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Anil K Mandal

Publications and source records attributed to Anil K Mandal.

At least 19 recordsLinked to original sources
PubMed2026

TNFα-dependent modulation of WT1-MMP9 regulatory axis links developmental and inflammatory pathways in glaucoma.

Glaucomas are heterogeneous optic neuropathies associated with extracellular matrix dysregulation, abnormal ocular morphogenesis, and inflammatory signaling. Targeted deep sequencing of 586 primary congenital glaucoma (PCG) cases and 1,757 controls identified rare pathogenic variants in multiple genes, including WT1 and MMP9. Notably, WT1 variants clustered within the nuclear export sequence. Further, functional analyses showed that combined wt1-pax6 suppression in zebrafish disrupted ocular morphogenesis, highlighting developmental interdependence. In human trabecular meshwork cells, WT1 acted as a transcriptional repressor of MMP9, while TNF-α signaling triggered nitric oxide-dependent nuclear export of WT1, resulting in delayed MMP9 upregulation. This effect was reversible by inhibiting nuclear export or nitric oxide synthase. A patient-derived mutation in the nuclear-export region of WT1, disrupted this regulatory switch, causing abnormal MMP9 expression. These findings position WT1 as an important regulator linking developmental and inflammatory mechanisms in glaucoma pathogenesis.

anterior segment dysgenesis↗
PubMed2006

Disease-causing mutations in proteins: structural analysis of the CYP1B1 mutations causing primary congenital glaucoma in humans.

In this communication, we report an in-depth structure-based analysis of the human CYP1b1 protein carrying disease-causing mutations that are discovered in patients suffering from primary congenital glaucoma (PCG). The "wild-type" and the PCG mutant structures of the human CYP1b1 protein obtained from comparative modeling were subjected to long molecular dynamics simulations with an intention of studying the possible impact of these mutations on the protein structure and hence its function. Analysis of time evolution as well as time averaged values of various structural properties--especially of those of the functionally important regions: the heme binding region, substrate binding region, and substrate access channel--gave some insights into the possible structural characteristics of the disease mutant and the wild-type forms of the protein. In a nutshell, compared to the wild-type the core regions in the mutant structures are associated with subtle but significant changes, and the functionally important regions seem to adopt such structures that are not conducive for the wild-type-like functionality.

Amino Acid Sequence↗
PubMed2006

Globally, CYP1B1 mutations in primary congenital glaucoma are strongly structured by geographic and haplotype backgrounds.

PURPOSE: To obtain a global perspective on the distribution and evolution of CYP1B1 mutations in primary congenital glaucoma (PCG) worldwide. METHODS: Five intragenic single-nucleotide polymorphisms in CYP1B1-R48G, A119S, V432L, D449D, and N453S-were used to generate haplotype data from 138 Indian patients with PCG and 132 ethnically matched normal controls, which were then analyzed in conjunction with data from other populations. Maximum-likelihood estimates of haplotype frequencies were estimated from the genotype data. Subsets of patients and normal control subjects were also genotyped with respect to eight short tandem repeat (STR) markers around the CYP1B1 locus (D2S305, D2S165, D2S367, D2S2259, D2S391, D2S3337, D2S23678, and D2S286), to gain evolutionary insights. RESULTS: Common mutations in CYP1B1 that are causal of PCG occurred on a uniform haplotype background among Indian patients, which is completely distinct from the modal haplotype background found among unaffected control subjects. Comparison of these data with data from other global regions reveals strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds. The two distinct modal haplotypes found among Indian patients with PCG and control subjects are both ancient with ages of similar magnitudes, as indicated by large variances in the number of repeats at eight STR loci. Together with data from chimpanzee and normal control subjects from India and other global regions, it was possible to make a parsimonious reconstruction of the evolution of these haplotypes. CONCLUSIONS: The strong association of specific haplotypes with some predominant CYP1B1 mutations underlying PCG and the observed geographical clustering, probably due to founder effects, may be useful for predictive testing.

Africa↗
PubMed2005

Endothelial cell injury by high glucose and heparanase is prevented by insulin, heparin and basic fibroblast growth factor.

