The First Steps of the Visual Cycle in Human Rod and Cone Photoreceptors.

Purpose: Light detection destroys the visual pigment. Its regeneration, necessary for the recovery of light sensitivity, is accomplished through the visual cycle. Release of all-trans retinal by the light-activated visual pigment and its reduction to all-trans retinol comprise the first steps of the visual cycle. In this study, we determined the kinetics of all-trans retinol formation in human rod and cone photoreceptors. Methods: Single living rod and cone photoreceptors were isolated from the retinas of human cadaver eyes (ages 21 to 90 years). Formation of all-trans retinol was measured by imaging its outer segment fluorescence (excitation, 360 nm; emission, >420 nm). The extent of conversion of released all-trans retinal to all-trans retinol was determined by measuring the fluorescence excited by 340 and 380 nm. Measurements were repeated with photoreceptors isolated from Macaca fascicularis retinas. Experiments were carried out at 37°C. Results: We found that ∼80% to 90% of all-trans retinal released by the light-activated pigment is converted to all-trans retinol, with a rate constant of 0.24 to 0.55 min-1 in human rods and ∼1.8 min-1 in human cones. In M. fascicularis rods and cones, the rate constants were 0.38 ± 0.08 min-1 and 4.0 ± 1.1 min-1, respectively. These kinetics are several times faster than those measured in other vertebrates. Interphotoreceptor retinoid-binding protein facilitated the removal of all-trans retinol from human rods. Conclusions: The first steps of the visual cycle in human photoreceptors are several times faster than in other vertebrates and in line with the rapid recovery of light sensitivity exhibited by the human visual system.

Future Trends in Presbyopia Correction.

Presbyopia affects 1.8 billion people worldwide. This reduction in distance corrected near visual acuity impacts quality of life, which prompts patients to seek treatment. Presbyopia is an early manifestation of the "crystalline lens optical dysfunction through aging," or dysfunctional lens syndrome, and appropriate management of presbyopia is dependent on coexisting factors such as increased higher order aberrations, reduced contrast sensitivity, light scatter, and lenticular opacification. This review of published literature (PubMed and MEDLINE) is presented in narrative format and discusses medical and surgical treatments available to patients who experience presbyopia, while highlighting future therapies. Numerous strategies exist for the management of presbyopia. These strategies include pharmacological therapy, glasses and contact lenses, corneal, scleral, and lenticular procedures. This article discusses the role of several new and existing presbyopia treatments, as well as which patients are candidates for these novel therapies. Although no single treatment is ideal for all patients with presbyopia, new medical and surgical strategies increase the number of options available when addressing different stages of presbyopia and dysfunctional lens syndrome. [J Refract Surg. 2021;37(6 Suppl):S28-S34.].

Autofluorescence Lifetimes Measured with Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) Are Affected by Age, but Not by Pigmentation or Gender.

Purpose: Fluorescence lifetime imaging ophthalmoscopy (FLIO) is a novel modality to investigate the human retina. This study aims to characterize the effects of age, pigmentation, and gender in FLIO. Methods: A total of 97 eyes from 97 healthy subjects (mean age 37 ± 18 years, range 9-85 years) were investigated in this study. This study included 47 (49%) females and 50 males. The pigmentation analysis was a substudy including 64 subjects aged 18 to 40 years (mean age 29 ± 6 years). These were categorized in groups A (darkly pigmented, 8), B (medium pigmented, 20), and C (lightly pigmented, 36). Subjects received Heidelberg Engineering FLIO and optical coherence tomography imaging. Retinal autofluorescence lifetimes were detected in two spectral channels (short spectral channel [SSC]: 498-560 nm; long spectral channel [LSC]: 560-720 nm), and amplitude-weighted mean fluorescence lifetimes (τm) were calculated. Additionally, autofluorescence lifetimes of melanin were measured in a cuvette. Results: Age significantly affected FLIO lifetimes, and age-related FLIO changes in the SSC start at approximately age 35 years, whereas the LSC shows a consistent prolongation with age from childhood. There were no gender- or pigmentation-specific significant differences of autofluorescence lifetimes. Conclusions: This study confirms age-effects in FLIO but shows that the two channels are affected differently. The LSC appears to show the lifelong accumulation of lipofuscin. Furthermore, it is important to know that neither gender nor pigmentation significantly affect FLIO lifetimes. Translational Relevance: This study helps to understand the FLIO technology better, which will aid in conducting future clinical studies.

Imaging of Hydroxychloroquine Toxicity with Fluorescence Lifetime Imaging Ophthalmoscopy.

