Purpose: To compare the safety and efficacy of two different techniques for implantation of the X... more Purpose: To compare the safety and efficacy of two different techniques for implantation of the XEN Gel Stent, a minimally invasive surgical device for the treatment of refractory glaucoma. Methods: A retrospective chart review of eyes that received ab interno or ab externo XEN Gel Stent placement from February 2017 to October 2019 was conducted. A single surgeon (NMR) performed all operations. Eyes that received the XEN implant concomitant with a glaucoma drainage device insertion or that were lost to 6-month follow-up were excluded. Intraocular pressure (IOP) change, change in glaucoma medications, frequency of slit lamp revision procedures, and frequency of secondary glaucoma surgeries were the primary outcomes compared between groups. Results: Fifty eyes that underwent ab interno placement and 30 eyes that underwent ab externo placement were studied. The ab interno cohort demonstrated a mean IOP reduction of 8.4 ± 1.7 mmHg (28.6% decrease) by 12 months, compared to a mean reduction of 12.8 ± 3.0 mmHg (40.1% decrease) in the ab externo group (p = 0.208). Mean reduction in medication use was 1.81 ± 0.29 medications in the ab interno group and 1.86 ± 0.37 in the ab externo group (p = 0.913). By 12 months, 58% of ab interno eyes had required 5-fluorouracil injection compared to 36.7% of ab externos (p = 0.105). Bleb needling was applied to 42% and 26.7% of the eyes, respectively (p = 0.231). A second glaucoma surgery was necessary for 20% of the ab interno cohort and 10% of the ab externo cohort (p = 0.351). Conclusion: There were no differences in outcomes between ab interno and ab externo placement of the XEN Gel Stent. Both approaches are safe and effective for lowering IOP.
Sclerochoroidal calcifications are an important entity to recognize on ophthalmoscopy. Although u... more Sclerochoroidal calcifications are an important entity to recognize on ophthalmoscopy. Although uncommon, idiopathic, and primarily benign, they are commonly misdiagnosed as malignant tumors. Here, we present a case of an individual with sclerochoroidal calcifications with associated imaging findings in the setting of elevated serum parathyroid hormone levels. We also review background information, pathology, pathogenesis, differential diagnoses, diagnostic approach, management, and prognosis. It is crucial that patients with this finding have subsequent clinical imaging and laboratory workup to exclude other serious ocular and systemic diseases.
Purpose This review will provide an update on surgical techniques, outcomes, and complications fo... more Purpose This review will provide an update on surgical techniques, outcomes, and complications for two new translimbal bleb-forming surgical glaucoma devices. Recent findings The XEN Gel Microstent and PreserFlo MicroShunt comprise a category of subconjunctival microinvasive glaucoma surgery developed with the aim of improving the predictability and safety profile of bleb-forming procedures. Both devices are made of noninflammatory material which limits postsurgical inflammation and scarring and have a valve-less intrinsic flow-limiting design, which decreases the risk of hypotony. There are various techniques of implantation for the XEN Gel Microstent each with their own advantages and disadvantages. Summary These devices have demonstrated promising outcomes in early experimental literature with similar intraocular pressure-lowering effects to traditional incisional surgery such as trabeculectomy or tube shunt surgery, but with fewer risks. Future randomized, prospective studies should be done to compare these gel stents and microshunts both to each other and to other traditional glaucoma surgeries.
Recently introduced microincisional glaucoma surgeries that enhance conventional outflow offer a ... more Recently introduced microincisional glaucoma surgeries that enhance conventional outflow offer a favorable risk profile over traditional surgeries, but can be unpredictable. Two paramount challenges are the lack of an adequate training model for angle surgeries and the absence of an intraoperative quantification of surgical success. To address both, we developed an ex vivo training system and a differential, quantitative canalography method that uses slope adjusted fluorescence intensities of two different chromophores to avoid quenching. We assessed outflow enhancement by trabecular microbypass (TMB) implantation or by ab interno trabeculectomy (AIT). In this porcine model, TMB resulted in an insignificant (p>0.05) outflow increase of 13±5%, 14±8%, 9±3%, and 24±9% in the inferonasal, superonasal, superotemporal, and inferotemporal quadrant, respectively. AIT caused a 100±50% (p=0.002), 75±28% (p=0.002), 19±8%, and 40±21% increase in those quadrants. The direct gonioscopy and tactile feedback provided a surgical experience that was very similar to that in human patients. Despite the more narrow and discontinuous circumferential drainage elements in the pig with potential for underperformance or partial stent obstruction, unequivocal patterns of focal outflow enhancement by TMB were seen in this training model. AIT achieved extensive access to outflow pathways beyond the surgical site itself.
Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan ... more Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long‐lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart‐specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long‐lived flies were tested in the heart‐specific manner. Interestingly, the expressions of anti‐aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart‐specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart‐specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly’s response to the environment.
d espite the various roles of regulator of G protein signaling (rGs) protein in the G protein sig... more d espite the various roles of regulator of G protein signaling (rGs) protein in the G protein signaling pathway that have been defined, the function of rGs has not been characterized in longevity signaling pathways. we found that reduced expression of loco, a drosophila rGs protein, resulted in a longer lifespan of flies with stronger resistance to stress, higher mnsod activity and increased fat content. in contrast, overexpression of the loco gene shortened the fly lifespan significantly, lowered stress resistance and reduced fat content, also indicating that the rGs domain containing Gtpase-activating protein (Gap) activity is related to the regulation of longevity. interestingly, expressional changes of yeast rGs2 and rat rGs14, homologs to the fly loco, also affected oxidative stress resistance and longevity in the respective species. it is known that loco inactivates inhibi-tory Gαi • GTP protein to reduce activity of adenylate cyclase (ac) and rGs14 interacts with activated h-ras and raf-1 kinases, which subsequently inhibits ErK phosphorylation. we propose that loco/rGs14 protein may regulate stress resistance and longevity as an activator in ac-camp-pKa pathway and/or as a molecular scaffold that sequesters active Ras and Raf from Ras • GTP-Raf-MEK-ErK signaling pathway. consistently, our data showed that downregulation of loco significantly diminishes camp amounts and increases pErK levels with higher resistance to the oxidative stress.
Prior glaucoma severity staging systems were mostly concerned with visual field function and reti... more Prior glaucoma severity staging systems were mostly concerned with visual field function and retinal nerve fiber layer, but did not include intraocular pressure or medications to capture resistance to treatment. We recently introduced a simple index that combines pressure, medications,
Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exi... more Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exists within the trabecular meshwork but also at the level of Schlemm's canal and further downstream within the outflow system. Viral vectors allow to take advantage of naturally evolved, highly efficient mechanisms of gene transfer, a process that is termed transduction. They can be produced at biosafety level 2 in the lab using protocols that have evolved considerably over the last 15-20 years. Applied by an intracameral bolus, vectors follow conventional as well as uveoscleral outflow pathways. They may affect other structures in the anterior chamber depending on their transduction kinetics which can vary among species when using the same vector. Not all vectors can express long-term, a desirable feature to address the chronicity of glaucoma. Vectors that integrate into the genome of the target cell can achieve transgene function for the life of the transduced cell but are mutagenic by definition. The most prominent long-term expressing vector systems are based on lentiviruses that are derived from HIV, FIV, or EIAV. Safety considerations make non-primate lentiviral vector systems easier to work with as they are not derived from human pathogens. Non-integrating vectors are subject to degradation and attritional dilution during cell division. Lentiviral vectors have to integrate in order to express while adeno-associated viral vectors (AAV) often persist as intracellular concatemers but may also integrate. Adeno- and herpes viral vectors do not integrate and earlier generation systems might be relatively immunogenic. Nonviral methods of gene transfer are termed transfection with few restrictions of transgene size and type but often a much less efficient gene transfer that is also short-lived. Traditional gene transfer delivers exons while some vectors (lentiviral, herpes and adenoviral) allow transfer of entire genes that include introns. Recent insights have highlighted the role of non-coding RNA, most prominently, siRNA, miRNA and lncRNA. SiRNA is highly specific, miRNA is less specific, while lncRNA uses highly complex mechanisms that involve secondary structures and intergenic, intronic, overlapping, antisense, and bidirectional location. Several promising preclinical studies have targeted the RhoA or the prostaglandin pathway or modified the extracellular matrix. TGF-β and glaucoma myocilin mutants have been transduced to elevate the intraocular pressure in glaucoma models. Cell based therapies have started to show first promise. Past approaches have focused on the trabecular meshwork and the inner wall of Schlemm's canal while new strategies are concerned with modification of outflow tract elements that are downstream of the trabecular meshwork.
Purpose: To quantify regional changes of conventional outflow caused by ab interno trabeculectomy... more Purpose: To quantify regional changes of conventional outflow caused by ab interno trabeculectomy (AIT). Methods: Gonioscopic, plasma-mediated ab interno trabeculectomy (AIT; Trabectome, Neomedix, Tustin, CA) was established in enucleated pig eyes. We developed a program to automatically quantify outflow changes (R, package eye-canalogram, github.com) using a fluorescent tracer reperfusion technique. Trabecular meshwork (TM) ablation was demonstrated with fluorescent spheres in 6 eyes before formal outflow quantification with two dye reperfusion canalograms in 6 further eyes. Eyes were perfused with a central, intracameral needle at 15 mmHg. Canalograms and histology were correlated for each eye. Results: The pig eye provided a model with high similarity to AIT in human patients. Histology indicated ablation of TM and unroofing of most Schlemm’s canal segments. Spheres highlighted additional circumferential and radial outflow beyond the immediate area of ablation. Differential canalograms showed that AIT caused an increase of outflow of 17±5 fold inferonasally (IN), 14±3 fold superonasally (SN) and also an increase in the opposite quadrants with a 2±1 fold increase superotemporally (ST) and 3±3 inferotemporally (IT). Perilimbal specific flow image analysis showed an accelerated nasal filling with an additional perilimbal flow direction into adjacent quadrants. Conclusion: A quantitative, differential canalography technique was developed that allows to quantify supraphysiological outflow enhancement by AIT.
Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan ... more Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increa...
The increasing prevalence of glaucoma, a leading cause of blindness, makes the development of saf... more The increasing prevalence of glaucoma, a leading cause of blindness, makes the development of safer and more effective treatment more urgent. Recently introduced microincisional glaucoma surgeries that enhance conventional outflow offer a favorable risk profile but can be unpredictable. Two paramount challenges are the lack of an adequate surgical training model for new surgeries and the absence of pre-or intraoperative guidance to sites of reduced flow.
To describe the characteristics, demographics, anatomic and functional outcomes, and complication... more To describe the characteristics, demographics, anatomic and functional outcomes, and complications of diabetic eyes with traction retinal detachment (TRD) or combined traction/rhegmatogenous retinal detachment that underwent pars plana vitrectomy (PPV) silicone oil (SO) tamponade. In this retrospective chart review, exclusion criteria included previous PPV. Forty eyes were identified. The mean preoperative complexity score (CS) of the TRDs was 5.95 (range 4-8). In patients with ≥6 months of follow-up (33; 82.5%), eyes with lower CSs had a better mean final visual acuity (VA): ~20/400 for CS 4, and hand motions (HM)-1/200 for CS >5. Eyes with macula-sparing TRDs had better final VA (~20/400) than those with a detached macula (~HM). Eyes with >3 panretinal photocoagulation sessions attained better mean final VA (20/400) than eyes without any history of laser treatment (~HM). The most frequent complications were cataract (46%), preretinal fibrosis (33%), recurrent TRD (15%), oil migration to the anterior chamber (12%), corneal edema (12%), and oil emulsification (9%). Eleven (27.5%) eyes underwent SO removal. The average complexity score was high in this series. Use of SO tamponade for diabetic TRDs is not without complications, but may be beneficial in stabilizing vision in eyes with otherwise poor prognosis.
Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exi... more Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exists within the trabecular meshwork but also at the level of Schlemm's canal and further downstream within the outflow system. Viral vectors allow to take advantage of naturally evolved, highly efficient mechanisms of gene transfer, a process that is termed transduction. They can be produced at biosafety level 2 in the lab using protocols that have evolved considerably over the last 15e20 years. Applied by an intracameral bolus, vectors follow conventional as well as uveoscleral outflow pathways. They may affect other structures in the anterior chamber depending on their transduction kinetics which can vary among species when using the same vector. Not all vectors can express long-term, a desirable feature to address the chronicity of glaucoma. Vectors that integrate into the genome of the target cell can achieve transgene function for the life of the transduced cell but are mutagenic by definition. The most prominent long-term expressing vector systems are based on lentiviruses that are derived from HIV, FIV, or EIAV. Safety considerations make non-primate lentiviral vector systems easier to work with as they are not derived from human pathogens. Non-integrating vectors are subject to degradation and attritional dilution during cell division. Lentiviral vectors have to integrate in order to express while adenoassociated viral vectors (AAV) often persist as intracellular concatemers but may also integrate. Adenoand herpes viral vectors do not integrate and earlier generation systems might be relatively immunogenic. Nonviral methods of gene transfer are termed transfection with few restrictions of transgene size and type but often a much less efficient gene transfer that is also short-lived. Traditional gene transfer delivers exons while some vectors (lentiviral, herpes and adenoviral) allow transfer of entire genes that include introns. Recent insights have highlighted the role of non-coding RNA, most prominently, siRNA, miRNA and lncRNA. SiRNA is highly specific, miRNA is less specific, while lncRNA uses highly complex mechanisms that involve secondary structures and intergenic, intronic, overlapping, antisense, and bidirectional location. Several promising preclinical studies have targeted the RhoA or the prostaglandin pathway or modified the extracellular matrix. TGF-b and glaucoma myocilin mutants have been transduced to elevate the intraocular pressure in glaucoma models. Cell based therapies have started to show first promise. Past approaches have focused on the trabecular meshwork and the inner wall of Schlemm's canal while new strategies are concerned with modification of outflow tract elements that are downstream of the trabecular meshwork.
To compare intraocular pressure (IOP) after trabectome-mediated ab interno trabeculectomy surgery... more To compare intraocular pressure (IOP) after trabectome-mediated ab interno trabeculectomy surgery in phakic patients (T) and trabectome with same session phacoemulsification (PT) using Coarsened Exact Matching. Although phacoemulsification is associated with IOP reduction when performed on its own, it is not known how much it contributes in PT. Subjects were divided into phakic T and PT. Exclusion criteria were follow-up for <12 months and additional glaucoma surgery. Demographics were compared by the Mann-Whitney U test and chi-squared test for continuous and categorical variables, respectively. Multiple imputation was utilized to avoid eliminating data with missing values. Groups were then matched using Coarsened Exact Matching based on age, race, type of glaucoma, baseline IOP, and number of preoperative glaucoma medications. Univariate linear regression was used to examine IOP reduction after surgery; those variables that were statistically significant were included in the fi...
