Fatty acid binding protein 5 inhibition attenuates pronociceptive cytokine/chemokine expression and suppresses osteoarthritis pain: A comparative human and rat study.

OBJECTIVE: Osteoarthritis (OA) is often accompanied by debilitating pain that is refractory to available analgesics due in part to the complexity of signaling molecules that drive OA pain and our inability to target these in parallel. Fatty acid binding protein 5 (FABP5) is a lipid chaperone that regulates inflammatory pain; however, its contribution to OA pain has not been characterized. DESIGN: This combined clinical and pre-clinical study utilized synovial tissues obtained from subjects with end-stage OA and rats with monoiodoacetate-induced OA. Cytokine and chemokine release from human synovia incubated with a selective FABP5 inhibitor was profiled with cytokine arrays and ELISA. Immunohistochemical analyses were conducted for FABP5 in human and rat synovium. The efficacy of FABP5 inhibitors on pain was assessed in OA rats using incapacitance as an outcome. RNA-seq was then performed to characterize the transcriptomic landscape of synovial gene expression in OA rats treated with FABP5 inhibitor or vehicle. RESULTS: FABP5 was expressed in human synovium and FABP5 inhibition reduced the secretion of pronociceptive cytokines (interleukin-6 [IL6], IL8) and chemokines (CCL2, CXCL1). In rats, FABP5 was upregulated in the OA synovium and its inhibition alleviated incapacitance. The transcriptome of the rat OA synovium exhibited >6000 differentially expressed genes, including the upregulation of numerous pronociceptive cytokines and chemokines. FABP5 inhibition blunted the upregulation of the majority of these pronociceptive mediators. CONCLUSIONS: FABP5 is expressed in the OA synovium and its inhibition suppresses pronociceptive signaling and pain, indicating that FABP5 inhibitors may constitute a novel class of analgesics to treat OA.

Acute postoperative pain and dorsal root ganglia transcriptomic signatures following total knee arthroplasty (TKA) in rats: An experimental study.

Total knee arthroplasty (TKA) is the final treatment option for patients with advanced knee osteoarthritis (OA). Unfortunately, TKA surgery is accompanied by acute postoperative pain that is more severe than arthroplasty performed in other joints. Elucidating the molecular mechanisms specific to post-TKA pain necessitates an animal model that replicates clinical TKA procedures, induces acute postoperative pain, and leads to complete functional recovery. Here, we present a new preclinical TKA model in rats and report on functional and behavioral outcomes indicative of pain, analgesic efficacy, serum cytokine levels, and dorsal root ganglia (DRG) transcriptomes during the acute postoperative period. Following TKA, rats exhibited marked deficits in weight bearing that persisted for 28 days. Home cage locomotion, rearing, and gait were similarly impacted and recovered by day 14. Cytokine levels were elevated on postoperative days one and/or two. Treatment with morphine, ketorolac, or their combination improved weight bearing while gabapentin lacked efficacy. When TKA was performed in rats with OA, similar functional deficits and comparable recovery time courses were observed. Analysis of DRG transcriptomes revealed upregulation of transcripts linked to multiple molecular pathways including inflammation, MAPK signaling, and cytokine signaling and production. In summary, we developed a clinically relevant rat TKA model characterized by resolution of pain and functional recovery within five weeks and with pain-associated behavioral deficits that are partially alleviated by clinically administered analgesics, mirroring the postoperative experience of TKA patients.

Successful long-term treatment of paraneoplastic optic neuropathy with mycophenolate mofetil, prednisone, and plasmapheresis.

PURPOSE: To report long-term follow-up of a case of paraneoplastic optic neuropathy (PON) successfully treated with combination therapy. OBSERVATIONS: We present a confirmed case of PON from cutaneous melanoma with nearly six years of meticulous follow-up in which vision was preserved and disease remission was successfully induced with combination mycophenolate mofetil, prednisone, and plasmapheresis therapy. CONCLUSIONS AND IMPORTANCE: Treatment of PON and long-term follow-up are not well described in the literature. In our case of PON, vision was preserved and disease remission was achieved with mycophenolate mofetil, prednisone, and plasmapheresis. Such information may be useful for future cases of PON.

CONCURRENT SCLERAL BUCKLE AND INTRAVITREAL BEVACIZUMAB FOR ADVANCED RETINOPATHY OF PREMATURITY-RELATED RETINAL DETACHMENT.

