Etiology including epigenetic defects of retinoblastoma.

Retinoblastoma (RB), originating from the developing retina, is an aggressive intraocular malignant neoplasm in childhood. Biallelic loss of RB1 is conventionally considered a prerequisite for initiating RB development in most RB cases. Additional genetic mutations arising from genome instability following RB1 mutations are proposed to be required to promote RB development. Recent advancements in high throughput sequencing technologies allow a deeper and more comprehensive understanding of the etiology of RB that additional genetic alterations following RB1 biallelic loss are rare, yet epigenetic changes driven by RB1 loss emerge as a critical contributor promoting RB tumorigenesis. Multiple epigenetic regulators have been found to be dysregulated and to contribute to RB development, including noncoding RNAs, DNA methylations, RNA modifications, chromatin conformations, and histone modifications. A full understanding of the roles of genetic and epigenetic alterations in RB formation is crucial in facilitating the translation of these findings into effective treatment strategies for RB. In this review, we summarize current knowledge concerning genetic defects and epigenetic dysregulations in RB, aiming to help understand their links and roles in RB tumorigenesis.

Investigation of Biomaterial Ink Viscosity Properties and Optimization of the Printing Process Based on Pattern Path Planning.

Extruded bioprinting is widely used for the biomanufacturing of personalized, complex tissue structures, which requires biomaterial inks with a certain viscosity to enable printing. However, there is still a lack of discussion on the controllable preparation and printability of biomaterial inks with different viscosities. In this paper, biomaterial inks composed of gelatin, sodium alginate, and methylcellulose were utablesed to investigate the feasibility of adjustment of rheological properties, thereby analyzing the effects of different rheological properties on the printing process. Based on the response surface methodology, the relationship between the material components and the rheological properties of biomaterial inks was discussed, followed by the prediction of the rheological properties of biomaterial inks. The prediction accuracies of the power-law index and consistency coefficient could reach 96% and 79%, respectively. The material group can be used to prepare biomaterial inks with different viscosity properties in a wide range. Latin hypercube sampling and computational fluid dynamics were used to analyze the effects of different rheological properties and extrusion pressure on the flow rate at the nozzle. The relationship between the rheological properties of the biomaterial ink and the flow rate was established, and the simulation results showed that the changes in the rheological properties of the biomaterial ink in the high-viscosity region resulted in slight fluctuations in the flow rate, implying that the printing process for high-viscosity biomaterial inks may have better versatility. In addition, based on the characteristics of biomaterial inks, the printing process was optimized from the planning of the print pattern to improve the location accuracy of the starting point, and the length accuracy of filaments can reach 99%. The effect of the overlap between the fill pattern and outer frame on the print quality was investigated to improve the surface quality of complex structures. Furthermore, low- and high-viscosity biomaterial inks were tested, and various printing protocols were discussed for improving printing efficiency or maintaining cell activity. This study provides feasible printing concepts for a wider range of biomaterials to meet the biological requirements of cell culture and tissue engineering.

Emerging Roles of cGAS-STING Signaling in Mediating Ocular Inflammation.

Cyclic GMP-AMP (cGAMP) synthase (cGAS), a sensor of cytosolic DNA, recognizes cytoplasmic nucleic acids to activate the innate immune responses via generation of the second messenger cGAMP and subsequent activation of the stimulator of interferon genes (STINGs). The cGAS-STING signaling has multiple immunologic and physiological functions in all human vital organs. It mediates protective innate immune defense against DNA-containing pathogen infection, confers intrinsic antitumor immunity via detecting tumor-derived DNA, and gives rise to autoimmune and inflammatory diseases upon aberrant activation by cytosolic leakage of self-genomic and mitochondrial DNA. Disruptions in these functions are associated with the pathophysiology of various immunologic and neurodegenerative diseases. Recent evidence indicates important roles of the cGAS-STING signaling in mediating inflammatory responses in ocular inflammatory and inflammation-associated diseases, such as keratitis, diabetic retinopathy, age-related macular degeneration, and uveitis. In this review, we summarize the recently emerging evidence of cGAS-STING signaling in mediating ocular inflammatory responses and affecting pathogenesis of these complex eye diseases. We attempt to provide insightful perspectives on future directions of investigating cGAS-STING signaling in ocular inflammation. Understanding how cGAS-STING signaling is modulated to mediate ocular inflammatory responses would allow future development of novel therapeutic strategies to treat ocular inflammation and autoimmunity.

Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation.

Dysregulation of Th17 cell differentiation and pathogenicity contributes to multiple autoimmune and inflammatory diseases. Previously growth hormone releasing hormone receptor (GHRH-R) deficient mice have been reported to be less susceptible to the induction of experimental autoimmune encephalomyelitis. Here, we show GHRH-R is an important regulator of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation. We find that GHRH-R is not expressed in naïve CD4+ T cells, while its expression is induced throughout Th17 cell differentiation in vitro. Mechanistically, GHRH-R activates the JAK-STAT3 pathway, increases the phosphorylation of STAT3, enhances both non-pathogenic and pathogenic Th17 cell differentiation and promotes the gene expression signatures of pathogenic Th17 cells. Enhancing this signaling by GHRH agonist promotes, while inhibiting this signaling by GHRH antagonist or GHRH-R deficiency reduces, Th17 cell differentiation in vitro and Th17 cell-mediated ocular and neural inflammation in vivo. Thus, GHRH-R signaling functions as a critical factor that regulates Th17 cell differentiation and Th17 cell-mediated autoimmune ocular and neural inflammation.

Exome Sequencing Reveals SLC4A11 Variant Underlying Congenital Hereditary Endothelial Dystrophy (CHED2) Misdiagnosed as Congenital Glaucoma.

Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) may be misdiagnosed as primary congenital glaucoma (PCG) due to similar clinical phenotypes during early infancy. In this study, we identified a family with CHED2, which was previously misdiagnosed as having PCG, and followed up for 9 years. Linkage analysis was first completed in eight PCG-affected families, followed by whole-exome sequencing (WES) in family PKGM3. The following in silico tools were used to predict the pathogenic effects of identified variants: I-Mutant 2.0, SIFT, Polyphen-2, PROVEAN, mutation taster and PhD-SNP. After detecting an SLC4A11 variant in one family, detailed ophthalmic examinations were performed again to confirm the diagnosis. Six out of eight families had CYP1B1 gene variants responsible for PCG. However, in family PKGM3, no variants in the known PCG genes were identified. WES identified a homozygous missense variant c.2024A>C, p.(Glu675Ala) in SLC4A11. Based on the WES findings, the affected individuals underwent detailed ophthalmic examinations and were re-diagnosed with CHED2 leading to secondary glaucoma. Our results expand the genetic spectrum of CHED2. This is the first report from Pakistan of a Glu675Ala variant with CHED2 leading to secondary glaucoma. The p.Glu675Ala variant is likely a founder mutation in the Pakistani population. Our findings suggest that genome-wide neonatal screening is worthwhile to avoid the misdiagnosis of phenotypically similar diseases such as CHED2 and PCG.

Protocorm-like-body extract of Phalaenopsis aphrodite combats watermelon fruit blotch disease.

Bacterial fruit blotch, caused by the seedborne gram-negative bacterium Acidovorax citrulli, is one of the most destructive bacterial diseases of cucurbits (gourds) worldwide. Despite its prevalence, effective and reliable means to control bacterial fruit blotch remain limited. Transcriptomic analyses of tissue culture-based regeneration processes have revealed that organogenesis-associated cellular reprogramming is often associated with upregulation of stress- and defense-responsive genes. Yet, there is limited evidence supporting the notion that the reprogrammed cellular metabolism of the regenerated tissued confers bona fide antimicrobial activity. Here, we explored the anti-bacterial activity of protocorm-like-bodies (PLBs) of Phalaenopsis aphrodite. Encouragingly, we found that the PLB extract was potent in slowing growth of A. citrulli, reducing the number of bacteria attached to watermelon seeds, and alleviating disease symptoms of watermelon seedlings caused by A. citrulli. Because the anti-bacterial activity can be fractionated chemically, we predict that reprogrammed cellular activity during the PLB regeneration process produces metabolites with antibacterial activity. In conclusion, our data demonstrated the antibacterial activity in developing PLBs and revealed the potential of using orchid PLBs to discover chemicals to control bacterial fruit blotch disease.

