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1.  Pattern of Pseudoexfoliation Deposits on the Lens and Their Clinical Correlation- Clinical Study and Review of Literature 
PLoS ONE  2014;9(12):e113329.
Purpose
To study the clinical correlates of pattern of deposits over the lens in patients with pseudoexfoliation syndrome (PXF) or pseudoexfoliation glaucoma.
Methods
This retrospective observational study screened 346 patients with PXF seen in glaucoma clinic of a tertiary hospital from 2011–2013. Details like pattern of deposits, location on the lens surface and pupillary abnormalities in slit lamp photographs and their correlation with clinical and demographic variables, were analysed.
Results
A total of 84 eyes of 42 patients with bilateral PXF were included for the study. Glaucoma was seen in 30 eyes with baseline IOP of 24+3.8 mm Hg. Comparing the type of deposits, namely classical (n = 39 eyes), radial pigmentary (RP) form (n = 39 eyes) and combined classical and radial pigmentary (CR) forms (n = 6 eyes) of deposits, pupillary ruff atrophy was common in all forms while poor dilatation was rare in the RP type (n = 5 vs n = 25 in classical forms, p<0.001). Mean deviation (MD) was worse in the classical and CR form as compared to RP type with the latter presenting much earlier, 43±3.2 years vs 48±4.1 years in CR and 56±5.7 years in classical form, p<0.001. The baseline IOP in the RP group (18±2.3 mm Hg) was significantly lower than the other two forms (CR 20±3.2 mm Hg, classical 28±2.3 mm Hg), p<0.001, with only 2 eyes on anti-glaucoma drugs at presentation.
Conclusion
Pattern of exfoliation deposits may indicate the stage and severity of the disease process in evolution with the RP representing an earlier/less severe form of pseudoexfoliation syndrome.
doi:10.1371/journal.pone.0113329
PMCID: PMC4257528  PMID: 25478872
2.  Response of BRAF mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis 
Cancer discovery  2014;4(4):423-433.
Deregulated glucose metabolism fulfils the energetic and biosynthetic requirements for tumour growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including HIF1α, c-Myc and MondoA, drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor-resistant melanoma cells. Thus, we provide a proof of principle for treatment of melanoma with combinations of BRAF inhibitors and glycolysis inhibitors.
doi:10.1158/2159-8290.CD-13-0440
PMCID: PMC4110245  PMID: 24469106
BRAF; melanoma; metabolism; vemurafenib; glycolysis
3.  Anatomical Attributes of the Optic Nerve Head in Eyes with Parafoveal Scotoma in Normal Tension Glaucoma 
PLoS ONE  2014;9(3):e90554.
Purpose
To evaluate optic nerve characteristics independent of systemic factors predisposing to parafoveal scotoma in normal tension glaucoma.
Methods
We included 40 patients with bilateral normal tension glaucoma with parafoveal scotoma (visual field defect in one hemifield within 10° of fixation with at least one point at p<1% lying at the two innermost paracentral points) in only one eye (Parafoveal group, PF, n = 40) identified from the hospital database in this observational cross sectional study. The other eye with no parafoveal scotoma constituted the control group (n = 32). Red free fundus photographs were evaluated using Image J software analyzing parameters including vertical and horizontal disc diameter, disc haemorrhage, location and angular width of the retinal nerve fibre layer depth and displacement of the central vessel trunk, CVT (vertical and horizontal). Clinical characteristics and disc parameters were compared in the two groups.
Results
The PF group had lower mean deviation(MD) and visual field index (VFI) and higher pattern standard deviation (PSD) than control group (p≤0.001) for similar untreated IOP, (p = 0.9). Disc haemorrhages were more frequent in the PF group, p = 0.01. The PF group had greater width of nerve fibre layer defects, p = 0.05 and greater vertical displacement of the central vessel trunk, p = 0.001. On multivariate logistic regression, parafoveal scotoma was significantly associated with increased vertical distance of the CVT, p = 0.0001.
Conclusion
Increased vertical displacement of the CVT is associated with parafoveal scotoma in normal tension glaucoma. Localising the vessel trunk may help clinicians in identifying patients at risk for parafoveal involvement.
doi:10.1371/journal.pone.0090554
PMCID: PMC3940960  PMID: 24595065
4.  Comparison of relation between visual function index and retinal nerve fiber layer structure by optical coherence tomography among primary open angle glaucoma and primary angle closure glaucoma eyes 
Purpose:
To compare the visual field index (VFI) in primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) eyes, and to study the correlation with disc variables on optical coherence tomography (OCT) in all stages of severity.
Materials and Methods:
Thirty POAG and PACG underwent Humphrey visual field 24-2 along with detailed examination. They also underwent stratus OCT imaging of the optic nerve and retinal nerve fiber layer (RNFL). The correlation of VFI with RNFL thickness was compared in POAG and PACG.