PURPOSE: To stratify outcomes of trabectome-mediated ab interno trabeculectomy (AIT) by glaucoma ... more PURPOSE: To stratify outcomes of trabectome-mediated ab interno trabeculectomy (AIT) by glaucoma severity using a simple and clinically useful glaucoma index. Based on prior data of trabectome after failed trabeculectomy, we hypothesized that more severe glaucoma might have a relatively more reduced facility compared to mild glaucoma and respond with a larger IOP reduction to trabecular meshwork ablation. METHODS: Patients with primary open angle glaucoma who had undergone AIT without any other same session surgery and without any second eye surgery during the following 12 months were analyzed. Eyes of patients that had less than 12 months follow up or were diagnosed with neovascular glaucoma were excluded. A glaucoma index (GI) was created to capture glaucoma severity based on visual field, number of preoperative medications, and preoperative IOP. Visual field (VF) was separated into 3 categories: mild, moderate, and advanced (assigned 1, 2, and 3 points, respectively). Preoperative number of medications (meds) was divided into 4 categories: ≤1, 2, 3 or ≥4, and assigned with a value of 1 to 4. Baseline IOP (IOP) was divided into 3 categories: 12-18 (Group 3) and >18 (Group 4). Linear regression was used to determine if there was an association between GI group and IOP reduction after one year or age, gender, race, diagnosis, cup to disc (C/D) ratio, and Shaffer grade. RESULTS: Out of 1340 patients, 843 were included in the analysis. The GI group distribution was GI1 = 164, GI2 = 202, GI3 = 260, and GI4 = 216. Mean IOP reduction after one year was 4.0±5.4, 6.4±5.8, 9.0±7.6, 12.0±8.0 mmHg for GI groups 1 to 4, respectively. Linear regression showed that IOP reduction was associated with GI group after adjusting for age, gender, race, diagnosis, cup to disc ratio, and Shaffer grade. Each GI group increase of 1 was associated with incremental IOP reductions of 2.95±0.29 mmHg. Success rate at 12 months was 90%, 77%, 77%, and 71% for GI groups 1 to 4. The log-rank test suggested significant differences between GI groups. CONCLUSION: A simple glaucoma index, GI, was created to capture glaucoma severity and a relative resistance to treatment. A higher GI was associated with a larger IOP reduction in trabectome surgery. This indicates that there is a role for AIT beyond mild glaucoma and ocular hypertension.
Purpose: To compare the safety and efficacy of two different techniques for implantation of the X... more Purpose: To compare the safety and efficacy of two different techniques for implantation of the XEN Gel Stent, a minimally invasive surgical device for the treatment of refractory glaucoma. Methods: A retrospective chart review of eyes that received ab interno or ab externo XEN Gel Stent placement from February 2017 to October 2019 was conducted. A single surgeon (NMR) performed all operations. Eyes that received the XEN implant concomitant with a glaucoma drainage device insertion or that were lost to 6-month follow-up were excluded. Intraocular pressure (IOP) change, change in glaucoma medications, frequency of slit lamp revision procedures, and frequency of secondary glaucoma surgeries were the primary outcomes compared between groups. Results: Fifty eyes that underwent ab interno placement and 30 eyes that underwent ab externo placement were studied. The ab interno cohort demonstrated a mean IOP reduction of 8.4 ± 1.7 mmHg (28.6% decrease) by 12 months, compared to a mean reduction of 12.8 ± 3.0 mmHg (40.1% decrease) in the ab externo group (p = 0.208). Mean reduction in medication use was 1.81 ± 0.29 medications in the ab interno group and 1.86 ± 0.37 in the ab externo group (p = 0.913). By 12 months, 58% of ab interno eyes had required 5-fluorouracil injection compared to 36.7% of ab externos (p = 0.105). Bleb needling was applied to 42% and 26.7% of the eyes, respectively (p = 0.231). A second glaucoma surgery was necessary for 20% of the ab interno cohort and 10% of the ab externo cohort (p = 0.351). Conclusion: There were no differences in outcomes between ab interno and ab externo placement of the XEN Gel Stent. Both approaches are safe and effective for lowering IOP.
Sclerochoroidal calcifications are an important entity to recognize on ophthalmoscopy. Although u... more Sclerochoroidal calcifications are an important entity to recognize on ophthalmoscopy. Although uncommon, idiopathic, and primarily benign, they are commonly misdiagnosed as malignant tumors. Here, we present a case of an individual with sclerochoroidal calcifications with associated imaging findings in the setting of elevated serum parathyroid hormone levels. We also review background information, pathology, pathogenesis, differential diagnoses, diagnostic approach, management, and prognosis. It is crucial that patients with this finding have subsequent clinical imaging and laboratory workup to exclude other serious ocular and systemic diseases.
