Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: a case report.

BACKGROUND: We describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL) with central nervous system (CNS) involvement. CASE PRESENTATION: A 65-year-old Asian female with Ph+-ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Ophthalmic examination revealed remarkable optic disc swelling with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and retinal hemorrhages in both eyes. She was subsequently referred to the treating oncologist and diagnosed with Ph+-ALL relapse with multiple relapsed diseases involving the bone marrow and CNS. After intrathecal (IT) therapy, her visual acuity dramatically improved, and her leukemic infiltrates decreased. CONCLUSIONS: To the best of our knowledge, this is the first case report of ALL relapse with CNS involvement presenting as bilateral optic nerve infiltration and leukemic retinopathy in an adult. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting leukemia relapse.

Neural Stem/Progenitor Cell Transplantation in Parkinson's Rodent Animals: A Meta-Analysis and Systematic Review.

The effects of neural stem/progenitor cells (NSPCs) have been extensively evaluated by multiple studies in animal models of Parkinson's disease (PD), but the therapeutic efficacy was inconsistent. Here, we searched 4 databases (PubMed, Embase, Scopus, and Web of Science) and performed a meta-analysis to estimate the therapeutic effects of unmodified NSPCs on neurological deficits in rodent animal models of PD. Data on study quality score, behavioral outcomes (apomorphine or amphetamine-induced rotation and limb function), histological outcome (densitometry of TH+ staining in the SNpc), and cell therapy-related severe adverse events were extracted for meta-analysis and systematic review. Twenty-one studies with a median quality score of 6 (range from 4 to 9) in 11 were examined. Significant improvement was observed in the overall pooled standardized mean difference (SMD) between animals transplanted with NSPCs and with control medium (1.22 for apomorphine-induced rotation, P < .001; 1.50 for amphetamine-induced rotation, P < .001; 0.86 for limb function, P < .001; and -1.96 for the densitometry of TH+ staining, P < .001). Further subgroup analysis, animal gender, NSPCs source, NSPCs dosage, and pretreatment behavioral assessment were closely correlated with apomorphine-induced rotation and amphetamine-induced rotation. In conclusion, unmodified NSPCs therapy attenuated behavioral deficits and increased dopaminergic neurons in rodent PD models, supporting the consideration of early-stage clinical trial of NSPCs in patients with PD.

RNA interference targeting NOX4 protects visual function in an experimental model of retinal detachment by alleviating blood-retinal barrier damage.

AIM: To observe the effects of the inhibition of NADPH oxidase 4 (NOX4) expression on the retinal vascular barriers and visual function after retinal detachment (RD). METHODS: RD model was established 3wk after adeno-associaned virus vector injection. The retinal tissue was harvested 3d after RD, and the death of retinal vascular endothelial cells and photoreceptors was observed using electron microscopy. The NOX4 expression was detected by Western blot. Confocal microscopy was used to observe a retinal patch that had been perfused with Evans blue. A modified water maze test was used to detect the time required to find the platform on the water surface. The visual function of the rats was evaluated and reactive oxygen species (ROS) expression was detected by a fluorescence microplate reader. RESULTS: The retinal patch showed that NOX4 interference significantly reduced the destruction of the tight junctions between the retinal endothelium of RD rats and reduced leakage. Western blotting showed decreased expression of the NOX4 protein and decreased expression of ROS in retinal tissue; the Morris water maze test results showed that NOX4 interference significantly decreased the escape latency of the rats. CONCLUSION: NOX4 interference reduces the production of ROS in retinal vascular endothelial cells after experimental RD, thereby protecting the blood-retinal barrier and protecting visual function.

PJ34 Protects Photoreceptors from Cell Death by Inhibiting PARP-1 Induced Parthanatos after Experimental Retinal Detachment.

