Manoli I, Sysol JR, Epping MW, Li L, Wang C, Sloan JL, Pass A, Gagné J, Ktena YP, Li L, Trivedi NS, Ouattara B, Zerfas PM, Hoffmann V, Abu-Asab M, Tsokos MG, Kleiner DE, Garone C, Cusmano-Ozog K, Enns GM, Vernon HJ, Andersson HC, Grunewald S, Elkahloun AG, Girard CL, Schnermann J, DiMauro S, Andres-Mateos E, Vandenberghe LH, Chandler RJ, Venditti CP.
FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI Insight 2018;3(23)
AbstractMethylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
Margeta MA, Lad EM, Proia AD.
CD163+ macrophages infiltrate axon bundles of postmortem optic nerves with glaucoma. Graefes Arch Clin Exp Ophthalmol 2018;256(12):2449-2456.
AbstractPURPOSE: Prior research in animal models has shown that macrophages and microglia play an important role in pathogenesis of glaucoma, but the phenotype and distribution of macrophages in human glaucomatous tissue have not been sufficiently characterized. METHODS: We analyzed H&E, CD68-, and CD163-immunostained slides from 25 formaldehyde-fixed, paraffin-embedded autopsy eyes: 12 control eyes and 13 eyes with glaucoma. The diagnosis of glaucoma was made based on a history of glaucoma as reported in the medical record and histological changes characteristic of glaucoma. Glaucoma cases and controls were matched in terms of age, sex, and race. RESULTS: Qualitative analysis of the conventional outflow pathway and the optic nerve revealed that all eyes contained CD163+ cells but a negligible number of CD68+ cells. CD163+ macrophages infiltrated the trabecular meshwork and surrounded Schlemm's canal of normal eyes and eyes with glaucoma, but the pattern was variable and qualitatively similar between groups. In optic nerves of control eyes, CD163+ macrophages were present at low levels and restricted to septa between axon bundles. In glaucomatous optic nerves, the number of CD163+ cells was increased both qualitatively and quantitatively (glaucoma 5.1 ± 0.6 CD163+ cells/mm, control 2.5 ± 0.3 CD163+ cells/mm, p < 0.001), with CD163+ cells infiltrating axon bundles in cases of both mild and severe diseases. CONCLUSIONS: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.
Momtazi L, Dartt DA, Nilsen O, Eidet JR.
Molecular layer deposition builds biocompatible substrates for epithelial cells. J Biomed Mater Res A 2018;106(12):3090-3098.
AbstractThe demand for novel biocompatible materials as surface coating in the field of regenerative medicine is high. We explored molecular layer deposition (MLD) technique for building surface coatings and introduced a new group of substrates consisting of amino acids, or nucleobases, and the biocompatible metal titanium. The substrates were built from titanium tetraisopropoxide (TTIP) with l-lysine, glycine, l-aspartic acid, l-arginine, thymine, uracil, and adenine. Substrates based on zirconium chloride and terephthalic acid were also included. Titanium oxide (TiO ) substrates made by atomic layer deposition and uncoated cover slips served as controls. Rat conjunctival epithelial goblet cells were grown in RPMI 1640 and RT-PCR, immunofluorescence, cell attachment, proliferation, and viability were analyzed. Cells cultured on MLD and uncoated substrates were proliferating (positive for Ki67). Cell attachment after 3 h of culture on MLD substrates was similar to uncoated coverslips (p > 0.05). Compared to uncoated coverslips, cell proliferation assayed with alamarBlue® after 4 days was significantly higher on all MLD substrates (p < 0.05), whereas terephthalic acid-containing MLD substrates reduced proliferation (p < 0.01). Viability assessed by LIVE/DEAD® was high (>85%) for all substrates after 5 days. The novel MLD technique is promising for building biocompatible substrates that direct epithelial cell growth. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3090-3098, 2018.
Moustafa GA, Borkar DS, McKay MK, Eton EA, Koulisis N, Lorch AC, Kloek CE, Kloek CE.
Outcomes in resident-performed cataract surgeries with iris challenges: Results from the Perioperative Care for Intraocular Lens study. J Cataract Refract Surg 2018;44(12):1469-1477.
AbstractPURPOSE: To assess the outcomes of resident-performed cataract surgeries with iris challenges and to compare these outcomes with similar surgeries performed by attending surgeons. SETTING: Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. DESIGN: Retrospective chart review. METHODS: All cases of cataract extraction by phacoemulsification with intraocular lens implantation, performed by comprehensive ophthalmologists between January 1 and December 31, 2014, were reviewed. Cases with preoperative or intraoperative miosis, iris prolapse, and intraoperative floppy iris syndrome, were included for analysis. Visual outcomes and the rate of perioperative adverse events were compared between resident and attending surgeon cases. Factors predicting adverse events were also assessed. RESULTS: In total, 1931 eye cases of 1434 patients were reviewed, and 65 resident cases and 168 attending surgeon cases were included. The mean logarithm of the minimum angle of resolution corrected distance visual acuity was better in the resident group 1 month after surgery (0.051 ± 0.10 [SD] versus 0.132 ± 0.30, P = .03); however, the difference was eliminated when controlling for macular disease. The mean operative time was 43.8 ± 26.5 minutes and 30.9 ± 12.6 minutes for cases performed by resident surgeons and attending surgeons, respectively (P .0001). Residents utilized supplemental pharmacologic dilation or retraction more frequently than attending surgeons (98% versus 87% of cases, P = .008). The overall rate of adverse events was no different between residents and attending surgeons (P = 0.16). Dense nuclear sclerosis predicted adverse events in cataract cases with iris challenges (adjusted odds ratio, 1.86; 95% confidence interval, 1.17-2.94; P = .001). CONCLUSION: Although requiring longer operative times and more surgical manipulation, residents who performed cataract surgeries with iris challenges achieved outcomes comparable to those performed by attending surgeons, and residents should be given the opportunity to operate on these eyes.