Epigallocatechin-3-Gallate Protects Trabecular Meshwork Cells from Endoplasmic Reticulum Stress.

Primary open-angle glaucoma (POAG) is the most common form of glaucoma, for which elevated intraocular pressure (IOP) is a major risk factor. IOP is mainly regulated by dynamic balance of aqueous humor (AH) production and outflow via the conventional trabecular meshwork/Schlemm's canal (TM/SC) pathway. Dysfunctions of TM cells due to endoplasmic reticulum (ER) stress have been demonstrated to increase the resistance of AH outflow, resulting in IOP elevation. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenolic component in green tea, has been shown to alleviate ER stress in several diseases while its potential roles in alleviating ER stress in TM cells have not been determined. In this study, we investigate the mitigation of tunicamycin-induced ER stress in TM cells by EGCG. MTT assay was used to measure the cell viability of human TM (HTM) cells and primary porcine TM (PTM) cells. ER stress levels in both HTM cells and primary PTM cells were detected by quantitative real-time PCR. The primary PTM cells isolated from porcine TM tissues were characterized by immunostaining. We found that 40 µM and 80 µM EGCG pretreatment substantially promoted HTM cell survival under 3 µM tunicamycin-induced ER stress. Pretreatment of 40 µM EGCG markedly reduced the expression of ER stress markers ATF4, HSPA5, and DDIT3, evoked by 3 µM tunicamycin in HTM cells. Furthermore, 40 µM EGCG pretreatment significantly decreased the expressions of ATF4, HSPA5, and DDIT3 at the mRNA level induced by 3 µM tunicamycin and improved cell viability in primary PTM cells. Our results show that EGCG is capable of protecting TM cells from ER stress. EGCG provides a promising therapeutic option for POAG treatment.

Triglyceride-Glucose Index and Intravenous Thrombolysis Outcomes for Acute Ischemic Stroke: A Multicenter Prospective-Cohort Study.

BACKGROUND: The triglyceride-glucose (TyG) index has recently been proposed as a reliable marker of insulin resistance. There is insufficient evidence to verify that the TyG index is correlated with functional outcomes and hemorrhagic transformation and in patients with stroke treated with intravenous thrombolysis (IVT). METHODS: We designed a multicenter cohort study, which enrolled patients with acute ischemic stroke treated with IVT between December 2004 and December 2016. The TyG index was divided into tertiles and calculated on a continuous scale. Unfavorable functional outcomes were defined by the modified Rankin Scale of 3-6 at 90 days and the incident rates of symptomatic intracranial hemorrhage (SICH) within 36 h of IVT onset were surveyed. Stroke severity was defined as mild (4-8), moderate (9-15), or high (≥16) based on the National Institutes of Health Stroke Scale (NIHSS) scores. RESULTS: Among 914 enrolled patients, the tertiles of the TyG index were 8.48 for T1, 8.48-9.04 for T2, and 9.04 for T3. T3 showed an increased risk of unfavorable functional outcomes at 90 days [odds ratio (OR): 1.76; P = 0.0132]. The TyG index was significantly associated with unfavorable functional outcomes at 90 days (OR: 1.32; P = 0.0431 per unit increase). No association was found between the TyG index and SICH. These findings were applicable for T3 with stroke of moderate (OR, 2.35; P = 0.0465) and high severity (OR: 2.57, P = 0.0440) patients with stroke. CONCLUSION: This study supports the strong association between the increased TyG index and increased unfavorable functional outcomes at 90 days in patients with acute ischemic stroke treated with IVT. These findings were found to be robust in patients with moderate and high stroke severity.