PURPOSE: Our previous study discoveredreactive oxygen species (ROS) and apoptosis inducing factor (AIF) increased after retinal detachment. Parthanatos is a cell death form involving ROS and AIF, which is induced by poly (ADP-ribose) polymerase-1 (PARP-1). Therefore, we investigated whether PJ34 (a PARP-1 inhibitor) could inhibit parthanatos and protect the photoreceptors from cell death after retinal detachment (RD). METHODS: Experimental retinal detachment modelswere created in Sprague-Dawley rats by subretinal injection of sodium hyaluronate.PJ34 orDMSO were introduced into subretinal space at RD induction, respectively. The structure of retinas and the morphology of photoreceptors were observed by hematoxylin eosin (H&E) staining and transmission electron microscope (TEM). Parthanatos related proteins (PARP-1, PAR,AIF) were detected by Western blot. The vision-dependent behavior of rat was tested by Morris water maze. RESULTS: H&E staining and TEM results indicated that the structure and outer nuclear layer (ONL) thickness of retinas were preserved, and the photoreceptors death decreasedwith PJ34 treatment. Western blot showed that the expression of PARP-1, PAR and AIF were decreased withPJ34 treatment. In addition, administration of PJ34 also improved the vision-dependent behavior of rat. CONCLUSIONS: These findings suggested that PJ34 is a potential therapeutic agent that attenuated photoreceptor parthanatos death in retinal detachment through inhibition of PARP-1/AIF pathway.

TRPML1 Inhibited Photoreceptor Apoptosis and Protected the Retina by Activation of Autophagy in Experimental Retinal Detachment.

OBJECTIVE: In this study, we used a rat model of retinal detachment (RD) to investigate the effects of transient receptor potential mucolipin 1 (TRPML1) on photoreceptor cells and the underlying mechanism. METHODS: An RD model was established by subretinal injection of sodium hyaluronate, and mucolipin synthetic agonist 1 (ML-SA1) and dimethyl sulphoxide were subretinally injected after RD induction. Retinal morphology was observed using haematoxylin-eosin staining, and the apoptosis of photoreceptor cells was detected by transmission electron microscopy. Reactive oxygen species (ROS) were examined with an ROS detection kit. The retinal expression levels of TRPML1, the autophagy-related protein microtubule-associated protein 1 light chain 3 (LC3), Beclin 1, and cleaved caspase 3 were detected by Western blotting. The Morris water maze was used to test vision-dependent behaviour. RESULTS: We found that retinal structure and the outer nuclear layer were improved and that the apoptosis of photoreceptor cells was reduced after ML-SA1 injection. The expression of ROS was reduced, and the loss of TRPML1 was inhibited after ML-SA1 treatment. The LC3-II to LC3-I ratio and Beclin 1 expression were enhanced, and cleaved caspase 3 expression was decreased after ML-SA1 treatment. Treatment with ML-SA1 also improved vision-dependent behaviour. CONCLUSIONS: Our findings suggest that ML-SA1 attenuates photoreceptor apoptosis and improves vision-dependent behaviour by activation of autophagy.

Rapamycin Inhibited Photoreceptor Necroptosis and Protected the Retina by Activation of Autophagy in Experimental Retinal Detachment.

Purpose: After experimental retinal detachment (RD), the applications of caspase inhibitor z-vad-fmk (a pan-caspase inhibitor) could inhibit apoptosis, but increased receptor interacting protein (RIP)-mediated necroptosis. In this study, we investigated whether rapamycin could inhibit necroptosis and cooperate with z-vad-fmk to protect the retina after RD. Methods: RD animal models were established in Sprague-Dawley rats by subretinal injection of sodium hyaluronate and treated with subretinal injections of z-vad-fmk or z-vad-fmk combined with rapamycin. On day 3 after RD, retinas were collected and analyzed by transmission electron microscopy (TEM), ROS assay, and western blot (for beclin-1, LC-3, RIP-1, AIF). On day 7 after RD, retinas were observed by H&E staining. Vision-dependent behavior of rats was tested by the modified Morris water maze. Results: TEM and H&E staining indicated that rapamycin combined with z-vad-fmk could reduce photoreceptor necrosis and preserve the ONL thickness after RD. The modified Morris water maze test showed that vision-dependent behavior was also significantly improved in the rapamycin + z-vad-fmk group.Western Blotting results demonstrated that rapamycin promoted the activation of autophagy by promoting beclin-1 and LC-3 induction and inhibited z-vad-fmk-induced necroptosis by inhibiting RIP-1 expression. In addition, rapamycin could also inhibit ROS production and AIF release. Conclusions: These findings indicated that rapamycin is a promising therapeutic agent that inhibits z-VAD-induced necroptosis, and protects photoreceptors and improves functional outcome in combination with z-vad-fmk.