Results:
The VFI significantly differed between POAG and PACG, with POAG eyes apparently having a better VFI at all severities of glaucoma. There were statistically significant differences in the superior max (Smax) and inferior max (Imax) in early and moderate POAG and PACG eyes. In early and moderate glaucoma, multivariate regression showed that maximum correlation of the VFI was seen with the mean deviation (b = 1.7, P < 0.001), average and superior RNFL thickness (b = 2.1, P < 0.001 and b = 1.8, P = 0.03, respectively), and age (b = 0.7, P = 0.04); while no correlation was seen with intraocular pressure (IOP), axial length, sex, or other clinical variables. VFI did not correlate well with RNFL thickness or other disc variables on OCT in severe glaucoma.
Conclusion:
VFI may not serve as a useful indicator of visual function in severe glaucoma. More useful indicators are required to monitor glaucoma patients with severe damage.
doi:10.4103/0974-620X.127911
PMCID: PMC4008907  PMID: 24799794
Primary angle closure glaucoma; primary open angle glaucoma; retinal nerve fiber layer thickness; visual field index
5.  Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells1 
Cancer Research  2012;72(13):3196-3206.
Ineffective recognition of tumor cells by CD8+ T cells is a limitation of cancer immunotherapy. Therefore, treatment regimens that coordinately promote enhanced anti-tumor CD8+ T cell activation, delivery, and target cell recognition should yield greater clinical benefit. Using an MCA205 sarcoma model, we show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the HSP90 client protein EphA2 and the subsequent increased recognition of tumor cells by Type-1 anti-EphA2 CD8+ T cells. In vivo administration of 17-DMAG to tumor-bearing mice led to slowed tumor growth, enhanced/prolonged recognition of tumor cells by anti-EphA2 CD8+ T cells, reduced levels of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) in the tumor microenvironment (TME), and activation of tumor-associated vascular endothelial cells in association with elevated levels of Type-1 tumor infiltrating lymphocytes (TIL). When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG co-treatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease. Taken together, our findings indicate that 17-DMAG functions as an immune adjuvant in the context of vaccines targeting EphA2.
doi:10.1158/0008-5472.CAN-12-0538
PMCID: PMC3389149  PMID: 22552283
HSP90; EphA2; CD8+ T cells; Tumor; Immunotherapy
6.  Combined vaccine + axitinib therapy yields superior anti-tumor efficacy in a murine melanoma model 
Melanoma Research  2012;22(3):236-243.
Axitinib, a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors has demonstrated modest efficacy when applied as a single agent in the setting of advanced-stage melanoma. Based on the reported ability of axitinib to “normalize” the tumor vasculature, we hypothesize that combination therapy employing axitinib plus specific peptide-based vaccination would promote superior activation and recruitment of protective T cells into the melanoma microenvironment, leading to enhanced treatment benefit. Using a s.c. M05 (B16.OVA) melanoma model, we observed that a treatment regimen consisting of a 7 day course of axitinib (0.5 mg/day provided orally) combined with a s.c. vaccine (OVA peptide-pulsed syngenic dendritic cells (DC) adenovirally-engineered to produce IL-12p70) yielded superior protection against melanoma growth and extended overall survival when compared to animals receiving either single modality therapy. Treatment benefits were associated with: i.) a reduction in suppressor cell (myeloid-derived suppressor cells (MDSC) and Treg) populations in the tumor, ii.) activation of tumor vascular endothelial cells, and iii.) activation and recruitment of Type-1, vaccine-induced CD8+ T cells into tumors. These results support the therapeutic superiority of combined vaccine + axitinib immunotherapy and the translation of such approaches into the clinic for the treatment of patients with advanced-stage melanoma.
doi:10.1097/CMR.0b013e3283538293
PMCID: PMC3340498  PMID: 22504156
axitinib; vaccine; dendritic cell; melanoma; myeloid derived suppressor cells; Treg
7.  Shock block for improved immunotherapy 
Oncoimmunology  2012;1(8):1427-1429.
Cancer cells use heat shock proteins (HSP) to stabilize growth/survival-associated client proteins such as receptor tyrosine kinases (RTKs), in vivo. Our recent work suggests that chemical HSP90 inhibitors combined with a vaccination strategy targeting HSP90 client proteins that are (over)expressed in the tumor microenvironment yields superior therapeutic benefit.
doi:10.4161/onci.21174
PMCID: PMC3518526  PMID: 23243617
adoptive immunotherapy; antigen presentation; heat shock protein; tumor microenvironment; vaccine
8.  Clinical and Optical Coherence Tomography Features in Unilateral versus Bilateral Pseudoexfoliation Syndrome 
Purpose
To compare clinical findings and peripapillary retinal nerve fiber layer (RNFL) thickness using optical coherence tomography (OCT) in affected and fellow eyes of patients with unilateral pseudoexfoliation (PXF) syndrome with that of bilateral cases.