Effects of Dabigatran on Dementia Pathogenesis and Neuropsychological Function: A Review.

BACKGROUND: Patients with atrial fibrillation (AF) carry higher risks of cognitive consequences and psychological burden. An optimal anticoagulant therapy would be expected to better preserve neuropsychological function in addition to effective prevention of stroke and systemic thromboembolism. OBJECTIVE: The aim of this review is to explore the effects of the non-vitamin K antagonist oral anticoagulant (NOAC) dabigatran, a direct thrombin inhibitor, on cognitive and psychological function as well as dementia pathogenesis. METHODS: We performed a comprehensive search of PubMed/Medline for all types of relevant articles using a combination of dabigatran and associated keywords updated to August 31, 2021. All titles and abstracts were screened for eligibility, and potentially relevant papers were collected for inclusion. RESULTS: The pooled results demonstrated neutral to positive impacts of dabigatran on cognitive and psychological outcomes, including laboratory results in animal models of Alzheimer's disease, and reduced incidences of anxiety/depression and dementia for AF patients. Dabigatran also exhibited better therapeutic profiles than warfarin in preclinical and observational research. CONCLUSION: Given limited strength of evidence from heterogeneous studies, our review proposed modest beneficial effects of dabigatran on neuropsychological function. Further clinical trials are warranted to affirm the pleiotropic protective effects of NOACs on dementia treatment.

Comparison of Different Dosages of Alteplase in Atrial Fibrillation-Related Acute Ischemic Stroke After Intravenous Thrombolysis: A Nationwide, Multicenter, Prospective Cohort Study in Taiwan.

Background Insufficient evidence is available for patients with acute ischemic stroke with atrial fibrillation (AF) to determine the efficacy and safety of different dosages of intravenous thrombolysis treatment. This study examined clinical outcomes in Chinese patients with stroke with and without AF after intravenous thrombolysis treatment with different intravenous thrombolysis doses. Methods and Results This multicenter, prospective cohort study recruited 2351 patients with acute ischemic stroke (1371 with AF and 980 without AF) treated with intravenous thrombolysis using alteplase. The Totaled Health Risks in Vascular Events score is a validated risk-scoring tool used for assessing patients with acute ischemic stroke with and without AF. We evaluated favorable functional outcome at day 90 and symptomatic intracranial hemorrhage within 24 to 36 hours and outcomes of the patients receiving different doses of alteplase. Compared with the non-AF group, the AF group exhibited a 2- to 3-fold increased risk of symptomatic intracranial hemorrhage according to the National Institute of Neurological Disorders and Stroke standard (relative risk [RR], 2.10 [95% CI, 1.35-3.26]). Favorable functional outcome at 90 days and symptomatic intracranial hemorrhage rates according to the European Cooperative Acute Stroke Study II and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study standards did not significantly differ between the AF and non-AF groups. In addition, the low-dose alteplase subgroup exhibited an increased risk of symptomatic intracranial hemorrhage according to the National Institute of Neurological Disorders and Stroke standard (RR, 2.84 [95% CI, 1.63-4.96]). A validation study confirmed these findings after adjustment for scores determined using different stroke risk-scoring tools. Conclusions Different alteplase dosages did not affect functional status at 90 days in the AF and non-AF groups. Thus, the adoption of low-dose alteplase simply because of AF is not recommended.

Corrigendum: Pre-treatment of Single and Double Antiplatelet and Anticoagulant With Intravenous Thrombolysis for Older Adults With Acute Ischemic Stroke: The TTT-AIS Experience.

[This corrects the article DOI: 10.3389/fneur.2021.628077.].

Ruxolitinib Alleviates Uveitis Caused by Salmonella typhimurium Endotoxin.

