Retinal Detachment Model in Rodents by Subretinal Injection of Sodium Hyaluronate

Subretinal injection of sodium hyaluronate is a widely accepted method of inducing retinal detachment (RD)1-15. However, the height and duration of RD or the occurrence of subretinal hemorrhage can affect photoreceptor cell death in the detached retina16-21. Hence, it is advantageous to create reproducible RDs without subretinal hemorrhage for evaluating photoreceptor cell death. We modified a previously reported method to create bullous and persistent RDs in a reproducible location with rare occurrence of subretinal hemorrhage. The critical step of this modified method is the creation of a self-sealing scleral incision, which can prevent leakage of sodium hyaluronate after injection into the subretinal space. To make the self-sealing scleral incision, a scleral tunnel is created, followed by scleral penetration into the choroid with a 30 G needle. Although choroidal hemorrhage may occur during this step, astriction with a surgical spear reduces the rate of choroidal hemorrhage. This method allows a more reproducible and reliable model of photoreceptor death in diseases that involve RD such as rhegmatogenous RD, retinopathy of prematurity, diabetic retinopathy, central serous chorioretinopathy, and age-related macular degeneration (AMD)

Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey

Background Clozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men. Methods We investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness. Results Mean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27–0.79) mg/L] compared with men [0.44 (0.26–0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0–45.3)] for females compared with 32.5 (25.2–41.0) for males. Overall, BMI increased by 0.7 kg/m 2 over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose ≤6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (χ2  = 18.6, p < 0.0001). Conclusions We have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism

Modeling kicks from the merger of generic black-hole binaries

Recent numerical relativistic results demonstrate that the merger of comparable-mass spinning black holes has a maximum ``recoil kick'' of up to \sim 4000 \kms. However the scaling of these recoil velocities with mass ratio is poorly understood. We present new runs showing that the maximum possible kick perpendicular to the orbital plane does not scale as $\sim\eta^2$ (where $\eta$ is the symmetric mass ratio), as previously proposed, but is more consistent with $\sim\eta^3$, at least for systems with low orbital precession. We discuss the effect of this dependence on galactic ejection scenarios and retention of intermediate-mass black holes in globular clusters.Comment: 5 pages, 1 figure, 3 tables. Version published in Astrophys. J. Let

Advances in Age-related Macular Degeneration Understanding and Therapy

While the development of anti-vascular endothelial growth factor (anti-VEGF) as a therapy for neovascular age-related macular degeneration (AMD) was a great success, the pathologic processes underlying dry AMD that eventually leads to photoreceptor dysfunction, death, and vision loss remain elusive to date, with a lack of effective therapies and increasing prevalence of the disease. There is an overwhelming need to improve the classification system of AMD, to increase our understanding of cell death mechanisms involved in both neovascular and non-neovascular AMD, and to develop better biomarkers and clinical endpoints to eventually be able to identify better therapeutic targets—especially early in the disease process. There is no doubt that it is a matter of time before progress will be made and better therapies will be developed for non-neovascular AMD

Getting a kick out of numerical relativity

Recent developments in numerical relativity have made it possible to follow reliably the coalescence of two black holes from near the innermost stable circular orbit to final ringdown. This opens up a wide variety of exciting astrophysical applications of these simulations. Chief among these is the net kick received when two unequal mass or spinning black holes merge. The magnitude of this kick has bearing on the production and growth of supermassive black holes during the epoch of structure formation, and on the retention of black holes in stellar clusters. Here we report the first accurate numerical calculation of this kick, for two nonspinning black holes in a 1.5:1 mass ratio, which is expected based on analytic considerations to give a significant fraction of the maximum possible recoil. We have performed multiple runs with different initial separations, orbital angular momenta, resolutions, extraction radii, and gauges. The full range of our kick speeds is 86--116 km s$^{-1}$, and the most reliable runs give kicks between 86 and 97 km s$^{-1}$. This is intermediate between the estimates from two recent post-Newtonian analyses and suggests that at redshifts $z\gtrsim 10$, halos with masses $\lesssim 10^9 M_\odot$ will have difficulty retaining coalesced black holes after major mergers.Comment: Updated. Accepted by ApJ Letter

Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis

Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspase-dependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders

Intercalibration of four spectrofluorometric protocols for measuring RNA/DNA ratios in larval and juvenile fish

The ratio of tissue RNA to DNA (R/D) is a widely used index of recent growth and nutritional condition in larval and juvenile fish. To date, however, no standard technique for measuring nucleic acids has been adopted. Because methodological details can affect the estimate of R/D, researchers using different analytical protocols have been unable to compare ratios directly. Here, we report on the results of an international interlaboratory calibration of 4 spectrofluorometric protocols to quantify nucleic acids. Replicate sets of 5 tissue samples and 2 standards (common standards) were supplied to each of 5 researchers for analysis with their own methods and standards. Two approaches were evaluated for mitigating the observed differences in values: 1) the use of common nucleic acid standards and 2) standardizing to a common slope ratio (slope of DNA standard curve/slope of RNA standard curve or mDNA/mRNA). Adopting common standards slightly reduced the variability among protocols but did not overcome the problem. When tissue R/Ds were standardized based on a common mDNA/mRNA slope ratio, the variance attributed to analytical protocol decreased dramatically from 57.1% to 3.4%. We recommend that the ratio of the slopes of the standard curves be provided to facilitate intercomparability of R/D results among laboratories using different spectrofluorometric methods for the analysis of nucleic acids in fish

Modeling kicks from the merger of generic black-hole binaries

Recent numerical relativistic results demonstrate that the merger of comparable-mass spinning black holes has a maximum ``recoil kick'' of up to \sim 4000 \kms. However the scaling of these recoil velocities with mass ratio is poorly understood. We present new runs showing that the maximum possible kick perpendicular to the orbital plane does not scale as $\sim\eta^2$ (where $\eta$ is the symmetric mass ratio), as previously proposed, but is more consistent with $\sim\eta^3$, at least for systems with low orbital precession. We discuss the effect of this dependence on galactic ejection scenarios and retention of intermediate-mass black holes in globular clusters.Comment: 5 pages, 1 figure, 3 tables. Version published in Astrophys. J. Let