Methods
This cross-sectional study enrolled 91 subjects with PXF including 32 unilateral and 59 bilateral cases. Subjects with elevated intraocular pressure or findings suggestive of glaucoma were excluded. RNFL thickness and optic nerve head profile were studied in all eyes using the RNFL and optic nerve head analysis OCT protocol. Clinical and OCT features were compared in affected and unaffected eyes of unilateral PXF subjects to bilateral cases.
Results
Bilateral cases with PXF were older (P<0.01) and had thinner RNFL (P=0.04) than unilateral cases. From a total of 32 unilateral PXF cases, 7 subjects demonstrated RNFL thinning in the clinically normal fellow eye; all of these eyes had evidence of pupillary ruff atrophy on slit lamp examination in the absence of evident exfoliation material in the eye. Similar ruff atrophy with RNFL thinning was seen in 38 of 59 bilateral and in 16 of 32 unilateral cases. Pupillary ruff atrophy predicted RNFL thinning with sensitivity of 88.9% (95% CI, 73-96.7%) and 79.2% (95% CI, 74-84.5%) in bilateral and unilateral cases respectively, with low specificity of 45.8% (95% CI, 33.9-51.7%) and 45.5% (95% CI, 22.9-68.8%) in the same order.
Conclusion
Patients with bilateral PXF have significantly thinner RNFL as compared to unilateral cases. Iris sphincter abnormality, clinically detected as pupillary ruff atrophy, may reflect early glaucomatous damage; however the specificity of this sign for predicting RNFL thinning is low.
PMCID: PMC3520587  PMID: 23264861
Pseudoexfoliation Syndrome; Exfoliative Glaucoma; Optical Coherence Tomography
9.  Atypical features of nanophthalmic macula- a spectral domain OCT study 
BMC Ophthalmology  2012;12:12.
Background
To report atypical features on Spectral domain optical coherence tomography (SD-OCT) in a case of non-familial pure adult nanophthalmos.
Case presentation
A 39 year old male hyperope was found to have biometric and fundus findings typical of nanophthalmos. The additional atypical features included serous pigment epithelial detachment (PED) in right eye and a cuff of subretinal fluid with underlying yellow deposits along superotemporal arcade in the left eye. Fundus flourescein angiogram showed hyperfluorescence due to window defect, dye pooling due to serous PED in right eye and leak superior to disc in right eye and superotemporally in left eye. Cirrus-SD OCT horizontal line scan passing through the fovea showed extensive inner limiting membrane corrugations causing distorted foveal contour in both eyes. A large juxtafoveal serous PED and a small extrafoval PED were seen with folds in the retinal pigment epithelium (RPE)-choriocapillary layer in the right eye.
Conclusion
Structural disruptions in the RPE-choriocapillary complex in the form of folds or juxtafoveal serous PED and RPE folds can be atypical features of nanophthalmic macula better discerned on high resolution OCT.
doi:10.1186/1471-2415-12-12
PMCID: PMC3441246  PMID: 22672150
Nanophthalmos
10.  Isolated Bilateral Congenital Iris Sphincter Agenesis 
Purpose. We herein report a patient with bilateral congenital total iris sphincter agenesis with no other abnormality detected on systemic examination. Methods. A 24-year-old laborer presented to us for a routine checkup with complaint of photophobia and inability to work under sunlight. Examination revealed bilateral absence of sphincter and 6.5 mm pupil in both eyes in the undilated state. Results. Accommodation was poor in both eyes. Systemic examination was within normal limits. He was prescribed bifocal photochromic glasses for constant wear. Conclusions. Congenital sphincter agenesis can occur in an isolated form without systemic abnormalities which can be managed conservatively.
doi:10.1155/2011/479092
PMCID: PMC3350239  PMID: 22606462
11.  Anomalous vessels over a trabeculectomy bleb in Sturge-Weber syndrome 
Summary
Trabeculectomy for treatment of glaucoma associated with Sturge-Weber syndrome has a poor success rate. We report the presence of anomalous vessels over the trabeculectomy bleb in a patient with Sturge-Weber syndrome after trabeculectomy combined with mitomycin.
doi:10.5693/djo.02.2010.12.001
PMCID: PMC3516157  PMID: 23362384
12.  Proteomic Identification of OprL as a Seromarker for Initial Diagnosis of Pseudomonas aeruginosa Infection of Patients with Cystic Fibrosis▿  
Journal of Clinical Microbiology  2009;47(8):2483-2488.