Uveitis is characterized by inflammatory lesions of intraocular structures. It is one of the important manifestations in patients with Reiter's syndrome, an inflammatory arthritis, which is caused by enteric infection with bacteria, including Salmonella typhimurium. Corticosteroids remain the most frequently used therapies against uveitis associating with inflammatory arthritis. However, the long-term administration of steroids results in many side effects, and some uveitis patients do not respond to steroid treatment. Non-steroidal treatments are needed for uveitis patients. Our previous study found that Janus kinase (JAK) 1/2 inhibitor, ruxolitinib could suppress the expression of proinflammatory mediators in the ciliary body and iris. However, the impacts of ruxolitinib on ophthalmic features in uveitic eyes are still unknown. In this study, Salmonella typhimurium endotoxin-induced uveitis (EIU) was induced in Sprague Dawley rats by the injection of lipopolysaccharide (LPS). Compared with LPS-induced rats treated with water, ruxolitinib significantly attenuated the clinical manifestations, infiltrating cells and protein exudation in the aqueous humor, and retina-choroid thickening. Amplitudes of b-wave in both scotopic and photopic electroretinogram (ERG), and the amplitude of a-wave in scotopic ERG in EIU animals were alleviated by ruxolitinib. Collectively, we propose ruxolitinib could attenuate endotoxin-induced uveitis and rescue visual functions in rats by inhibiting the JAK2-STAT3 pathway.

Pre-treatment of Single and Double Antiplatelet and Anticoagulant With Intravenous Thrombolysis for Older Adults With Acute Ischemic Stroke: The TTT-AIS Experience.

Background: This study aimed to investigate the safety and efficacy of single antiplatelet, anticoagulant and Dual Antiplatelet pre-treatment (DAPP) in older, moderate to high severity acute ischemic stroke patients treated with intravenous thrombolysis (IVT). Methods: A prospective cohort study was conducted to monitor the development of symptomatic intracranial hemorrhage (SICH) and functional outcomes at 90 days. Two different dosages of alteplase were used for IVT. Logistic regression models were used for analysis of the safety and efficacy outcomes. Results: A total of 1,156 patients were enrolled and categorized into six groups based on their pre-treatment medications: (1) aspirin (n = 213), (2) clopidogrel (n = 37), (3) DAPP of aspirin + clopidogrel (n= 27), (4) warfarin (n = 44), (5) any of the above pre-medications (n = 331), and (6) none of these medications as controls (n = 825). The DAPP group showed significantly increased SICH by the NINDS (adjusted OR: 4.90, 95% CI 1.28-18.69) and the ECASS II (adjusted OR: 5.09, 95% CI: 1.01-25.68) standards. The aspirin group was found to significantly improve the favorable functional outcome of the modified Rankin Scale (mRS) of 0-1 (adjusted OR: 1.91, 95% CI, 1.31.2.78), but no significance for mRS of 0-2 (adjusted OR: 1.39, 95% CI, 0.97-1.99). The DAPP group also significantly increased mortality (adjusted OR: 4.75, 95% CI: 1.77-12.72). A significant interaction between different dosages for IVT and the functional status was noted. Compared to standard dose, the DAPP group showed higher proportions of disability and mortality with low dose of IVT. Conclusion: For older adults with higher baseline severity of acute ischemic stroke, DAPP may increase the risk of SICH and mortality post IVT. However, DAPP is still not an indication to withdraw IVT and to prescribe low-dose IVT for older adults.

The long-term risk of epilepsy after transient global amnesia: A population-based cohort study.

