CRISPR-CasRx-mediated disruption of Aqp1/Adrb2/Rock1/Rock2 genes reduces intraocular pressure and retinal ganglion cell damage in mice.

Glaucoma affects approximately 80 million individuals worldwide, a condition for which current treatment options are inadequate. The primary risk factor for glaucoma is elevated intraocular pressure. Intraocular pressure is determined by the balance between the secretion and outflow of aqueous humor. Here we show that using the RNA interference tool CasRx based on shH10 adenovirus-associated virus can reduce the expression of the aqueous humor circulation related genes Rock1 and Rock2, as well as aquaporin 1 and ß2 adrenergic receptor in female mice. This significantly reduced intraocular pressure in female mice and provided protection to the retina ganglion cells, ultimately delaying disease progression. In addition, we elucidated the mechanisms by which the knockdown of Rock1 and Rock2, or aquaporin 1 and ß2 adrenergic receptor in female mice, reduces the intraocular pressure and secures the retina ganglion cells by single-cell sequencing.

Development of graphitic carbon nitride quantum dots-based oxygen self-sufficient platforms for enhanced corneal crosslinking.

Keratoconus, a disorder characterized by corneal thinning and weakening, results in vision loss. Corneal crosslinking (CXL) can halt the progression of keratoconus. The development of accelerated corneal crosslinking (A-CXL) protocols to shorten the treatment time has been hampered by the rapid depletion of stromal oxygen when higher UVA intensities are used, resulting in a reduced cross-linking effect. It is therefore imperative to develop better methods to increase the oxygen concentration within the corneal stroma during the A-CXL process. Photocatalytic oxygen-generating nanomaterials are promising candidates to solve the hypoxia problem during A-CXL. Biocompatible graphitic carbon nitride (g-C3N4) quantum dots (QDs)-based oxygen self-sufficient platforms including g-C3N4 QDs and riboflavin/g-C3N4 QDs composites (RF@g-C3N4 QDs) have been developed in this study. Both display excellent photocatalytic oxygen generation ability, high reactive oxygen species (ROS) yield, and excellent biosafety. More importantly, the A-CXL effect of the g-C3N4 QDs or RF@g-C3N4 QDs composite on male New Zealand white rabbits is better than that of the riboflavin 5'-phosphate sodium (RF) A-CXL protocol under the same conditions, indicating excellent strengthening of the cornea after A-CXL treatments. These lead us to suggest the potential application of g-C3N4 QDs in A-CXL for corneal ectasias and other corneal diseases.

Genome Editing VEGFA Prevents Corneal Neovascularization In Vivo.

Corneal neovascularization (CNV) is a common clinical finding seen in a range of eye diseases. Current therapeutic approaches to treat corneal angiogenesis, in which vascular endothelial growth factor (VEGF) A plays a central role, can cause a variety of adverse side effects. The technology of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 can edit VEGFA gene to suppress its expression. CRISPR offers a novel opportunity to treat CNV. This study shows that depletion of VEGFA with a novel CRISPR/Cas9 system inhibits proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Importantly, subconjunctival injection of this dual AAV-SpCas9/sgRNA-VEGFA system is demonstrated which blocks suture-induced expression of VEGFA, CD31, and α-smooth muscle actin as well as corneal neovascularization in mice. This study has established a strong foundation for the treatment of corneal neovascularization via a gene editing approach for the first time.

Nuclear Radiation Knowledge and Anxiety Levels among Residents around a Nuclear Power Plant in Liaoning Province, China.