Purpose This review will provide an update on surgical techniques, outcomes, and complications fo... more Purpose This review will provide an update on surgical techniques, outcomes, and complications for two new translimbal bleb-forming surgical glaucoma devices. Recent findings The XEN Gel Microstent and PreserFlo MicroShunt comprise a category of subconjunctival microinvasive glaucoma surgery developed with the aim of improving the predictability and safety profile of bleb-forming procedures. Both devices are made of noninflammatory material which limits postsurgical inflammation and scarring and have a valve-less intrinsic flow-limiting design, which decreases the risk of hypotony. There are various techniques of implantation for the XEN Gel Microstent each with their own advantages and disadvantages. Summary These devices have demonstrated promising outcomes in early experimental literature with similar intraocular pressure-lowering effects to traditional incisional surgery such as trabeculectomy or tube shunt surgery, but with fewer risks. Future randomized, prospective studies should be done to compare these gel stents and microshunts both to each other and to other traditional glaucoma surgeries.
Recently introduced microincisional glaucoma surgeries that enhance conventional outflow offer a ... more Recently introduced microincisional glaucoma surgeries that enhance conventional outflow offer a favorable risk profile over traditional surgeries, but can be unpredictable. Two paramount challenges are the lack of an adequate training model for angle surgeries and the absence of an intraoperative quantification of surgical success. To address both, we developed an ex vivo training system and a differential, quantitative canalography method that uses slope adjusted fluorescence intensities of two different chromophores to avoid quenching. We assessed outflow enhancement by trabecular microbypass (TMB) implantation or by ab interno trabeculectomy (AIT). In this porcine model, TMB resulted in an insignificant (p>0.05) outflow increase of 13±5%, 14±8%, 9±3%, and 24±9% in the inferonasal, superonasal, superotemporal, and inferotemporal quadrant, respectively. AIT caused a 100±50% (p=0.002), 75±28% (p=0.002), 19±8%, and 40±21% increase in those quadrants. The direct gonioscopy and tactile feedback provided a surgical experience that was very similar to that in human patients. Despite the more narrow and discontinuous circumferential drainage elements in the pig with potential for underperformance or partial stent obstruction, unequivocal patterns of focal outflow enhancement by TMB were seen in this training model. AIT achieved extensive access to outflow pathways beyond the surgical site itself.
Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan ... more Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long‐lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart‐specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long‐lived flies were tested in the heart‐specific manner. Interestingly, the expressions of anti‐aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart‐specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart‐specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly’s response to the environment.
d espite the various roles of regulator of G protein signaling (rGs) protein in the G protein sig... more d espite the various roles of regulator of G protein signaling (rGs) protein in the G protein signaling pathway that have been defined, the function of rGs has not been characterized in longevity signaling pathways. we found that reduced expression of loco, a drosophila rGs protein, resulted in a longer lifespan of flies with stronger resistance to stress, higher mnsod activity and increased fat content. in contrast, overexpression of the loco gene shortened the fly lifespan significantly, lowered stress resistance and reduced fat content, also indicating that the rGs domain containing Gtpase-activating protein (Gap) activity is related to the regulation of longevity. interestingly, expressional changes of yeast rGs2 and rat rGs14, homologs to the fly loco, also affected oxidative stress resistance and longevity in the respective species. it is known that loco inactivates inhibi-tory Gαi • GTP protein to reduce activity of adenylate cyclase (ac) and rGs14 interacts with activated h-ras and raf-1 kinases, which subsequently inhibits ErK phosphorylation. we propose that loco/rGs14 protein may regulate stress resistance and longevity as an activator in ac-camp-pKa pathway and/or as a molecular scaffold that sequesters active Ras and Raf from Ras • GTP-Raf-MEK-ErK signaling pathway. consistently, our data showed that downregulation of loco significantly diminishes camp amounts and increases pErK levels with higher resistance to the oxidative stress.