BACKGROUND: Uncontrolled hyperglycemia is the main risk factor in the development of diabetic vascular complications. The endothelial cells are the first cells targeted by hyperglycemia. The mechanism of endothelial injury by high glucose is still poorly understood. Heparanase production, induced by hyperglycemia, and subsequent degradation of heparan sulfate may contribute to endothelial injury. Little is known about endothelial injury by heparanase and possible means of preventing this injury. OBJECTIVES: To determine if high glucose as well as heparanase cause endothelial cell injury and if insulin, heparin and bFGF protect cells from this injury. METHODS: Cultured porcine aortic endothelial cells were treated with high glucose (30 mM) and/or insulin (1 U/ml) and/or heparin (0.5 microg/ml) and /or basic fibroblast growth factor (bFGF) (1 ng/ml) for seven days. Cells were also treated with heparinase I (0.3 U/ml, the in vitro surrogate heparanase), plus insulin, heparin and bFGF for two days in serum free medium. Endothelial cell injury was evaluated by determining the number of live cells per culture and lactate dehydrogenase (LDH) release into medium expressed as percentage of control. RESULTS: A significant decrease in live cell number and increase in LDH release was found in endothelial cells treated with high glucose or heparinase I. Insulin and/or heparin and/or bFGF prevented these changes and thus protected cells from injury by high glucose or heparinase I. The protective ability of heparin and bFGF alone or in combination was more evident in cells damaged with heparinase I than high glucose. CONCLUSION: Endothelial cells injured by high glucose or heparinase I are protected by a combination of insulin, heparin and bFGF, although protection by heparin and/or bFGF was variable.

Animals↗
PubMed2005

Gln48His is the prevalent myocilin mutation in primary open angle and primary congenital glaucoma phenotypes in India.

PURPOSE: Myocilin gene defects have been originally implicated in primary open angle glaucoma (POAG). Based on multiple reports for the occurrence of Gln48His mutation (c.144G>T; HGMD accession number CM023962) among Indian POAG patients, we wanted to estimate the prevalence of this mutation in primary open angle and primary congenital glaucoma (PCG) in India and assess its role in the causation of the disease. METHODS: Two hundred cases each of POAG and PCG were screened for the Gln48His mutation by RFLP (AccI) analysis of the PCR amplicons followed by confirmation of the c.144G>T change by direct sequencing. RESULTS: The Gln48His mutation was detected in 9 different glaucoma patients (four POAG and five PCG). While all four POAG cases were heterozygous, among PCG cases, four were heterozygous and one exhibited homozygous genotype for the mutation. One each of POAG and PCG patients was detected to be heterozygous for CYP1B1 mutation (c.1656C>T, Pro437Leu) and (c.1449G>A, Arg368His), respectively. None of the 300 ethnically matched normal controls contained either the MYOC or CYP1B1 mutation(s). CONCLUSIONS: The myocilin mutation, Gln48His, represents an allelic condition involving a spectrum of glaucoma phenotypes in Indian populations, and could be a potential risk factor towards disease predisposition among patients of Indian origin. The study also highlights the role of MYOC as a candidate in different glaucoma subtypes that needs to be investigated further.

Adult↗
PubMed2005

Medical therapy of pediatric glaucoma and glaucoma in pregnancy.

Although surgery remains the definitive treatment for congenital and other childhood glaucomas, medical therapy can be effective in lowering intraocular pressure as a temporizing measure before surgery or as long-term adjunctive treatment in disease refractory to surgical measures. Carbonic anhydrase inhibitors, beta-blockers, cholinergic drugs, and the prostaglandin-related drugs all play an effective role in pediatric glaucoma management. The usefulness and safety profile of the adrenergic agonists and the osmotic agents are less well established. In medically treating the pediatric patient or the pregnant woman for glaucoma, the clinician must be mindful of the possibility of adverse effects and be prepared to alter or terminate treatment if needed.

Adolescent↗
PubMed2005

Glaucoma drainage implants in pediatric patients.

Approximately, one fifth of primary congenital glaucoma patients fail primary surgery. Also, some pediatric glaucomas respond poorly to goniotomy or trabeculectomy. In these situations, clinicians often choose trabeculectomy with mitomycin-C or a drainage implant as a surgical treatment. Glaucoma drainage device implantation is a useful option in refractory patients. When other surgical treatments have a poor prognosis for success, prior conventional surgery fails, or significant conjunctival scarring precludes filtration surgery, glaucoma drainage implant may effectively control intraocular pressure. Patients often require adjunctive glaucoma medications after surgery and may develop complications. Most of these complications, however, are reversible or resolve spontaneously, and most are not associated with vision loss.

Adolescent↗
PubMed2004

Long-term surgical and visual outcomes in Indian children with developmental glaucoma operated on within 6 months of birth.