BACKGROUND: The preoperative use of intravitreal bevacizumab in Stage 4 or 5 retinopathy of prematurity (ROP) can reduce vascular endothelial growth factor load and bleeding risk; however, it can induce traction and exacerbate a tractional retinal detachment. Concurrent placement of a scleral buckle may reduce these risks and obviate future vitrectomy. METHODS: A retrospective analysis of eyes treated for Stage 4 and 5 ROP with concurrent intravitreal bevacizumab and scleral buckle was performed. Retinal reattachment and need for vitrectomy were studied. RESULTS: Thirteen eyes from 10 infants were treated with concurrent intravitreal bevacizumab and scleral buckle. Nine eyes were Stage 4a, 2 were Stage 4b, and 2 were Stage 5. All eyes with Stage 4 ROP achieved macular attachment at last follow-up. All the eyes with 4a ROP achieved retinal reattachment: 4 (44.4%) with buckle alone and 5 (55.6%) with subsequent vitrectomy. All 4 eyes with Stage 4b or 5 ROP required vitrectomy. CONCLUSION: Concurrent intravitreal bevacizumab and scleral buckle may serve as a bridge to vitrectomy and, in some instances, may obviate the need for subsequent intervention.

Two-Year Anatomical and Functional Outcomes After Macular Hole Surgery: A Prospective, Controlled Study.

BACKGROUND AND OBJECTIVE: To determine 2-year anatomical and functional outcomes after macular hole (MH) surgery. PATIENTS AND METHODS: The surgical eye (SE) and fellow eye (FE) of 10 patients undergoing MH surgery were examined preoperatively and at 3, 12, and 24 months postoperatively. Retinal nerve fiber layer (RNFL), external limiting membrane (ELM), inner segment/outer segment (IS/OS) junction, cone outer-segment tips (COST) line, and ganglion cell inner plexiform layer (GCIPL) thickness were analyzed on spectral-domain optical coherence tomography. RESULTS: Inferior peripapillary RNFL was thinner in the SE at 110 ± 12.2 versus 123 ± 9.82 for FE (P < .05). Defect size in ELM (r = 0.61; P < .001), IS/ OS (r = 0.67; P < .001) junction, and COST (r = .67; P < .001) line correlated with visual recovery. Average GCIPL was thinner in SE compared to FE (P < .05). CONCLUSION: Eyes after MH repair demonstrated inferior RNFL and GCIPL thinning. Defect size in ELM, IS/OS junction, and COST line predicted visual recovery.

Evaluation of microsurgical tasks with OCT-guided and/or robot-assisted ophthalmic forceps.

Real-time intraocular optical coherence tomography (OCT) visualization of tissues with surgical feedback can enhance retinal surgery. An intraocular 23-gauge B-mode forward-imaging co-planar OCT-forceps, coupling connectors and algorithms were developed to form a unique ophthalmic surgical robotic system. Approach to the surface of a phantom or goat retina by a manual or robotic-controlled forceps, with and without real-time OCT guidance, was performed. Efficiency of lifting phantom membranes was examined. Placing the co-planar OCT imaging probe internal to the surgical tool reduced instrument shadowing and permitted constant tracking. Robotic assistance together with real-time OCT feedback improved depth perception accuracy. The first-generation integrated OCT-forceps was capable of peeling membrane phantoms despite smooth tips.

Prospective Retinal and Optic Nerve Vitrectomy Evaluation (PROVE) study: twelve-month findings.