ABSTRACT: Awareness of radiation-related knowledge (RRK) and nuclear energy-related knowledge (NERK) among residents around a nuclear power plant (NPP), as well as their concerns about a NPP, were investigated. A face-to-face survey was conducted among 1,775 residents within 30 km around the NPP in Liaoning Province, China. A single-item Likert scale, Spearman's/Pearson's correlation coefficients, Student's t-test, ANOVA, and multiple-linear regression analysis were employed. Awareness of RRK and NERK among residents around the NPP was 27.7% and 36.6%, respectively. The anxiety level of respondents was negatively corelated with the distance from their residence to the NPP and age. Also, 55.6% of respondents thought that the publicity about nuclear energy/NPPs was insufficient, and 82.7% of respondents wanted to know relevant information about NPPs. Awareness of RRK and NERK among residents around the NPP was relatively low, which was related to education, occupation, and income. The anxiety level among residents was related to distance and age. The public was eager to know about RRK and NERK. These findings indicate that the publicity and education of RRK and NERK among residents around the NPP should be strengthened.

Engineering Hibiscus-Like Riboflavin/ZIF-8 Microsphere Composites to Enhance Transepithelial Corneal Cross-Linking.

Riboflavin-5-phosphate (RF) is the most commonly used photosensitizer in corneal cross-linking (CXL), but its hydrophilicity and negative charge limit its penetration through the corneal epithelium into the stroma. To enhance the corneal permeability of RF and promote its efficacy in the treatment of keratoconus, novel hibiscus-like RF@ZIF-8 microsphere composites [6RF@ZIF-8 NF (nanoflake)] are prepared using ZIF-8 nanomaterials as carriers, which are characterized by their hydrophobicity, positive potential, biocompatibility, high loading capacities, and large surface areas. Both hematoxylin and eosin endothelial staining and TUNEL assays demonstrate excellent biocompatibility of 6RF@ZIF-8 NF. In in vivo studies, the 6RF@ZIF-8 NF displayed excellent corneal permeation, and outstanding transepithelial CXL (TE-CXL) efficacy, slightly better than the conventional CXL protocol. Furthermore, the special hibiscus-like structures of 6RF@ZIF-8 NF meant that it has better TE-CXL efficacy than that of 6RF@ZIF-8 NP (nanoparticles) due to the larger contact area with the epithelium and the shorter RF release passage. These results suggest that the 6RF@ZIF-8 NF are promising for transepithelial corneal cross-linking, avoiding the need for epithelial debridement.

Globus Pallidus Internus (GPi) Deep Brain Stimulation for Parkinson's Disease: Expert Review and Commentary.

INTRODUCTION: The globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson's disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients. METHODS: The literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping. RESULTS: There are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD. CONCLUSION: GPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.

Microenvironment-Triggered Degradable Hydrogel for Imaging Diagnosis and Combined Treatment of Intraocular Choroidal Melanoma.

Human choroidal melanoma (HCM) is one of the most common primary intraocular tumors and easily provokes liver metastases owing to the lack of sensitive and noninvasive therapeutic methods. Concerning the imaging diagnostics and therapeutic predicaments for choroidal melanoma, we designed microenvironment-triggered degradable hydrogels (RENP-ICG@PNIPAM:Dox-FA) based on ultrasmall (<5 nm) rare-earth nanoparticles (RENPs) with enhanced NIR-II luminescence. The ultrasmall diameter can significantly enhance the NIR-II luminescence performance of RENPs. RENPs were encapsulated by a dual-response PNIPAM hydrogel, which could release drug by responding to heat energy and glutathione under the tumor microenvironment. The in vitro/in vivo NIR-II imaging detection and antitumor activity were also compared systematically after different treatment conditions on ocular choroidal melanoma-1 cells and tumor-bearing mice, respectively. Besides, the degradability of the hydrogel composites under physiological conditions could be conducive to enhance the photothermal-chemotherapeutic effect and alleviate long-term biological toxicity. Our work on the microenvironment-triggered hydrogels with enhanced NIR imaging and easy metabolism may provide a promising strategy for sensitive and noninvasive imaging and phototherapy in ocular tumors.

Medications, Deep Brain Stimulation, and Other Factors Influencing Impulse Control Disorders in Parkinson's Disease.