OBJECTIVE: Transient global amnesia (TGA) is characterized by sudden onset of larger anterograde and milder retrograde amnesia lasting up to 24 h. We aimed to investigate the long-term risk of epilepsy up to 8 years in subjects after TGA in the population-based cohort study. PATIENTS AND METHODS: We conducted a control cohort study with an 8-year follow-up period. All data was collected retrospectively. From all potential participants more than 18 years of age without epilepsy and TGA history, we identified TGA subjects and non-TGA controls with age, gender and comorbidities matched in a 1:3 ratio. The yearly incidence of epilepsy was compared in TGA and non-TGA cohorts. The cumulative hazard ratio of epilepsy was estimated. The risk factors of epilepsy after TGA were investigated. RESULTS: A total of 185 TGA subjects and 555 non-TGA controls were included in the study. There were 7 epilepsy cases in the 185 TGA cohorts during the follow-up period with yearly incidence rates of 9.629 per 1000 person. The adjusted hazard ratio for epilepsy in TGA cohorts was 6.50 (95 % confidence interval 1.87-22.68, p = 0.003) compared with non-TGA cohorts after adjusting for age, gender and comorbidities. No notable factor was significantly associated with epilepsy after TGA. CONCLUSION: Our study highlighted TGA is associated with increased long-term risk of epilepsy.

Factors of post-stroke dementia: A nationwide cohort study in Taiwan.

AIM: We investigated the long-term risk of dementia for up to 10 years in patients with stroke and broadened the correlates. METHODS: We carried out a case-control study using the Taiwan National Health Insurance Research database in 2000 with a sampled population of 1 million. The study cohort comprised 8236 patients with stroke and no dementia history. We carried out a 1:1 case-control matched analysis on estimated propensity scores. Cox proportional hazards regressions were carried out to estimate the risk of dementia during the 5- and 10-year follow-up periods. The risk factors were also investigated. RESULTS: The stroke cohort was significantly at more risk of dementia during the 5- and 10-year follow-up periods, with adjusted hazard ratios 1.87 and 1.53, respectively. The patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage had a significantly higher risk of dementia after 5 and 10 years, with adjusted hazard ratios of 1.81 and 1.49, 1.92 and 1.61, and 2.14 and 1.61, respectively. The significant risk factors of dementia were age ≥60 years, resident in southern and eastern regions, having low insurance range, and antiplatelet use. CONCLUSIONS: Stroke and the subtypes, including ischemic stroke, transient ischemic attack and intracerebral hemorrhage, increase the long-term risk of dementia. The incidence of post-stroke dementia increases yearly, but the relative risk decreases gradually. Older adults, residents in southern and eastern regions, having low insurance range and antiplatelet use were prominent risk factors of post-stroke dementia in Taiwan. Careful management of stroke and risk factors of post-stroke dementia with long-term follow up of cognition should be reinforced. Geriatr Gerontol Int 2019; 19: 815-822.

Statins and the risk of bleeding in patients taking dabigatran.

OBJECTIVES: Dabigatran etexilate is a direct thrombin inhibitor that clinicians increasingly prescribe to prevent stroke in patients with non-valvular atrial fibrillation (NVAF). Clinicians also commonly prescribe statins for primary and secondary prevention of cardiovascular diseases. Little is known about the bleeding risk in patients taking a statin and dabigatran together. The aim of this study was to evaluate the safety and persistence of dabigatran after co-medication with statins. MATERIALS AND METHODS: We performed a prospective, multicenter registry study of stroke patients with NVAF who initiated dabigatran therapy within 3 months after a clinically evident ischemic cerebrovascular event between 2013 and 2017. The main outcome measure was symptomatic bleeding after 90, 180, and 360 days. RESULTS: In total, 652 patients (336 statin users, 316 non-users) were followed for 1 year after dabigatran therapy. Cox multivariate analysis demonstrated that male sex, prior use of aspirin, and concurrent use of an antiarrhythmic drug were associated with a higher risk of bleeding at 360 days. After adjusting time-dependent covariates, statin users had a significantly lower bleeding risk (adjusted hazard ratio: 0.11, P < 0.001) than non-users. Kaplan-Meier analysis indicated that patients prescribed with statins had a higher rate of bleeding-free survival (P = 0.028). CONCLUSION: For secondary prevention of stroke in patients with NVAF who are taking dabigatran etexilate, co-prescription with a statin was associated with a lower risk of bleeding complications. Future research is needed to determine the pharmacological mechanism underlying this effect.