PURPOSE: To report 1-year outcomes of the Prospective Retinal and Optic Nerve Vitrectomy Evaluation study. DESIGN: Prospective, controlled, observational study. PARTICIPANTS: Eighty eyes of 40 participants undergoing pars plana vitrectomy for epiretinal membrane (ERM), macular hole (MH), or vitreous opacities. METHODS: Enrolled participants underwent baseline evaluation of the study (surgical) and fellow (control) eyes by a masked fellowship-trained glaucoma specialist; evaluation included intraocular pressure (IOP; Goldmann applanation and Tono-Pen), central corneal thickness, gonioscopy, and cup-to-disc ratio measurement. Baseline testing included bilateral color fundus and optic disc photography, fundus autofluorescence, automated perimetry, and optical coherence tomography (OCT) of the macula and optic nerve. Evaluations were repeated at 3 months and 1 year after surgery. MAIN OUTCOME MEASURES: The primary outcome measure was changes in peripapillary retinal nerve fiber layer (pRNFL) thickness. Secondary outcomes included changes in macular thickness and IOP. RESULTS: Thirty-eight of 40 patients completed 1 year of follow-up. Mean visual acuity (VA) improved in study eyes from baseline (P = 0.003) but remained worse than fellow eyes (P<0.001). Study eyes had thinner inferior pRNFL thickness (114±16.8 µm) compared with fellow eyes (123±14.7 µm; P = 0.004). Mean IOP difference between study eyes and fellow eyes increased from baseline to 1 year. At 1 year, MH study eyes had higher mean IOP (16.0±3.7 mmHg) compared with fellow eyes (14.8±3.4 mmHg; P = 0.08). Mean IOP for pseudophakic study eyes increased from 14.5±3.2 mmHg at baseline to 16.0±2.8 mmHg at 1 year (P = 0.04). Central subfield thickness (CST) and cube volume decreased in study eyes at 1 year but remained greater than that of fellow eyes (P<0.05). Reduction in CST from baseline correlated with degree of VA improvement (P<0.05). Mean deviation (MD) improved in ERM study eyes at 1 year when compared with baseline (-2.2 vs. -4.0; P = 0.02) but remained worse than fellow eyes (-1.2; P = 0.002). CONCLUSIONS: One year after vitrectomy, VA, CST, and MD improved in study eyes but not to the level of fellow eyes. Inferior pRNFL thickness decreased in study eyes. Reduction in CST from baseline correlated with degree of VA improvement. Pseudophakic study eyes demonstrated increased IOP when compared with baseline.

Ocular findings at initial pan retinal photocoagulation for proliferative diabetic retinopathy predict the need for future pars plana vitrectomy.

PURPOSE: To determine the 1-year and 2-year likelihood of vitrectomy in diabetic patients undergoing initial pan retinal photocoagulation (PRP). METHODS: Diabetic eyes receiving initial PRP for proliferative diabetic retinopathy (PDR) were analyzed to determine their risk for vitrectomy based on clinical findings. RESULTS: In total, 374 eyes of 272 patients were analyzed. The percentage of eyes undergoing vitrectomy 1 year and 2 years following initial PRP was 19.1% and 26.2%, respectively. Of the eyes in Group 1 (PDR alone), Group 2 (PDR and vitreous hemorrhage), and Group 3 (PDR and iris neovascularization, vitreous hemorrhage with traction or fibrosis, or fibrosis alone), the percentage receiving pars plana vitrectomy at 1 year and 2 years was 9.73% (18/185) and 15.7% (29/185), 26.9% (43/160) and 34.4% (55/160), and 37.9% (11/29) and 48.3% (14/29), respectively. Eyes in Group 2 had 2.78 times greater likelihood (P < 0.0001) and eyes in Group 3 had 3.54 times higher likelihood (P < 0.0001) of requiring pars plana vitrectomy within 2 years than those with PDR alone. CONCLUSION: Eyes receiving PRP for PDR with associated hemorrhage or traction were more likely to undergo pars plana vitrectomy within 1 year and 2 years following initial PRP compared with eyes with only PDR, providing important prognostic information for PRP-naive patients.

Peripapillary retinal nerve fiber layer thickness in sickle-cell hemoglobinopathies using spectral-domain optical coherence tomography.

PURPOSE: To determine whether patients with a sickle-cell hemoglobinopathy without glaucoma have peripapillary retinal nerve fiber layer (RNFL) thinning by spectral-domain optical coherence tomography. DESIGN: Prospective study. METHODS: All patients with a sickle cell hemoglobinopathy (sickle-cell disease, sickle-cell hemoglobin C disease, and sickle-cell thalassemia) and age-similar, race-matched controls underwent a comprehensive eye examination and spectral-domain optical coherence tomography of the macula and optic nerve head using the Heidelberg Spectralis (Heidelberg Engineering, Inc, Carlsbad, California, USA). Participants with prior retinal treatments (laser or surgery), diabetes mellitus, glaucoma, or other ocular diseases were excluded. The sickle-cell disease patients were grouped into those with focal macular thinning and those without. Those with macular thinning were grouped further into mild, moderate, and severe thinning groups based on temporal macular thickness. Analysis of variance testing and post hoc analysis with the Tukey test and Pearson correlation were performed to assess for peripapillary RNFL thickness differences among different groups. RESULTS: One hundred fifty-one eyes of 88 sickle-cell patients and 55 eyes of 30 age-similar and race-matched (black) controls were included. Sickle-cell patient eyes with macular thinning (n = 81) had thinner mean peripapillary RNFL thicknesses in the nasal sector (P = .01) compared with non-sickle-cell control eyes and in the superotemporal sector (P = .01) compared with sickle-cell patient eyes without macular thinning (n = 70). In the severe macular thinning subgroup (n = 55), the mean peripapillary RNFL thickness was significantly thinner than that of controls (P < .05) in 6 of 7 sectors. There is a positive linear relationship between temporal macular thickness and global peripapillary RNFL thickness with a Pearson correlation coefficient of 0.60 (P < .0001). CONCLUSIONS: Nonglaucomatous, black sickle-cell patients with focal macular thinning on spectral-domain optical coherence tomography have significantly thinner peripapillary RNFL than those without macular thinning or controls. The degree of thinning correlates with severity of temporal macular thinning. These patients may require different peripapillary RNFL thickness thresholds for future glaucoma evaluations.