PURPOSE: To investigate the impact of retinal toxicity from hydroxychloroquine (HCQ) on fundus autofluorescence lifetimes using fluorescence lifetime imaging ophthalmoscopy (FLIO). DESIGN: Cross-sectional study. PARTICIPANTS: Twenty-four eyes of 12 patients with definite HCQ toxicity, 31 eyes of 16 clinically normal patients at high risk of developing HCQ toxicity (taking HCQ longer than 5 years), and 16 eyes of 8 clinically normal patients at low risk of developing HCQ toxicity (taking HCQ fewer than 5 years), as well as 22 age-matched healthy subjects. METHODS: Fluorescence lifetime images of a 30° retinal field centered at the fovea were collected at the Moran Eye Center, Salt Lake City, Utah. A prototype Heidelberg Engineering Spectralis-based FLIO was used to detect autofluorescence lifetimes in short (SSC; 498-560 nm) and long (LSC; 560-720 nm) spectral channels. Mean fluorescence lifetimes were calculated. OCT scans and macular pigment measures were also recorded. Additionally, the autofluorescence lifetimes of HCQ were measured in a cuvette. MAIN OUTCOME MEASURES: Mean autofluorescence lifetimes (τm). RESULTS: All patients with HCQ toxicity showed significantly prolonged FLIO lifetimes in regions of damage, typically in a bulls-eye distribution corresponding to toxic lesions in the retina (SSC: lesion, 400 ps; unremarkable retina, 294 ps; P < 0.001; LSC: lesion, 404 ps; unremarkable retina, 316 ps; P < 0.001). Some clinically normal patients at high risk (9 of 16) and at low risk (2 of 8) of developing HCQ toxicity also showed prolonged FLIO lifetimes in the parafoveal region, whereas age-matched healthy subjects did not. HCQ at a concentration of 46 mM exhibited long autofluorescence lifetimes of around 1100 ps in either spectral channel. CONCLUSIONS: Fluorescence lifetime imaging ophthalmoscopy seems to detect retinal toxicity from HCQ at very early stages and could be a novel method to detect retinal toxicity before irreversible damage is manifest.

Combined flanged intrascleral intraocular lens fixation with corneal transplant.

PURPOSE: To report clinical outcomes and surgical technique of flanged intrascleral intraocular lens fixation with double-needle combined with either penetrating keratoplasty (PKP) or ultrathin Descemet-stripping automated endothelial keratoplasty (UT-DSAEK). OBSERVATIONS: Five patients underwent combined flanged intrascleral intraocular lens fixation with double-needle technique and keratoplasty. Three patients underwent triple procedure (open sky intrascleral intraocular lens fixation with double-needle and PKP) secondary to ocular trauma or a failed corneal transplant. Two patients underwent combined UT-DSAEK and intrascleral intraocular lens fixation for pseudophakic bullous keratopathy (PBK) and anterior chamber intraocular lens (AC IOL). CONCLUSION: Flanged intrascleral intraocular lens fixation with double-needle technique combined with PKP or UT-DSAEK was shown to be a safe and effective method of visual rehabilitation without additional intraoperative complications.

Prefrontal versus motor cortex transcranial direct current stimulation (tDCS) effects on post-surgical opioid use.

BACKGROUND: Pain is often a complaint that precedes total knee arthroplasty (TKA), however the procedure itself is associated with considerable post-operative pain lasting days to weeks which can predict longer-term surgical outcomes. Previously, we reported significant opioid-sparing effects of motor cortex transcranial direct current stimulation from a single-blind trial. In the present study, we used double-blind methodology to compare motor cortex tDCS and prefrontal cortex tDCS to both sham and active-control (active electrodes over non-pain modulating brain areas) tDCS. METHODS: 58 patients undergoing unilateral TKA were randomly assigned to receive 4 20-min sessions (a total of 80 min) of tDCS (2 mA) post-surgery with electrodes placed to create 4 groups: 1) MOTOR (n = 14); anode-motor/cathode-right prefrontal, 2) PREFRONTAL (n = 16); anode-left-prefrontal/cathode-right-sensory, 3) ACTIVE-CONTROL (n = 15); anode-left-temporal-occipital junction/cathode-medial-anterior-premotor-area, and 4) SHAM (n = 13); 0 mA-current stimulation using placements 1 or 2. Patient controlled analgesia (PCA; hydromorphone) use was tracked during the ∼72-h post-surgery. RESULTS: Patients in the sham group and the active-control group used 15.4 mg (SD = 14.1) and 16.0 mg (SD = 9.7) of PCA hydromorphone respectively. There was no difference between the slopes of the cumulative PCA usage curves between these two groups (p = 0.25; ns). Patients in the prefrontal tDCS group used an average of 11.7 mg (SD = 5.0) of PCA hydromporhone, and the slope of the cumulative PCA usage curve was significantly lower than sham (p < 0.0001). However, patients in the motor tDCS group used an average of 19.6 mg (SD = 11.9) hydromorphone and the slope of the PCA use curve was significantly higher than sham (p < 0.0001). CONCLUSIONS: Results from this double-blind cortical-target-optimization study suggest that anodal transcranial direct current stimulation (tDCS) over the left prefrontal cortex may be a reasonable approach to reducing post-TKA opioid requirements. Given the unexpected finding that motor cortex failed to produce an opioid sparing effect in this follow-up trial, further research in the area of post-operative cortical stimulation is still needed.

Brain Default Mode Network Changes after Renal Transplantation: A Diffusion-Tensor Imaging and Resting-State Functional MR Imaging Study.