PURPOSE: To determine the long-term surgical and visual outcomes in Indian children with developmental glaucoma operated within 6 months of birth. DESIGN: Retrospective consecutive, noncomparative case series. PARTICIPANTS: All children with developmental glaucoma who underwent surgery within 6 months of birth over a 12-year period were included. METHODS: Two hundred ninety-nine eyes of 157 consecutive patients who underwent primary combined trabeculotomy-trabeculectomy for developmental glaucoma from January 1990 through December 2001 by a single surgeon were studied. However, for the purpose of statistical analysis, only 1 randomly chosen eye of patients with a bilateral affliction (142, 90.4%) was considered. MAIN OUTCOME MEASURES: The main outcome measures were preoperative and postoperative intraocular pressures (IOPs), corneal clarity and diameters, visual acuities, refractive errors, success rate, time of surgical failure, and complications. RESULTS: The series consisted of 299 primary combined trabeculotomy-trabeculectomy surgeries during 157 anesthesias. The intraocular pressure was reduced from 26.6+/-6.2 mmHg to 14.4+/-4.9 mmHg, with a mean percentage reduction of 41.1+/-28.8 (P<0.0001). The probability of success (IOP<21 mmHg) was 94.4%, 92.1%, 86.7%, 79.4%, 72.9%, and 63.1% at first, second, third, fourth, fifth, and sixth year, respectively (Kaplan-Meier analysis). The mean follow-up period was 26.5+/-25.1 months. Preoperatively, 133 eyes (84.7%) had significant corneal edema. Postoperatively, normal corneal clarity was achieved in 83 of 133 eyes (62.4%) with corneal edema. There were no major intraoperative complications. Postoperatively, 17 eyes (10.8%) had a shallow anterior chamber develop; 3 of these eyes (17.6%) required surgical reformation. There was no incidence of endophthalmitis or any other sight-threatening complication. Data on visual acuity were available in 49 patients (31.2%). At the final follow-up visit, 20 patients (40.8%) had normal visual acuity (best-corrected visual acuity of >/=20/60 in the better eye). CONCLUSIONS: Primary combined trabeculotomy-trabeculectomy is safe and effective for developmental glaucoma when performed within 6 months of birth. It leads to excellent IOP control and moderate visual outcome.

Cornea↗
PubMed2004

Correlations of genotype with phenotype in Indian patients with primary congenital glaucoma.

PURPOSE: To establish the genotype-phenotype correlations of various CYP1B1 (human cytochrome P450) mutations in patients in India with primary congenital glaucoma (PCG). METHODS: The study cohort comprised 146 patients with PCG from 138 pedigrees. Patients were analyzed for six distinct CYP1B1 mutations by sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. A severity index for grading various PCG phenotypes was constructed based on clinical parameters. RESULTS: Six mutations were identified in 45 patients analyzed and genotype-phenotype correlations were established for 43 of them. The percentages of severe phenotypes associated with various mutations in at least one eye were: frameshift, 100%; G61E, 66.7%; P193L, 62.5%; E229K, 80%; R368H, 72%; R390C, 83.3%. The frameshift mutation resulted in blindness. Based on the severity index, the disease severity was graded from normal to severe and the prognosis from good to very poor (blind). De novo mutation was identified in one family. CONCLUSIONS: This is the first study to attempt to devise a severity index for grading various PCG phenotypes and to use genotype as an indicator to predict the prognoses of the disorder. This index may help guide therapy and counseling of the afflicted family regarding the progression of the disorder. All patients with severe phenotypes showed poor prognoses (r = 0.976; P < 0.0001). The data derived from this study could be used as an added clinical tool in disease management. Integrated management of PCG that makes use of a genetic approach could yield better results than medical, surgical, and rehabilitation interventions alone.

Adult↗
PubMed2004

Glaucoma in aphakia and pseudophakia after congenital cataract surgery.

Glaucoma is one of the most common causes of visual loss despite successful congenital cataract surgery. The overall incidence does not appear to have decreased with modern microsurgical techniques. The onset of glaucoma may be acute or insidious and notoriously refractory to treatment. Angle closure glaucoma may occur in the early postoperative period; but the most common type of glaucoma to develop after congenital cataract surgery is open angle glaucoma. Several risk factors have been identified and both chemical and mechanical theories have been proposed for its pathogenesis. Unlike children with congenital glaucoma, those with paediatric glaucoma following congenital cataract surgery are usually asymptomatic despite high intraocular pressure. They may require regular evaluation under anaesthesia, whenever there are any suspicious findings. Unlike congenital glaucoma, the first line of treatment for glaucoma in aphakia/pseudophakia may be medical. Traditional trabeculectomy in paediatric glaucoma following congenital cataract surgery has met with limited success. The addition of antimetabolites to trabeculectomy is known to inhibit fibrosis and enhance the success, but carries the lifelong risk of bleb-related endophthalmitis. Drainage implant surgery is a viable option to achieve longterm intraocular pressure control in this refractory group of patients. Cycloablative procedures may provide temporising treatment and should be reserved for patients with low visual potential. Diagnosis of glaucoma following congenital cataract surgery requires lifelong surveillance and continuous assessment of the problem. Further research is needed to understand the pathophysiology, prevention and treatment of this sight-threatening complication following successful cataract surgery in children.