Purtscher-like retinopathy in association with metastatic pancreatic adenocarcinoma and capecitabine therapy.

PURPOSE: To report a case of Purtscher-like retinopathy in association with capecitabine chemotherapy for metastatic pancreatic adenocarcinoma. METHODS: Case report. RESULTS: Bilateral retinal hemorrhages and cotton-wool spots in a predominantly juxtapapillary distribution were observed coincident with decreased vision. There was gradual improvement of the retinopathy and patient's vision over several months until the time of death. CONCLUSION: Metastatic pancreatic cancer and capecitabine, a fluoropyrimidine chemotherapeutic agent, are a rare cause of Purtscher-like retinopathy.

Thirty-Year follow-up of an African American family with macular dystrophy of the retina, locus 1 (North Carolina macular dystrophy).

PURPOSE: To describe clinical characteristics, including visual acuity (VA), genetic analysis, and management of complications, over a 30-year period in an African American family with macular dystrophy of the retina, locus 1 (MCDR1), commonly referred to as "North Carolina macular dystrophy." DESIGN: Observational, cohort study. PARTICIPANTS: Twelve family members from a 4-generation pedigree. METHODS: A total of 12 African American patients in an affected family were examined. Clinical examination was documented during 2 different follow-up periods from 1979 to 1982 in 10 patients and from 2005 to 2009 in 11 patients. Genetic analysis was performed in 4 affected members during this time. Foveal microperimetry, fundus autofluorescence, and spectral domain optical coherence tomography (OCT) data were also obtained. MAIN OUTCOME MEASURES: Change in VA of 8 members followed over 3 decades and clinical data and management of complications for all patients. RESULTS: Nine of 11 living family members had classic findings ranging from disease grade 2 (confluent foveal drusen, 8 eyes) to grade 3 (central coloboma-like lesion, 10 eyes). Two members developed choroidal neovascularization (CNV) requiring laser ablation, and 1 member developed non-clearing vitreous hemorrhage and underwent 25-gauge pars plana vitrectomy. Another family member developed exotropia and amblyopia in 1 eye by age 7 years. Those without CNV had no significant change in VA over 30 years. Linkage studies of 4 affected family members showed the same short tandem repeats on markers spanning D6S249 and D6S283 within the MCDR1 region of chromosome 6q16. Microperimetry analysis of an affected member with grade 3 MCDR1 revealed absent function in the region of the central coloboma-like lesions, corresponding to photoreceptor absence on OCT, although there were preserved foveal function and intact photoreceptors adjacent to the lesion. CONCLUSIONS: This African American family shares similar clinical findings as other MCDR1 pedigrees and the same haplotype as the originally described family from North Carolina. Clinical characteristics, including retinal features and stable VA in the absence of amblyopia and CNV, are similar to those in other reports. Eccentric viewing around impaired photoreceptors may explain good VA in patients with clinically severe-appearing macular lesions. Sequencing of the MCDR1 interval may help identify a protein responsible for early macular development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Endoscopic free electron laser technique development for minimally invasive optic nerve sheath fenestration.