Impulse control disorders (ICDs) in Parkinson's disease (PD) have a high cumulative incidence and negatively impact quality of life. ICDs are influenced by a complex interaction of multiple factors. Although it is now well-recognized that dopaminergic treatments and especially dopamine agonists underpin many ICDs, medications alone are not the sole cause. Susceptibility to ICD is increased in the setting of PD. While causality can be challenging to ascertain, a wide range of modifiable and non-modifiable risk factors have been linked to ICDs. Common characteristics of PD patients with ICDs have been consistently identified across many studies; for example, males with an early age of PD onset and dopamine agonist use have a higher risk of ICD. However, not all cases of ICDs in PD can be directly attributable to dopamine, and studies have concluded that additional factors such as genetics, smoking, and/or depression may be more predictive. Beyond dopamine, other ICD associations have been described but remain difficult to explain, including deep brain stimulation surgery, especially in the setting of a reduction in dopaminergic medication use. In this review, we will summarize the demographic, genetic, behavioral, and clinical contributions potentially influencing ICD onset in PD. These associations may inspire future preventative or therapeutic strategies.

Comprehensive Comparison of Axial Length Measurement With Three Swept-Source OCT-Based Biometers and Partial Coherence Interferometry.

PURPOSE: To compare axial length measurements (and failure rate) of three swept-source optical coherence tomography (SS-OCT)-based biometers: IOLMaster 700 (Carl Zeiss Meditec, Jena, Germany), OA-2000 (Tomey, Nagoya, Japan), and Argos (Movu Inc., Komaki, Japan) to those provided by a partial coherence interferometry (PCI)-based optical biometer (IOLMaster v5.4 [Carl Zeiss Meditec]). METHODS: A total of 119 patients (171 eyes) undergoing cataract surgery were enrolled. Axial length was measured with the four biometers in a random order. Chi-square analysis was used to determine whether statistically significant differences in success rates were found between biometers. Within-subject standard deviation (Sw), test-retest repeatability (TRT), coefficient of variation (CoV), and intraclass correlation coefficients (ICCs) were calculated to analyze the intraobserver repeatability. Bland-Altman plots were used for agreement assessment. RESULTS: Axial length measurements were successfully measured in 166 eyes (97.08%) with the IOLMaster 700, 166 eyes (97.08%) with the OA-2000, 170 eyes (99.42%) with the Argos, and 138 eyes (80.70%) with the IOLMaster v5.4. Chi-square analysis indicated a significant difference in the failure rate between PCI- and SS-OCT-based biometers (P < .001). Intraobserver repeatability for the IOLMaster 700, OA-2000, and Argos showed excellent repeatability with low TRT (0.03, 0.06, and 0.05 mm, respectively), low CoV (0.04%, 0.10%, 0.07%, respectively), and high ICC (1.000, 0.999, and 1.000, respectively). The Bland-Altman 95% limits of agreement were as narrow as 0.09 mm, indicating excellent agreement among the three SS-OCT biometers and the PCI biometer. CONCLUSIONS: The three SS-OCT biometers showed a significantly higher success rate for axial length measurement than the IOLMaster v5.4 in various lens opacities. These SS-OCT biometers are likely to become the gold standard for axial measurement. [J Refract Surg. 2019;35(2):115-120.].

High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling.

It has previously been demonstrated that glucose is important in the process of stem cell aging. However, the mechanisms of cell senescence induced by high glucose (HG) remain to be elucidated. The preliminary study indicated that D­galactose induced mesenchymal stem cell (MSCs) aging. The present study demonstrated, following treatment with 11.0 or 22.0 mM HG for 14 days, that HG significantly promoted MSCs aging and the expression levels of phosphorylated (p-)phosphatidylinositol 3-kinase/protein kinase B (Akt) and p­mammalian target of rapamycin signaling (mTOR) in the HG groups were increased compared with the control group. However, following Akt inhibition with 1.0 or 10.0 nM MK­2206, which is an Akt­specific small molecule inhibitor, the senescence­cell value in the HG group was significantly decreased compared with the control group. These results indicated that HG induced MSCs senescence and this effect was primarily mediated via the Akt/mTOR signaling pathway.