Aphakia, Postcataract↗
PubMed2004

Lattice corneal dystrophy type III with corneal fistula. A case report.

Lattice corneal dystrophy is a distinct clinical entity characterised by amyloid deposits in the corneal stroma. We report a patient who presented with a corneal fistula in the right eye and thick lattice lines involving the peripheral cornea in both eyes suggestive of type III lattice dystrophy. The association of corneal fistula with lattice corneal dystrophy type III makes this a unique case.

Amyloidosis↗
PubMed2003

Outcome of surgery on infants younger than 1 month with congenital glaucoma.

PURPOSE: To determine the visual outcomes and surgical and anesthetic complication rates of patients with newborn glaucoma operated within 1 month of age. DESIGN: Retrospective, consecutive, noncomparative case series. PARTICIPANTS: All children with newborn glaucoma who underwent surgery between January 1990 and December 2000 were included. METHODS: The medical records of 25 consecutive patients (47 eyes) who underwent primary combined trabeculotomy and trabeculectomy either bilaterally in a single session or unilaterally were reviewed retrospectively. Outcomes were evaluated using Kaplan-Meier survival analysis. MAIN OUTCOME MEASURES: Clinical outcome assessment included corneal clarity, intraocular pressure (IOP), bleb characteristics, visual acuity, refractive errors, and identification of surgical and anesthetic complications. RESULTS: The mean follow-up was 3.1+/-1.8 years (range, 9.5 months-7.4 years). The mean preoperative IOP was 26.9+/-5.2 mmHg (range, 14-42 mmHg). At the final follow-up visit, the mean IOP was 14.5+/-3.8 mmHg (range, 8-28 mmHg). The percentage reduction in IOP was 43.3+/-21.5 (P<0.0001). Twelve-, 24-, and 36-month survival rates for complete success for IOP control were 89.4%, 83.6%, and 71.7%, respectively, which were maintained for 7 years of follow-up. After surgery, complete clearance of corneal edema was achieved in 66% of the eyes. Data on visual acuity was available for 19 patients. Final best spectacle-corrected visual acuity was 20/40 or better in the better eye in 5 patients (26.3%), 7 patients (36.8%) obtained 20/60 or better in the better eye, 8 patients (42.1%) achieved final visual acuity of less than 20/60 to 20/200 in the better eye (low vision), and four patients obtained less than 20/400 visual acuity in the better eye (blind) according to World Health Organization criteria. However, there was no eye with absent perception of light in the better eye. Myopia (mean spherical equivalent, 4.6+/-3.2 diopters) was the most common refractive error, present in approximately half of the eyes (n = 23; 53.8%). There were no significant intraoperative or postoperative complications in any patient. Anesthesia-related complications developed in 2 patients; however, they were resuscitated successfully. CONCLUSIONS: Primary combined trabeculotomy-trabeculectomy offers a viable surgical option in infants that have cloudy corneas at birth as a result of congenital glaucoma. It is associated with a favorable visual outcome and a low rate of anesthetic complications in an Indian population.

Cornea↗
PubMed2003

Identification of R368H as a predominant CYP1B1 allele causing primary congenital glaucoma in Indian patients.

PURPOSE: To investigate the predominant mutation in the CYP1B1 gene in patients in India with primary congenital glaucoma (PCG), using PCR-restriction fragment length polymorphism (RFLP) methods and to characterize the molecular defect in two generations of an affected family. METHODS: DNA samples from 146 patients with PCG from 138 pedigrees were analyzed for several distinct mutations in CYP1B1 by PCR-RFLP. RESULTS: PCR-RFLP screening revealed that 30.8% of patients were positive for any one of the six mutations (376insA, 528G-->A, 923C-->T, 959G-->A, 1449G-->A, and 1514C-->A), and 17.8% of the patients were found to have the rarely reported mutation R368H (1449G-->A). All mutations were confirmed by DNA sequencing. CONCLUSIONS: The results suggest extensive allelic heterogeneity in the Indian patients with PCG, with the predominant allele being R368H among the 146 Indian patients tested. It appears possible to use this approach for carrier detection in pedigrees with a positive family history and in population screening. The approach also offers a method for rapid screening of potential carriers and affected individuals.