Prior glaucoma severity staging systems were mostly concerned with visual field function and reti... more Prior glaucoma severity staging systems were mostly concerned with visual field function and retinal nerve fiber layer, but did not include intraocular pressure or medications to capture resistance to treatment. We recently introduced a simple index that combines pressure, medications,
Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exi... more Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exists within the trabecular meshwork but also at the level of Schlemm&#39;s canal and further downstream within the outflow system. Viral vectors allow to take advantage of naturally evolved, highly efficient mechanisms of gene transfer, a process that is termed transduction. They can be produced at biosafety level 2 in the lab using protocols that have evolved considerably over the last 15-20 years. Applied by an intracameral bolus, vectors follow conventional as well as uveoscleral outflow pathways. They may affect other structures in the anterior chamber depending on their transduction kinetics which can vary among species when using the same vector. Not all vectors can express long-term, a desirable feature to address the chronicity of glaucoma. Vectors that integrate into the genome of the target cell can achieve transgene function for the life of the transduced cell but are mutagenic by definition. The most prominent long-term expressing vector systems are based on lentiviruses that are derived from HIV, FIV, or EIAV. Safety considerations make non-primate lentiviral vector systems easier to work with as they are not derived from human pathogens. Non-integrating vectors are subject to degradation and attritional dilution during cell division. Lentiviral vectors have to integrate in order to express while adeno-associated viral vectors (AAV) often persist as intracellular concatemers but may also integrate. Adeno- and herpes viral vectors do not integrate and earlier generation systems might be relatively immunogenic. Nonviral methods of gene transfer are termed transfection with few restrictions of transgene size and type but often a much less efficient gene transfer that is also short-lived. Traditional gene transfer delivers exons while some vectors (lentiviral, herpes and adenoviral) allow transfer of entire genes that include introns. Recent insights have highlighted the role of non-coding RNA, most prominently, siRNA, miRNA and lncRNA. SiRNA is highly specific, miRNA is less specific, while lncRNA uses highly complex mechanisms that involve secondary structures and intergenic, intronic, overlapping, antisense, and bidirectional location. Several promising preclinical studies have targeted the RhoA or the prostaglandin pathway or modified the extracellular matrix. TGF-β and glaucoma myocilin mutants have been transduced to elevate the intraocular pressure in glaucoma models. Cell based therapies have started to show first promise. Past approaches have focused on the trabecular meshwork and the inner wall of Schlemm&#39;s canal while new strategies are concerned with modification of outflow tract elements that are downstream of the trabecular meshwork.
Purpose: To quantify regional changes of conventional outflow caused by ab interno trabeculectomy... more Purpose: To quantify regional changes of conventional outflow caused by ab interno trabeculectomy (AIT). Methods: Gonioscopic, plasma-mediated ab interno trabeculectomy (AIT; Trabectome, Neomedix, Tustin, CA) was established in enucleated pig eyes. We developed a program to automatically quantify outflow changes (R, package eye-canalogram, github.com) using a fluorescent tracer reperfusion technique. Trabecular meshwork (TM) ablation was demonstrated with fluorescent spheres in 6 eyes before formal outflow quantification with two dye reperfusion canalograms in 6 further eyes. Eyes were perfused with a central, intracameral needle at 15 mmHg. Canalograms and histology were correlated for each eye. Results: The pig eye provided a model with high similarity to AIT in human patients. Histology indicated ablation of TM and unroofing of most Schlemm’s canal segments. Spheres highlighted additional circumferential and radial outflow beyond the immediate area of ablation. Differential canalograms showed that AIT caused an increase of outflow of 17±5 fold inferonasally (IN), 14±3 fold superonasally (SN) and also an increase in the opposite quadrants with a 2±1 fold increase superotemporally (ST) and 3±3 inferotemporally (IT). Perilimbal specific flow image analysis showed an accelerated nasal filling with an additional perilimbal flow direction into adjacent quadrants. Conclusion: A quantitative, differential canalography technique was developed that allows to quantify supraphysiological outflow enhancement by AIT.
Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan ... more Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increa...
The increasing prevalence of glaucoma, a leading cause of blindness, makes the development of saf... more The increasing prevalence of glaucoma, a leading cause of blindness, makes the development of safer and more effective treatment more urgent. Recently introduced microincisional glaucoma surgeries that enhance conventional outflow offer a favorable risk profile but can be unpredictable. Two paramount challenges are the lack of an adequate surgical training model for new surgeries and the absence of pre-or intraoperative guidance to sites of reduced flow.
To describe the characteristics, demographics, anatomic and functional outcomes, and complication... more To describe the characteristics, demographics, anatomic and functional outcomes, and complications of diabetic eyes with traction retinal detachment (TRD) or combined traction/rhegmatogenous retinal detachment that underwent pars plana vitrectomy (PPV) silicone oil (SO) tamponade. In this retrospective chart review, exclusion criteria included previous PPV. Forty eyes were identified. The mean preoperative complexity score (CS) of the TRDs was 5.95 (range 4-8). In patients with ≥6 months of follow-up (33; 82.5%), eyes with lower CSs had a better mean final visual acuity (VA): ~20/400 for CS 4, and hand motions (HM)-1/200 for CS &amp;amp;amp;gt;5. Eyes with macula-sparing TRDs had better final VA (~20/400) than those with a detached macula (~HM). Eyes with &amp;amp;amp;gt;3 panretinal photocoagulation sessions attained better mean final VA (20/400) than eyes without any history of laser treatment (~HM). The most frequent complications were cataract (46%), preretinal fibrosis (33%), recurrent TRD (15%), oil migration to the anterior chamber (12%), corneal edema (12%), and oil emulsification (9%). Eleven (27.5%) eyes underwent SO removal. The average complexity score was high in this series. Use of SO tamponade for diabetic TRDs is not without complications, but may be beneficial in stabilizing vision in eyes with otherwise poor prognosis.
Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exi... more Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exists within the trabecular meshwork but also at the level of Schlemm's canal and further downstream within the outflow system. Viral vectors allow to take advantage of naturally evolved, highly efficient mechanisms of gene transfer, a process that is termed transduction. They can be produced at biosafety level 2 in the lab using protocols that have evolved considerably over the last 15e20 years. Applied by an intracameral bolus, vectors follow conventional as well as uveoscleral outflow pathways. They may affect other structures in the anterior chamber depending on their transduction kinetics which can vary among species when using the same vector. Not all vectors can express long-term, a desirable feature to address the chronicity of glaucoma. Vectors that integrate into the genome of the target cell can achieve transgene function for the life of the transduced cell but are mutagenic by definition. The most prominent long-term expressing vector systems are based on lentiviruses that are derived from HIV, FIV, or EIAV. Safety considerations make non-primate lentiviral vector systems easier to work with as they are not derived from human pathogens. Non-integrating vectors are subject to degradation and attritional dilution during cell division. Lentiviral vectors have to integrate in order to express while adenoassociated viral vectors (AAV) often persist as intracellular concatemers but may also integrate. Adenoand herpes viral vectors do not integrate and earlier generation systems might be relatively immunogenic. Nonviral methods of gene transfer are termed transfection with few restrictions of transgene size and type but often a much less efficient gene transfer that is also short-lived. Traditional gene transfer delivers exons while some vectors (lentiviral, herpes and adenoviral) allow transfer of entire genes that include introns. Recent insights have highlighted the role of non-coding RNA, most prominently, siRNA, miRNA and lncRNA. SiRNA is highly specific, miRNA is less specific, while lncRNA uses highly complex mechanisms that involve secondary structures and intergenic, intronic, overlapping, antisense, and bidirectional location. Several promising preclinical studies have targeted the RhoA or the prostaglandin pathway or modified the extracellular matrix. TGF-b and glaucoma myocilin mutants have been transduced to elevate the intraocular pressure in glaucoma models. Cell based therapies have started to show first promise. Past approaches have focused on the trabecular meshwork and the inner wall of Schlemm's canal while new strategies are concerned with modification of outflow tract elements that are downstream of the trabecular meshwork.
To compare intraocular pressure (IOP) after trabectome-mediated ab interno trabeculectomy surgery... more To compare intraocular pressure (IOP) after trabectome-mediated ab interno trabeculectomy surgery in phakic patients (T) and trabectome with same session phacoemulsification (PT) using Coarsened Exact Matching. Although phacoemulsification is associated with IOP reduction when performed on its own, it is not known how much it contributes in PT. Subjects were divided into phakic T and PT. Exclusion criteria were follow-up for <12 months and additional glaucoma surgery. Demographics were compared by the Mann-Whitney U test and chi-squared test for continuous and categorical variables, respectively. Multiple imputation was utilized to avoid eliminating data with missing values. Groups were then matched using Coarsened Exact Matching based on age, race, type of glaucoma, baseline IOP, and number of preoperative glaucoma medications. Univariate linear regression was used to examine IOP reduction after surgery; those variables that were statistically significant were included in the fi...
PURPOSE: To stratify outcomes of trabectome-mediated ab interno trabeculectomy (AIT) by glaucoma ... more PURPOSE: To stratify outcomes of trabectome-mediated ab interno trabeculectomy (AIT) by glaucoma severity using a simple and clinically useful glaucoma index. Based on prior data of trabectome after failed trabeculectomy, we hypothesized that more severe glaucoma might have a relatively more reduced facility compared to mild glaucoma and respond with a larger IOP reduction to trabecular meshwork ablation. METHODS: Patients with primary open angle glaucoma who had undergone AIT without any other same session surgery and without any second eye surgery during the following 12 months were analyzed. Eyes of patients that had less than 12 months follow up or were diagnosed with neovascular glaucoma were excluded. A glaucoma index (GI) was created to capture glaucoma severity based on visual field, number of preoperative medications, and preoperative IOP. Visual field (VF) was separated into 3 categories: mild, moderate, and advanced (assigned 1, 2, and 3 points, respectively). Preoperative number of medications (meds) was divided into 4 categories: ≤1, 2, 3 or ≥4, and assigned with a value of 1 to 4. Baseline IOP (IOP) was divided into 3 categories: 12-18 (Group 3) and >18 (Group 4). Linear regression was used to determine if there was an association between GI group and IOP reduction after one year or age, gender, race, diagnosis, cup to disc (C/D) ratio, and Shaffer grade. RESULTS: Out of 1340 patients, 843 were included in the analysis. The GI group distribution was GI1 = 164, GI2 = 202, GI3 = 260, and GI4 = 216. Mean IOP reduction after one year was 4.0±5.4, 6.4±5.8, 9.0±7.6, 12.0±8.0 mmHg for GI groups 1 to 4, respectively. Linear regression showed that IOP reduction was associated with GI group after adjusting for age, gender, race, diagnosis, cup to disc ratio, and Shaffer grade. Each GI group increase of 1 was associated with incremental IOP reductions of 2.95±0.29 mmHg. Success rate at 12 months was 90%, 77%, 77%, and 71% for GI groups 1 to 4. The log-rank test suggested significant differences between GI groups. CONCLUSION: A simple glaucoma index, GI, was created to capture glaucoma severity and a relative resistance to treatment. A higher GI was associated with a larger IOP reduction in trabectome surgery. This indicates that there is a role for AIT beyond mild glaucoma and ocular hypertension.