PURPOSE: To investigate structural and functional alterations of the default mode network (DMN) in the brain after renal transplantation in patients with end-stage renal disease by using diffusion-tensor imaging and resting-state functional MR imaging. MATERIALS AND METHODS: This prospective study was approved by the local medical research ethics committee, and written informed consent was obtained. Twenty-one patients with end-stage renal disease (15 men, six women; mean age ± standard deviation, 32 years ± 9.5) who were scheduled to undergo renal transplantation and 21 healthy control subjects (15 men, six women; mean age, 31 years ± 6.5) were included. Diffusion-tensor imaging and resting-state functional MR imaging were performed in all subjects. Patients were imaged both before and 1 month after renal transplantation. Structural (mean diffusivity, fractional anisotropy, path length, and number of tracts derived from diffusion-tensor imaging tractography) and functional (temporal correlation coefficient derived from resting-state functional MR imaging) connectivity of the DMN were quantitatively compared with two-sample t tests or paired t tests. Intergroup correlation analysis was performed to compare structural or functional indexes and results of neuropsychological or blood biochemistry tests. RESULTS: Mean diffusivity was decreased in the fiber bundles connecting the posterior cingulate cortex and the precuneus to the bilateral inferior parietal lobules in patients after renal transplantation compared with that in patients before transplantation (P < .05). Temporal correlation coefficients for patients after renal transplantation nearly reached the levels of those for control subjects (all, P > .05). The change in mean diffusivity of the fiber bundles connecting the posterior cingulate cortex and the precuneus to the right inferior parietal lobule positively correlated with the change in hematocrit levels (r = 0.522, P = .015), the change in temporal correlation coefficients between the posterior cingulate cortex or precuneus and left or right inferior parietal lobules correlated with changes in number connection test type A scores (r = -0.549, P = .010) and digit symbol test scores (r = 0.533, P = .013). CONCLUSION: Functional connectivity changes in the DMN, which were associated with improved hematocrit levels and cognitive function, may recover earlier than structural connectivity changes do 1 month after renal transplantation.

Topological Reorganization of the Default Mode Network in Irritable Bowel Syndrome.

The aim of this study was to investigate the topological reorganization of the brain default mode network (DMN) in patients with irritable bowel syndrome (IBS) using resting-state functional magnetic resonance imaging (rs-fMRI). With approval by our ethics committee, rs-fMRI was prospectively performed in 31 IBS patients (25 male, 27 ± 8 years) and 32 healthy controls (25 male, 29 ± 9 years). The DMN was determined by unbiased seed-based functional connectivity (FC) analysis and then parcellated into several subregions. FC across all pairs of DMN subregions was computed to construct the DMN architecture, for which topological properties were characterized by graph theoretical approaches. Pearson correlation was performed between abnormal DMN inter-regional FC and network measures and clinical indices in IBS patients. Compared to healthy controls, IBS patients showed decreased DMN inter-regional FC between the anterior cingulate cortex and precuneus, the medial orbital of the superior frontal gyrus (ORBsupmed) and precuneus, and the middle temporal gyrus and precuneus. IBS patients also showed decreased DMN global efficiency (E glob). Inclusion of anxiety and depression as covariates abolished FC between ORBsupmed and precuneus and some E glob differences. The average DMN FC was positively correlated with average E glob (r = 0.47, P = 0.008) and negatively correlated with symptom severity score (r = -0.37, P = 0.04) in IBS patients. In conclusion, IBS patients showed topological reorganization of the DMN to a non-optimized regularity configuration, which may partly be ascribed to high levels of anxiety and depression.

Radiation dose and image quality of 70 kVp cerebral CT angiography with optimized sinogram-affirmed iterative reconstruction: comparison with 120 kVp cerebral CT angiography.

OBJECTIVES: To evaluate radiation dose, image quality, and optimal level of sinogram-affirmed iterative reconstruction (SAFIRE) of cerebral CT angiography (CTA) at 70 kVp. METHODS: One hundred patients were prospectively classified into two groups: Group A (n = 50), 70 kVp cerebral CTA with 5 levels of SAFIRE reconstruction (S1-S5); and Group B (n = 50), 120 kVp with filtered back projection (FBP) reconstruction. CT attenuation values, noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the internal carotid artery (ICA) and middle cerebral artery (MCA) were measured. Subjective image quality was evaluated. Effective dose (ED) was estimated. RESULTS: CT attenuation and noise of the ICA and MCA in Group A were higher than those of Group B (all P < 0.001) while the SNRICA, SNRMCA, CNRICA, and CNRMCA of Group A at S4-5 were comparable to (P > 0.05) or higher than in Group B (P < 0.05). There was no difference in overall image quality between Group A S3-5 and Group B (P > 0.05). ED was 0.2 ± 0.0 mSv for Group A with 85 % ED reduction in comparison to Group B (1.3 ± 0.2 mSv). CONCLUSION: Cerebral CTA at 70 kVp is feasible, allowing for substantial radiation dose reduction. SAFIRE S4 level is recommended for obtaining optimal image quality. KEY POINTS: • 70 kVp cerebral CTA is feasible and provides diagnostic image quality. • 70 kVp cerebral CTA resulted in 85% effective dose reduction. • S4 level of SAFIRE is recommended for 70 kVp cerebral CTA.