Alleles↗
PubMed2003

Traumatic pseudophacocele.

Post-traumatic subconjunctival dislocation of an intraocular lens (pseudophacocele) is a rare but serious complication following cataract surgery. All the previously reported cases were managed by removal of the IOL rendering the eye aphakic. We report a case of traumatic pseudophacocele which was successfully managed by an IOL exchange.

Device Removal↗
PubMed2002

Enzymatic sclerostomy: pilot human study.

OBJECTIVE: To evaluate the feasibility and safety of enzymatic sclerostomy as a new modality to lower intraocular pressure in patients with open-angle glaucoma. METHODS: This single-center, prospective, noncomparative, interventional case series included 15 blind symptomatic eyes of 15 patients with primary open-angle glaucoma. Enzymatic sclerostomy was performed with the patient under topical or peribulbar anesthesia. A specially designed polymethylmethacrylate enzyme applicator filled with a mean +/- SD of 123 +/- 13 microg of collagenase was introduced through a 5-mm peritomy, and affixed to the limbus by means of cyanoacrylate tissue glue. After 22 to 24 hours, the applicators were removed and the patients were followed up for 1 year. Intraocular pressure changes from baseline and complications related to the procedure were the main outcome measures. RESULTS: Controlled thinning of the treated sclera associated with aqueous percolation and shallow filtration bleb was seen in all eyes in the immediate postoperative period. The mean +/- SD intraocular pressure decreased from 43.5 +/- 9.8 mm Hg (while the patients were receiving a mean +/- SD of 1.75 +/- 0.75 antiglaucoma medications) preoperatively to 24.8 +/- 10.6 mm Hg (a 43.0% decrease from baseline with no antiglaucoma medication) on the first postoperative day and to 34.8 +/- 10.5 mm Hg (a 20.0% decrease from baseline with no antiglaucoma medication) at the end of 1 year. Ophthalmic adverse effects were limited to the treated area and included immediate postoperative transient conjunctival reaction ranging from mild chemosis to conjunctival maceration. Immediate full-thickness perforation developed in 1 eye; the patient was treated and excluded from data analysis. Two eyes developed symptoms related to increase in intraocular pressure after 9 months; the patients were treated and excluded from further data analysis. No systemic complications were noted. CONCLUSIONS: Enzymatic sclerostomy demonstrated immediate and sustained intraocular pressure reduction and provided symptomatic relief in blind eyes with primary open-angle glaucoma. The procedure, however, needs further technical refinement.

Aged↗
PubMed2002

Subepithelial corneal amyloid deposits in a case of congenital glaucoma: a case report.

PURPOSE: To report a rare association of subepithelial amyloid deposits in a long-standing case of congenital glaucoma. METHODS: A 5-year-old girl was brought to the emergency service with complaints of bleeding from the left eye after injury to the eye with the door handle. Parents gave history of enlarged black portion of the eye since birth with increasing white opacity from the age of 6 months. On examination under general anesthesia, the left eye showed a limbal tear extending from 7 to 3.30 o'clock position and uveal prolapse. The right eye showed corneal edema, megalocornea, central white raised plaque, and high intraocular pressure. A diagnosis of bilateral congenital glaucoma with open globe injury, left eye, corneal scarring with degeneration, right eye was made and was advised enucleation. The enucleated eye was submitted for routine histologic examination. At a 3-year follow-up, there was an increase in the corneal scarring, with no significant improvement in vision. The child refused keratoplasty and was referred to low vision centre for visual rehabilitation. RESULTS: The enucleated eye was distorted and filled with blood. The cornea showed confluent pink homogenous wavy deposits in the subepithelial region. These deposits appeared brick red with Congo Red stain and showed apple green birefringence when viewed under polarized filters, confirming the amyloid nature of the deposits. There was loss of ganglion cell layer in the detached retina. CONCLUSION: The subepithelial amyloid deposits, presumably bilateral, in advanced case of congenital glaucoma were possibly secondary to the long-standing edema, scarring and vascularization. These secondary changes should be kept in mind as they could contribute to further deterioration in vision in advanced cases.

Amyloidosis↗