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Papers by Hardik Parikh
potential for underperformance or partial stent obstruction, unequivocal patterns of focal outflow enhancement by TMB were seen in this training model. AIT achieved extensive access to outflow pathways beyond the surgical site itself.
Drosophila melanogaster. Once revealed that long‐lived fruit flies exhibit limited cardiac decline, we investigated whether
Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three
different stressors (oxidation, starvation and heat), heart‐specific Rpd3 downregulation significantly enhanced stress
resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted
in other tissues or when other long‐lived flies were tested in the heart‐specific manner. Interestingly, the expressions of
anti‐aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart‐specific Rpd3
downregulation. Showing higher resistance to oxidative stress, the heart‐specific Rpd3 downregulation concurrently
exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated
heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with
decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation
of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in
cardiac function and longevity to systemically modulate the fly’s response to the environment.
Methods: Gonioscopic, plasma-mediated ab interno trabeculectomy (AIT; Trabectome, Neomedix, Tustin, CA) was established in enucleated pig eyes. We developed a program to automatically quantify outflow changes (R, package eye-canalogram, github.com) using a fluorescent tracer reperfusion technique. Trabecular meshwork (TM) ablation was demonstrated with fluorescent spheres in 6 eyes before formal outflow quantification with two dye reperfusion canalograms in 6 further eyes. Eyes were perfused with a central, intracameral needle at 15 mmHg. Canalograms and histology were correlated for each eye.
Results: The pig eye provided a model with high similarity to AIT in human patients. Histology indicated ablation of TM and unroofing of most Schlemm’s canal segments. Spheres highlighted additional circumferential and radial outflow beyond the immediate area of ablation. Differential canalograms showed that AIT caused an increase of outflow of 17±5 fold inferonasally (IN), 14±3 fold superonasally (SN) and also an increase in the opposite quadrants with a 2±1 fold increase superotemporally (ST) and 3±3 inferotemporally (IT). Perilimbal specific flow image analysis showed an accelerated nasal filling with an additional perilimbal flow direction into adjacent quadrants.
Conclusion: A quantitative, differential canalography technique was developed that allows to quantify supraphysiological outflow enhancement by AIT.
potential for underperformance or partial stent obstruction, unequivocal patterns of focal outflow enhancement by TMB were seen in this training model. AIT achieved extensive access to outflow pathways beyond the surgical site itself.
Drosophila melanogaster. Once revealed that long‐lived fruit flies exhibit limited cardiac decline, we investigated whether
Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three
different stressors (oxidation, starvation and heat), heart‐specific Rpd3 downregulation significantly enhanced stress
resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted
in other tissues or when other long‐lived flies were tested in the heart‐specific manner. Interestingly, the expressions of
anti‐aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart‐specific Rpd3
downregulation. Showing higher resistance to oxidative stress, the heart‐specific Rpd3 downregulation concurrently
exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated
heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with
decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation
of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in
cardiac function and longevity to systemically modulate the fly’s response to the environment.
Methods: Gonioscopic, plasma-mediated ab interno trabeculectomy (AIT; Trabectome, Neomedix, Tustin, CA) was established in enucleated pig eyes. We developed a program to automatically quantify outflow changes (R, package eye-canalogram, github.com) using a fluorescent tracer reperfusion technique. Trabecular meshwork (TM) ablation was demonstrated with fluorescent spheres in 6 eyes before formal outflow quantification with two dye reperfusion canalograms in 6 further eyes. Eyes were perfused with a central, intracameral needle at 15 mmHg. Canalograms and histology were correlated for each eye.
Results: The pig eye provided a model with high similarity to AIT in human patients. Histology indicated ablation of TM and unroofing of most Schlemm’s canal segments. Spheres highlighted additional circumferential and radial outflow beyond the immediate area of ablation. Differential canalograms showed that AIT caused an increase of outflow of 17±5 fold inferonasally (IN), 14±3 fold superonasally (SN) and also an increase in the opposite quadrants with a 2±1 fold increase superotemporally (ST) and 3±3 inferotemporally (IT). Perilimbal specific flow image analysis showed an accelerated nasal filling with an additional perilimbal flow direction into adjacent quadrants.
Conclusion: A quantitative, differential canalography technique was developed that allows to quantify supraphysiological outflow enhancement by AIT.