Unilateral thalamic deep brain stimulation in essential tremor demonstrates long-term ipsilateral effects.

INTRODUCTION: Deep Brain Stimulation (DBS) of thalamus in essential tremor (ET) is effective for the treatment of contralateral tremors. Bilateral DBS controls tremors on both sides but is associated with increased morbidity and risks. We evaluated if unilateral surgery had ipsilateral benefits on tremors and thus could be a potentially safer alternative to bilateral DBS. METHODS: Medication refractory ET patients undergoing unilateral thalamic DBS were included and longitudinally followed. Tremor rating scale was used to record total motor, arm tremor and activities of daily living (ADL) scores at baseline, six months and at last visit (three or more years after surgery). Postoperative scores were recorded with DBS turned OFF and ON. RESULTS: Twenty-two patients with a mean follow-up 3.4 ± 0.14 years were enrolled. When baseline scores were compared to scores with the DBS turned ON, significant improvements were noted in total tremor (40%), ADL (67%) and arm tremor scores both on the ipsilateral and the contralateral side at six months and at the last visit of follow-up (all p < 0.05). Ipsilateral arm tremor (∼56%) improvements were milder compared to the contralateral side (∼73%) tremors. CONCLUSION: Unilateral thalamic DBS in ET demonstrates significant long-term benefits for ipsilateral arm tremors and can be offered to higher risk and to select patients.

Pielotac como alternativa en el diagnóstico de la urolitiasis: experiencia en el hospital clínico UC / UHCT as an alternative in the diagnosis of urolithiasis: experience in UC clinical hospital

La utilización de la Tomografía Helicoidal Sin Contraste (PIELOTAC) para el diagnóstico de la urolitiasis es hoy en día una alternativa vigente y que aparece llevar a terapias más oportunas y efectivas. El objetivo de este trabajo es evaluar la experiencia de nuestra institución desde la incorporación rutinaria del Piolotac para diagnóstico de la urolitiasis, comparando con cifras históricas locales en las que el manejo diagnóstico se realizó con Pielografía IV como primer examen. Revisión retrospectiva de las fichas de urgencia entre enero a mayo del 2001, extrayendo aquellos pacientes que consultaron por litiasis urinaria. De estas se obtuvieron valores relacionados con edad, sexo, antecedentes clínicos, historia clínica actual, uso del Pielotac en su intento diagnóstico, número, tamaño ubicación de la litiasis y grado de repercusión en el sistema urinario, tiempo transcurrido al tratamiento sea médico y/o quirúrgico, así como también, la efectividad de éste. En un total de 111 pacientes que consultaron al servicio de urgencia, en su mayoría del sexo masculino (55 por ciento9, se logró obtener la confirmación de la urolitiasis a través del Pielotac. En su mayoría resultaron ser hombres con litiasis de ubicación uretral distal con escaso compromiso de dilatación del sistema urinario y que en un 93 por ciento fueron resueltas dentro de las 24 hrs. posterior al ingreso del paciente, con muy buena respuesta. En un 1,5 por ciento se requirió un nuevo intento de litotripsia. En un 12,6 por ciento de los pacientes se pudo diagnosticar otras entidades como diagnóstico diferencial, de ellas 1 pacientes se les diagnóstico enfermedad diverticular complicada, en 2 apendicitis aguda, un tumor renal, 4 tumores ováricos (teratomas quísticos) y 6 pielonefritis agudas. La Pielotac es hoy un examen que guarda cualidades técnicas que lo hacen ser de gran ayuda en la urolitiasis y a veces como diagnóstico diferencial de otras patologías que debieron ser resueltas quirúrgicamente. Sin embargo, sigue siendo de alto costo y no accesible en todo recinto hospitalario.