Identification of new immunogenic antigens that diagnose initial Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) alone or as an adjunct to microbiology is needed. In the present study, a proteomic analysis was performed to obtain a global assessment of the host immune response during the initial P. aeruginosa infection of patients with CF. Matrix-assisted laser desorption ionization-time of flight mass spectrometry was used to identify outer membrane protein L (OprL), a non-type III secretion system (TTSS) protein, as an early immunogenic protein during the initial P. aeruginosa infection of patients with CF. Longitudinal Western blot analysis of sera from 12 of 14 patients with CF detected antibodies to OprL during the initial P. aeruginosa infection. In addition, also detected were antibodies to ExoS, ExoU, or ExoS and ExoU, the latter indicating sequential P. aeruginosa infections during initial infections. Detection of serum reactivity to OprL, along with proteins of the TTSS, and in conjunction with microbiology may diagnose initial P. aeruginosa infections in patients with CF.
doi:10.1128/JCM.02182-08
PMCID: PMC2725635  PMID: 19553571
13.  Amniotic membrane transplant with superficial keratectomy in superficial corneal degenerations: Efficacy in a rural population of north India 
Indian Journal of Ophthalmology  2008;56(4):297-302.
Aim:
To evaluate the applicability and efficacy of superficial keratectomy with transplantation of preserved amniotic membrane in superficial corneal degenerations in a rural population of Northern India in terms of visual improvement and surface regularization.
Settings:
Peripheral referral center in rural north India.
Materials and Methods:
This was a prospective non-comparative interventional case series where 24 eyes of 20 farmers from peripheral rural areas (M:F = 19:1) with visually significant superficial degenerative disorders (15 eyes with climatic droplet keratopathy one of which was associated with Salzmann nodular degeneration and nine eyes with band-shaped keratopathy) were subjected to amniotic membrane transplantation (single or multiple layer) combined with superficial keratectomy. Subjective and objective outcomes after surgery were evaluated and analyzed and statistical significance of the outcomes in various disorders was evaluated.
Results:
Eighty-eight per cent (21 eyes) had symptomatic relief from distressing preoperative symptoms while postoperative visual improvement by two or more lines was achieved in 23 eyes (96%) over a mean follow-up period of 26.8 ± 10.2 months. The surface irregularity present preoperatively was relieved in 23 cases while postoperative decline of vision with visually significant scarring was seen in one case (4%), which was labeled as failure.
Conclusions:
Amniotic membrane transplant with superficial keratectomy helped achieve subjective comfort, visual rehabilitation and clinical regularization of the corneal surface in superficial corneal degenerations during the mean followup of 26.8 ± 10.2 months in rural setups.
PMCID: PMC2636175  PMID: 18579988
Amniotic membrane; phototherapeutic keratectomy; superficial corneal degeneration
14.  Sudoriferous cyst of the orbit of adult origin after trauma 
Indian Journal of Ophthalmology  2008;56(3):235-237.
A rare case of sudoriferous cyst of the orbit occurring in an adult, who had facial trauma, is reported. Several factors suggest its adult onset. The only other case reported in an adult is of presumed childhood origin. Very few congenital cases have been reported. A 65-year-old lady presented with recent onset of left-sided ptosis and a painless mass below the left supraorbital margin. The patient had traumatic ptosis after a road traffic accident 13 years ago. The ptosis was surgically repaired, which resulted in symmetrical palpebral apertures. Computed tomographic scan revealed a well-defined cystic mass in the anterior orbit. The mass was removed in toto by anterior orbitotomy. Histopathological examination revealed a single cyst lined by double-layered cuboidal epithelium in some areas and transitional epithelium at others. A periodic acid Schiff (PAS) positive, diastase-resistant glycocalyx lined the inner epithelium. Apical snouting suggested an apocrine nature. This confirmed a diagnosis of sudoriferous cyst.
PMCID: PMC2636125  PMID: 18417827
Apocrine; periodic acid Schiff diastase stain; sudoriferous cyst orbit
15.  Cystic fibrosis and renal disease: a case report 
Background
Cystic fibrosis (CF) is an autosomal recessive disease that is predominantly seen in the Caucasian population and involves multiple organs. Traditionally it has been thought that the kidney is the only organ which does not seem to be generally affected by the disease although the cystic fibrosis transmembrane conductance regulator (CFTR) gene is expressed in the kidney.
Case presentation
We report the case of an 11 year old boy with cystic fibrosis and nephrotic syndrome and review the literature that describes nephrotic syndrome and renal involvement in cystic fibrosis.
Conclusion
With continued advances in the management of cystic fibrosis and improvement in life expectancy, several unrecognized co-morbidities are expected to emerge. It is important to screen patients for possible co-morbidities. Urine analysis may be helpful in this group of patients and any proteinuria should raise the suspicion of cystic fibrosis-related renal disease.
doi:10.1186/1752-1947-1-24
PMCID: PMC1896172  PMID: 17547751

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