordinated process. Signaling from nuclear hormone receptors, like those for retinoic acid (RA), is important for normal spermatogenesis. However, the mechanisms regulating these signals are poorly understood. Mediator complex subunit 1 (MED1) is a transcriptional enhancer that directly modulates transcription from nuclear hormone receptors. MED1 is present in male germ cells throughout mammalian development, but its function during spermatogenesis is unknown. To determine its role, we generated mice lacking Med1 specifically in their germ cells beginning just before birth. Conditional Med1 knockout males are fertile, exhibiting normal testis weights and siring ordinary numbers of offspring. RA-responsive gene products stimulated by RA gene 8 (Stra8) and synaptonemal complex protein 3 (Sycp3) are first detected in knockout spermatogonia at the expected time points during the first wave of spermatogenesis, and persist with normal patterns of cellular distribution in adult knockout testes. Meiotic progression, however, is altered in the absence of Med1. At postnatal day 7 (P7), zygotene-stage knockout spermatocytes are already detected, unlike in control testes, with fewer pre-leptotene-stage cells and more leptotene spermatocytes observed in the knockouts. At P9, Med1 knockout spermatocytes prematurely enter pachynema. Once formed, greater numbers of knockout spermatocytes remain in pachynema relative to the other stages of meiosis throughout testis development and its maintenance in the adult. Meiotic exit is not inhibited. We conclude that MED1 regulates the temporal progression of primary spermatocytes through meiosis, with its absence resulting in abbreviated pre-leptotene, leptotene, and zygotene stages, and a prolonged pachytene stage., (© 2015 Society for Reproduction and Fertility.)

Obesity poses an increased risk of developing metabolic syndrome and closely associated nonalcoholic fatty liver disease, including liver cancer. Satiety hormone leptin-deficient (ob/ob) mice, considered paradigmatic of nutritional obesity, develop hepatic steatosis but are less prone to developing liver tumors. Sustained activation of peroxisome proliferator-activated receptor α (PPARα) in ob/ob mouse liver increases fatty acid oxidation (FAO), which contributes to attenuation of obesity but enhances liver cancer risk. To further evaluate the role of PPARα-regulated hepatic FAO and energy burning in the progression of fatty liver disease, we generated PPARα-deficient ob/ob (PPARα(Δ)ob/ob) mice. These mice become strikingly more obese compared to ob/ob littermates, with increased white and brown adipose tissue content and severe hepatic steatosis. Hepatic steatosis becomes more severe in fasted PPARα(Δ)ob/ob mice as they fail to up-regulate FAO systems. PPARα(Δ)ob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPARα agonist Wy-14,643. Although PPARα(Δ)ob/ob mice are severely obese, there was no significant increase in liver tumor incidence, even when maintained on a diet containing Wy-14,643. We conclude that sustained PPARα activation-related increase in FAO in fatty livers of obese ob/ob mice increases liver cancer risk, whereas deletion of PPARα in ob/ob mice aggravates obesity and hepatic steatosis. However, it does not lead to liver tumor development because of reduction in FAO and energy burning., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate visual outcome and endothelial cell density (ECD) after Descemet's Membrane Endothelial Keratoplasty (DMEK) in comparison with Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) in the fellow eye for Fuchs endothelial dystrophy (FED)., Design: Single-centre, retrospective case series., Methods: 30 eyes of 30 patients undergoing DMEK, who completed a 1-year follow-up, were compared with 30 fellow eyes which underwent DSAEK for bilateral FED. Main outcome measures studied included Best Corrected Visual Acuity (BCVA) and ECD during a 1-year follow-up period., Results: BCVA improved from 0.78 ± 0.35 logMAR, and 0.73 ± 0.31 logMAR before surgery to 0.22 ± 0.1 logMAR and 0.35 ± 0.12 logMAR 6 months after DMEK and DSEK, respectively (P < 0.001). At one year after surgery, the BCVA was maintained at 0.21 ± 0.12 logMAR and 0.34 ± 0.1 logMAR, respectively, after DMEK and DSAEK. A statistically better visual outcome was observed after DMEK compared to DSAEK (P < 0.05) in fellow eyes., Conclusions: DMEK provided better visual rehabilitation when compared to DSAEK. Nevertheless, there were no significant differences with regard to the ECD within a 1-year follow-up.

Purpose: To determine the incidence and density of Demodex species on the eyelashes of subjects with normal eyelids, anterior blepharitis (AB), meibomian-gland dysfunction (MGD), and mixed blepharitis (MB)., Materials and Methods: One hundred and fifty consecutive patients diagnosed with AB, MGD, and MB were recruited. An additional 50 individuals were recruited who were free of lid and margin disease to serve as a control group. All patients underwent a standard eye examination. Data on ocular symptomatology were gathered. Digital photography was performed of the lid margins. Lash sampling was performed by epilating the lashes and the lashes were checked for Demodex based on morphology using light microscopy. The total number of mites were tabulated for each eye. Comparison between the affected eyes and the control eyes was performed. Data were analyzed using the Chi-square test., Results: A total of 200 patients were included. Twenty percenth had AB, 40% had MGD, and 40% had MB. The incidence of Demodex infestation was 90% in cases of AB, 60% in MGD cases, and 90% in MB cases. The incidence of Demodex in control subjects was 18%., Conclusions: The incidence and density of Demodex infestation was highest in patients with AB and MB. Lid irritation and presence of cylindrical dandruff were indicative of a high-density infestation. These signs should alert the clinician to treat concomitant Demodex infestation.

MED1 (Mediator complex subunit 1) is a co-activator of various transcription factors that function in multiple transcriptional pathways. We have already established keratinocyte-specific MED1 null mice (Med1(epi-/-)) that develop epidermal hyperplasia. Herein, to investigate the function(s) of MED1 in skin wound healing, full-thickness skin wounds were generated in Med1(epi-/-) and age-matched wild-type mice and the healing process was analyzed. Macroscopic wound closure and the re-epithelialization rate were accelerated in 8-week-old Med1(epi-/-) mice compared with age-matched wild-type mice. Increased lengths of migrating epithelial tongues and numbers of Ki67-positive cells at the wounded epidermis were observed in 8-week-old Med1(epi-/-) mice, whereas wound contraction and the area of α-SMA-positive myofibroblasts in the granulation tissue were unaffected. Migration was enhanced in Med1(epi-/-) keratinocytes compared with wild-type keratinocytes in vitro. Immunoblotting revealed that the expression of follistatin was significantly decreased in Med1(epi-/-) keratinocytes. Moreover, the mitogen-activated protein kinase pathway was enhanced before and after treatment of Med1(epi-/-) keratinocytes with activin A in vitro. Cell-cycle analysis showed an increased ratio of S phase cells after activin A treatment of Med1(epi-/-) keratinocytes compared with wild-type keratinocytes. These findings indicate that the activin-follistatin system is involved in this acceleration of skin wound healing in 8-week-old Med1(epi-/-) mice. On the other hand, skin wound healing in 6-month-old Med1(epi-/-) mice was significantly delayed with decreased numbers of Ki67-positive cells at the wounded epidermis as well as BrdU-positive label retaining cells in hair follicles compared with age-matched wild-type mice. These results agree with our previous observation that hair follicle bulge stem cells are reduced in older Med1(epi-/-) mice, indicating a decreased contribution of hair follicle stem cells to epidermal regeneration after wounding in 6-month-old Med1(epi-/-) mice. This study sheds light on the novel function of MED1 in keratinocytes and suggests a possible new therapeutic approach for skin wound healing and aging.