Pharmacologic activation of autophagy without direct mTOR inhibition as a therapeutic strategy for treating dry macular degeneration.

Dry age-related macular degeneration (AMD) is marked by the accumulation of extracellular and intracellular lipid-rich deposits within and around the retinal pigment epithelium (RPE). Inducing autophagy, a conserved, intracellular degradative pathway, is a potential treatment strategy to prevent disease by clearing these deposits. However, mTOR inhibition, the major mechanism for inducing autophagy, disrupts core RPE functions. Here, we screened autophagy inducers that do not directly inhibit mTOR for their potential as an AMD therapeutic in primary human RPE culture. Only two out of more than thirty autophagy inducers tested reliably increased autophagy flux in RPE, emphasizing that autophagy induction mechanistically differs across distinct tissues. In contrast to mTOR inhibitors, these compounds preserved RPE health, and one inducer, the FDA-approved compound flubendazole (FLBZ), reduced the secretion of apolipoprotein that contributes to extracellular deposits termed drusen. Simultaneously, FLBZ increased production of the lipid-degradation product ß-hydroxybutyrate, which is used by photoreceptor cells as an energy source. FLBZ also reduced the accumulation of intracellular deposits, termed lipofuscin, and alleviated lipofuscin-induced cellular senescence and tight-junction disruption. FLBZ triggered compaction of lipofuscin-like granules into a potentially less toxic form. Thus, induction of RPE autophagy without direct mTOR inhibition is a promising therapeutic approach for dry AMD.

Long-term effect of gene therapy on Leber's congenital amaurosis.

BACKGROUND: Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS: We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS: Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS: Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

Risk factors for oxygen toxicity seizures in hyperbaric oxygen therapy: case reports from multiple institutions.

Oxygen toxicity seizures are a rare but recognized complication of hyperbaric oxygen (HBO2) therapy. Many patients undergoing HBO2 therapy have medical conditions or are taking medications that could contribute to seizures. Previous literature has not extensively reported on these factors in patients experiencing oxygen toxicity seizures. We conducted a chart review at several hyperbaric oxygen centers in the Milwaukee, Wisc., area to explore whether the patients who experienced seizures in the hyperbaric chamber had other medical comorbidities or were on medications which lowered their seizure threshold, thereby contributing to oxygen toxicity seizures. There were a total of seven cases of seizures in five patients. Each patient had risk factors for seizures, including hypercapnia secondary to chronic obstructive pulmonary disease, narcotic withdrawal, alcohol dependence, and antidepressant, tramadol or cephalosporin/ceftriaxone use. We hypothesize that patients who experience oxygen toxicity seizures may have other factors which contribute to the development of these seizures.

Use of integrated care delivery to improve the quality of diabetes management among African Americans.

The prevalence of type 2 diabetes is increasing, and racial disparities in that prevalence persist. Reimbursement policies do not match the innovative care delivery systems that have been developed. One key policy goal involves reimbursement for diabetes care delivered by physician and nonphysician health care professionals on the same day. Our evidence suggests that this integrated care improves outcomes among patients.

Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments.

PURPOSE: To define rod and cone function further in terms of visual cycle mechanism, the retinal phenotype resulting from Rpe65 (retinoid isomerase I) deficiency in Nrl(-)(/)(-) mice having a single class of photoreceptors resembling wild-type cones was characterized and outcomes of retinoid supplementation evaluated. METHODS: Rpe65(-)(/)(-)/Nrl(-)(/)(-) mice were generated by breeding Rpe65(-)(/)(-) and Nrl(-)(/)(-) strains. Retinal histology, protein expression, retinoid content, and electroretinographic (ERG) responses were evaluated before and after treatment with 11-cis retinal by intraperitoneal injection. Results Retinas of young Rpe65(-)(/-)/Nrl(-)(/-) mice exhibited normal lamination, but lacked intact photoreceptor outer segments at all ages examined. Rpe65, Nrl, and rhodopsin were not detected, and S-opsin and M/L-opsin levels were reduced. Retinyl esters were the only retinoids present. In contrast, Nrl(-)(/)(-) mice exhibited decreased levels of retinaldehydes and retinyl esters, and elevated levels of retinols. ERG responses were elicited from Rpe65(-)(/-)/Nrl(-)(/-) mice only at the two highest intensities over a 4-log-unit range. Significant retinal thinning and outer nuclear layer loss occurred in Rpe65(-)(/-)/Nrl(-)(/-) mice with aging. Administration of exogenous 11-cis retinal did not rescue retinal morphology or markedly improve ERG responses. CONCLUSIONS: The findings provide clarification of reported cone loss of function in Rpe65(-)(/-)/Nrl(-)(/-) mice, now showing that chromophore absence results in destabilized cone outer segments and rapid retinal degeneration. The data support the view that rod-dominant retinas do not have a cone-specific mechanism for 11-cis retinal synthesis and have potential significance for therapeutic strategies for rescue of cone-rich retinal regions affected by disease in the aging human population.

Driving improvement in patient care: lessons from Toyota.

Nurses today are attempting to do more with less while grappling with faulty error-prone systems that do not focus on patients at the point of care. This struggle occurs against a backdrop of rising national concern over the incidence of medical errors in healthcare. In an effort to create greater value with scarce resources and fix broken systems that compromise quality care, UPMC Health System is beginning to master and implement the Toyota Production System (TPS)--a method of managing people engaged in work that emphasizes frequent rapid problem solving and work redesign that has become the global archetype for productivity and performance. The authors discuss the rationale for applying TPS to healthcare and implementation of the system through the development of "learning unit" model lines and initial outcomes, such as dramatic reductions in the number of missing medications and thousands of hours and dollars saved as a result of TPS-driven changes. Tracking data further suggest that TPS, with sufficient staff preparation and involvement, has the potential for continuous, lasting, and accelerated improvement in patient care.