PURPOSE: This study proposed to develop a technique for efficiently accessing the posterior orbital space using endoscopy and attempted application of free electron laser (FEL) energy, biopsy forceps, electrocautery, and CO(2) insufflation to posterior orbital tissues. METHODS: Through an inferior transconjunctival incision, access to the posterior orbital space was attempted in 14 eyes of 7 non-survival pigs. FEL energy (6.1 microm, 30 Hz, delivered via 250 microm hollow-glass waveguide), biopsy forceps, and monopolar electrocautery application were endoscopically attempted in the posterior orbit. CO(2) gas insufflation effects were assessed by analyzing arterial blood gases at 30-minute intervals for 1.5 hours. RESULTS: The posterior orbit was accessed in 13 of 14 eyes, the optic nerve was encountered, and FEL energy was applied in 8 of 14 eyes. Use of biopsy forceps and electrocautery were successful. Although ANOVA results for arterial blood gas changes were not statistically significant, visibility was adequate without CO(2) insufflation. CONCLUSIONS: The posterior orbit was endoscopically accessed and the optic nerve was exposed and successfully treated with FEL energy. CO(2) insufflation did not alter blood gases, but did not further enhance visibility in this study.

Optic nerve sheath fenestration with endoscopic accessory instruments versus the free electron laser (FEL).

BACKGROUND AND OBJECTIVE: The free electron laser (FEL) can efficiently produce an optic nerve sheath fenestration using an endoscopic approach. To develop a surgical protocol, this study compared effectiveness of available accessory endoscopic instruments to endoscopic FEL delivery effectiveness in producing optic nerve sheath fenestrations. STUDY DESIGN/MATERIALS AND METHODS: An endoscope was used to perform optic nerve sheath fenestrations on goat optic nerves. Accessory endoscopic instruments and glass-hollow waveguides (250 and 320 microm in diameter) were inserted into the instrument channel for comparison. FEL energy (6.45 microm, 30 Hz) was delivered to the tissue through the waveguides and histological analysis was performed. RESULTS: The endoscopic instruments alone were unable to incise the optic nerve sheath. The FEL successfully incised the sheath and the biopsy forceps extricated the circular flap. CONCLUSIONS: Endoscopic optic nerve sheath fenestration using FEL energy followed by biopsy forceps for sheath extrication produced good results, thereby creating a feasible protocol for optic nerve sheath fenestration.

In vitro assessment of image-guided otologic surgery: submillimeter accuracy within the region of the temporal bone.

OBJECTIVES: Application of image-guided surgery to otology has been limited by the need for submillimeter accuracy via a fiducial system that is easily usable (noninvasive and nonobstructive). METHODS: A dental bite-block was fitted with a rigid frame with 7 fiducial markers surrounding each external ear. The temporal bones of 3 cadaveric skulls were removed and replaced with surgical targets arranged in a bull's-eye pattern about the centroid of each temporal bone. The surgical targets were identified both within CT scans and in physical space using an infrared optical tracking system. The difference between positions in CT space versus physical space was calculated as target registration error. RESULTS: A total of 234 independent target registration errors were calculated. Mean +/- standard deviation = 0.73 mm +/- 0.25 mm. CONCLUSIONS: These findings show that image-guided otologic surgery with submillimeter accuracy is achievable with a minimally invasive fiducial frame. Significance In vivo validation of the system is ongoing. With such validation, this system may facilitate clinically applicable image-guided otologic surgery. EBM RATING: A.

Submillimetric target-registration error using a novel, non-invasive fiducial system for image-guided otologic surgery.

OBJECTIVE: Otologic surgery is undertaken to treat ailments of the ear, including persistent infections, hearing loss, vertigo, and cancer. Typically performed on otherwise-healthy patients in outpatient facilities, the application of image-guided surgery (IGS) has been limited because accurate (<1 mm), non-invasive fiducial systems for otologic surgery have not been available. We now present such a fiducial system. METHODS: A dental bite-block was fitted with a custom-designed rigid frame with 7 fiducial markers surrounding each external ear. The bones containing the ear (i.e., the temporal bones) of 3 cadaveric skulls were removed and replaced with discs containing 13 surgical targets arranged in a cross-hair pattern about the centroid of each ear. The surgical targets (26/skull) and fiducial markers (14/skull) were identified both within CT scans using a published algorithm and in physical space using an infrared optical tracking system. Fiducial registration error (FRE), fiducial localization error (FLE), and target registration error (TRE) were calculated. RESULTS: For all trials, root mean square FRE = 0.66, FLE = 0.72, and TRE = 0.77 mm. The mean TRE for n = 234 independent targets was 0.73 with a standard deviation of 0.25 mm. CONCLUSIONS: Using a novel, non-invasive fiducial system (the EarMark), submillimetric accuracy was repeatably achieved. This system will facilitate image-guided otologic surgery.