Impaired conflict monitoring in cognitive decline.

Resolving conflicts is an important cognitive ability of executive function, and it may decrease with cognitive decline. The flanker task is a practical test used to assess the ability to suppress responses that are inappropriate in a particular context. The aims of the present study were to investigate conflict monitoring of cognitive control in subjects with different levels of cognitive impairment, and clarify the usefulness of the flanker task in screening cognitive decline. We recruited 50 subjects with mild cognitive impairment (MCI) and 34 patients with Alzheimer's disease (AD), and 44 mentally healthy elderly subjects as a control group. To evaluate cognitive performance, each participant underwent a neuropsychological assessment using the Cognitive Abilities Screening Instrument and a modified flanker task. Compared with the normal controls and those with MCI, the patients with AD had a significantly lower accuracy rate and longer reaction time in both congruent and incongruent trials. The diagnosis of AD predicted significantly poorer performances on the flanker tasks. Furthermore, behavioral data of the patients with AD were significantly correlated with the results of neuropsychological tests. Our results indicated that executive cognitive deficits in conflict monitoring as detected by the flanker task were significantly impaired in the patients with AD. The flanker task could be a quick and easier alternative tool for screening AD among elderly people with suspicious cognitive impairment.

Obstructive sleep apnea and cerebral white matter change: a systematic review and meta-analysis.

Obstructive sleep apnea (OSA) can cause sleep fragmentation and intermittent hypoxemia, which are linked to oxidative stress. White matter changes (WMCs) representing cerebrovascular burden and are at risk factor for oxidative ischemic injury. The current study explores the mutual relationships between OSA and WMCs. We performed a systematic review of electronic databases for clinical studies investigating OSA and WMCs. Random-effects models were used for pooled estimates calculation. A total of 22 studies were included in the meta-analysis. The results revealed a significantly higher prevalence rate of WMCs [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.52-2.80, p < 0.001] and significantly higher severity of WMCs (Hedges' g = 0.23, 95% CI 0.06-0.40, p = 0.009) in the patients with OSA than in controls. Furthermore, the results revealed a significantly higher apnea-hypopnea index (Hedges' g = 0.54, 95% CI 0.31-0.78, p < 0.001) and significantly higher prevalence rate of moderate-to-severe OSA (OR 2.86, 95% CI 1.44-5.66, p = 0.003) in the patients with WMCs than in controls, however there was no significant difference in the prevalence rate of mild OSA between the patients with WMCs and controls (OR 0.71, 95% CI 0.20-2.54, p = 0.603). OSA was associated with a higher prevalence and more severe WMCs, and the patients with WMCs had an increased association with moderate-to-severe OSA. Future large-scale randomized controlled trials with a longitudinal design are essential to further evaluate treatment in patients with OSA.

Unbiased Proteomic Study of the Axons of Cultured Rat Cortical Neurons.

The axon is a long projection connecting a neuron to its targets. Here, the axons of cultured rat cortical neurons were isolated with micropatterned chips that enable the separation of axons from their cell bodies. Proteins extracted from isolated axons and whole neurons were subjected to analyses using two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) analyses without and with stable isotope dimethyl labeling, resulting in the identification of >2500 axonal proteins and 103 axon-enriched proteins. A strong correlation exists between the abundances of axonal proteins and their counterparts in whole neurons. The proteomic results confirm the axonal protein constituents of the subcellular structures documented in earlier electron microscopic studies. Cortical axons have proteins that are components of machineries for protein degradation and the synthesis of soluble, membrane, and secretory proteins, although axons lack conventional Golgi apparatus. Despite the fact that axons lack nucleus, nuclear proteins were identified, and 67 of them were found enriched in axons. Some of the results obtained by the MS-based studies were validated by quantitative Western blotting and immunofluorescence staining analyses. The results represent the first comprehensive description of the axonal protein landscape. The MS proteomics data are available via ProteomeXchange with identifier PXD005527.