Michael L. Mulhern

Induction of endoplasmic reticulum stress in retinal pericytes by glucose deprivation

Diabetic retinopathy is one of the major microvascular complications associated with diabetes mellitus, and the selective degeneration of retinal capillary pericytes is considered to be a hallmark of early retinopathy. Because glucose fluctuations commonly occur in diabetes, we hypothesized that these fluctuations will increase the endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR) in retinal pericytes. To study whether ER stress and the UPR can be induced in retinal pericytes, rat retinal capillary pericytes were cultured in different concentrations of glucose. Hypoglycemia but not hyperglycemia was found to activate UPR-specific enzymes in pericytes. Strong UPR activation leading to apoptosis was also observed when pericytes were cultured in glucose concentrations that were reduced from high to low or no glucose. These results indicate that induction of UPR is related not only to absolute concentrations but also to a shifting from higher to lower concentrations of glucose.

Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells

Aging is enhanced by hypoxia and oxidative stress. As the lens is located in the hypoglycemic environment under hypoxia, aging lens with diabetes might aggravate these stresses. This study was designed to examine whether low glucose under hypoxic conditions induces the unfolded protein response (UPR), and also if the UPR then generates the reactive oxygen species (ROS) in lens epithelial cells (LECs). The UPR was activated within 1 h by culturing the human LECs (HLECs) and rat LECs in <1.5 mM glucose under hypoxic conditions. These conditions also induced the Nrf2-dependent antioxidant-protective UPR, production of ROS, and apoptosis. The rat LECs located in the anterior center region were the least susceptible to the UPR, whereas the proliferating LECs in the germinative zone were the most susceptible. Because the cortical lens fiber cells are differentiated from the LECs after the onset of diabetes, we suggest that these newly formed cortical fibers have lower levels of Nrf2, and are then oxidized resulting in cortical cataracts. Thus, low glucose and oxygen conditions induce the UPR, generation of ROS, and expressed the Nrf2 and Nrf2-dependent antioxidant enzymes at normal levels. But these cells eventually lose reduced glutathione (GSH) and induce apoptosis. The results indicate a new link between hypoglycemia under hypoxia and impairment of HLEC functions.

Outcome of retinopathy of prematurity patients following adoption of revised indications for treatment

BackgroundThe Early Treatment for Retinopathy of Prematurity study (ETROP), published in 2003, established new guidelines for treatment of retinopathy of prematurity (ROP) and demonstrated improved outcomes compared to previous guidelines. We examined outcomes before and after implementing the ETROP recommendations.MethodsA retrospective chart review was performed using records of infants who had laser ablations for ROP performed from January, 2000 through December, 2005. Data collected included date of birth; birth weight; estimated gestational age (EGA); grading of ROP; date of laser ablation; and outcome of laser surgery. Univariate association with threshold or prethreshold treatment (Pre-ETROP and Post-ETROP, respectively) were assessed using t-tests or Wilcoxon tests. Additional comparison between groups was performed using Fishers exact tests.Results581 patients were examined before and 464 after December 2003. Of these, 29/581 (5% – Pre-ETROP Group) and 53/464 (11% – Post-ETROP Group) patients advanced to criteria requiring laser treatment respectively (P = 0.0001). The average estimated gestational age (EGA) at birth was 26.3 and 25.2 weeks, with an average birth weight of 888 and 707 grams for Pre and Post-ETROP Groups, respectively. Stage 5 retinal detachment (RD) developed in 10.3% of eyes in the Pre-ETROP Group and 1.9% of eyes in the Post-ETROP Group (P = 0.02).ConclusionAfter the ETROP guidelines were implemented, there was a decrease from 10.3% to 1.9% of eyes developing Stage 5 retinal detachment, despite this group having a lower average EGA and lower average birth weight. These results underscore the importance of adoption of the Revised Indications.

Age-related macular degeneration: review of current treatments

The pathogenesis of choroidal neovascular membrane in neovascular age-related macular degeneration (AMD) is multifactorial and involves angiogenesis, inflammation and other yet to be discovered entities. The role of angiogenesis in this disease process has been exploited, and at present forms the basis of the most successful therapy. Ranibizumab is a nonselective antibody fragment found to not only maintain vision, but also improve vision when compared with sham injections and photodynamic therapy treatments. Bevacizumab, with a similar mechanism of action as ranibizumab, although not US FDA approved for intravitreal use, is being used with promising results of decreased vision and loss of foveal thickness in neovascular AMD. Several studies are underway, including those involving comparing ranibizumab and bevacizumab, and trials involving brachytherapy, sirolimus and topical mecamylamine, in the hope of tackling AMD by addressing its multiple contributing etiologies.