Analysis of microRNA expression in rat kidneys after VEGF inhibitor treatment under different degrees of hypoxia.

Previously, we found that the incidence of kidney injury in patients with chronic hypoxia was related to the partial pressure of arterial oxygen. However, at oxygen concentrations that contribute to kidney injury, the changes in the relationship between microRNAs (miRNAs) and the hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) axis and the key miRNAs involved in this process have not been elucidated. Therefore, we elucidated the relationship between VEGF and kidney injury at different oxygen concentrations and the mechanisms mediated by miRNAs. Sprague-Dawley rats were exposed to normobaric hypoxia and categorized into six groups based on the concentration of the oxygen inhaled and injection of the angiogenesis inhibitor bevacizumab, a humanized anti-VEGF monoclonal antibody. Renal tissue samples were processed to determine pathological and morphological changes and HIF-1α, VEGF, and miRNA expression. We performed a clustering analysis of high-risk pathways and key hub genes. The results were validated using two Gene Expression Omnibus datasets (GSE94717 and GSE30718). As inhaled oxygen concentration decreased, destructive changes in the kidney tissues became more severe. Although the kidney possesses a self-protective mechanism under an intermediate degree of hypoxia (10% O2), bevacizumab injections disrupted this mechanism, and VEGF expression was associated with the ability of the kidney to repair itself. rno-miR-124-3p was identified as a crucial miRNA; a key gene target, Mapk14, was identified during this process. VEGF plays an important role in kidney protection from injury under different hypoxia levels. Specific miRNAs and their target genes may serve as biomarkers that provide new insights into kidney injury treatment.NEW & NOTEWORTHY Renal tolerance to hypoxic environments is limited, and the degree of hypoxia does not show a linear relationship with angiogenesis. VEGF plays an important role in the kidney's self-protective mechanism under different levels of hypoxia. miR-124-3p may be particularly important in kidney repair, and it may modulate VEGF expression through the miR-124-3p/Mapk14 signaling pathway. These microRNAs may serve as biomarkers that provide new insights into kidney injury treatment.

Murine cytomegalovirus localization and uveitic cell infiltration might both contribute to trabecular meshwork impairment in Posner-Schlossman syndrome: Evidence from an open-angle rat model.

As a special type of glaucoma, Posner-Schlossman syndrome (PSS) is characterized by elevated intraocular pressure (IOP) and anterior uveitis. Cytomegalovirus (CMV) anterior chamber infection has now been considered the leading cause of PSS. We used murine CMV (MCMV) intracameral injection to establish a rat model manifested in IOP elevation and mild anterior uveitis, much like PSS; viral localization and gene expression at various time points and inflammatory cell infiltration derived from innate and adaptive immunity were investigated, as well as pathogenetic changes of the trabecular meshwork (TM). The IOP and uveitic manifestations peaked at 24 h post-infection (p.i.) and returned to normal after 96 h; the iridocorneal angle remained open consistently. At 24 h p.i., leucocytes gathered at the chamber angle. Maximum transcription of MCMV immediate early 1 (IE1) was reached at 24 h in the cornea and 48 h in the iris and ciliary body. MCMV localized in aqueous humor outflow facilities and the iris from 24 h to 28 d p.i. and was detected by in situ hybridization, though it did not transcribe after 7 d p.i. TM and iris pigment epithelial cells harboring viral inclusion bodies and autophagosomes were present at 28 d p.i. These findings shed light on how and where innate and adaptive immunity reacted after MCMV was found and transcribed in a highly ordered cascade, as well as pathogenetic changes in TM as a result of virus and uveitis behaviors.

Iris abnormalities may influence the efficacy and filtration strategies of Posner-Schlossman syndrome: a retrospective study involving trabeculectomy, ExPRESS and Ahmed valve implants.

PURPOSE: To evaluate and compare the one-year efficacy and influencing factors of different filtration surgeries on Posner-Schlossman syndrome (PSS) patients. METHODS: A retrospective study enrolling 91 PSS patients who underwent filtering surgeries and were followed for at least one year. Unilateral PSS was diagnosed as recurrent attacks of mild, unilateral, non-granulomatous anterior uveitis, elevated intraocular pressure (IOP), keratic precipitates (KPs) on the corneal endothelium, open angle, no posterior synechia, and no inflammatory lesions in the posterior segment; the IOP and anterior segment returned to normal between attacks. Medical histories and thorough ocular examination results were collected. Trabeculectomy and ExPRESS were chosen as the first line and AGV was considered for those under high risk of fibrosis. Follow-up data, mainly IOP, best-corrected visual acuity (BCVA), and anterior segment manifestations at the 1st week, 6th month, and 12th month were generated and analyzed. Iris abnormalities were determined by depigmentation or atrophic changes on the anterior segment photograph. Complete surgical success was defined as 5 mmHg < IOP ≤ 21 mmHg without IOP-lowering drug or needle revision; qualified surgical success was defined as 5 mmHg < IOP ≤ 21 mmHg with IOP-lowering drugs or needle revisions. Survival analysis was performed to obtain the success rates. RESULTS: At the 12th month, the complete surgical success rate of trabeculectomy (N = 54), ExPRESS (N = 23), and AGV group (N = 14) was 58.97% (95%CI 46.91-77.09%), 84.21% (95%CI 68.33-100.87%), and 100%; the qualified success rate was 71.79% (95%CI 62.46-88.34%), 89.47% (95%CI 77.07-103.33%), and 100%, respectively. Patients undergoing trabeculectomy experienced the largest decline of BCVA (from 0.58±0.46 to 1.01±0.51, P < .05); the trabeculectomy group endured the highest IOP (20.84±9.92 mmHg) compared to ExPRESS (14.51±2.86 mmHg, P < .05) and AGV group (13.17±3.32 mmHg, P < .05). At the 12th month, in the ExPRESS group, patients with iris abnormalities had higher IOP than the normal ones (15.65±2.05 mmHg, 12.93±3.17 mmHg, P < .05). ExPRESS helped patients with iris abnormalities maintain lower IOP than trabeculectomy (15.65±2.05 mmHg, 22.52±10.67 mmHg, P < .05). Three patients developed hypotony at the 3rd month (1 in ExPRESS and 2 in trabeculectomy group). CONCLUSION: AGV and ExPRESS performed better than trabeculectomy in PSS patients in terms of IOP and success rate. Iris abnormalities might influence the postoperative IOP and this may be valuable in guiding filtration strategies. TRIAL REGISTRATION: Chinese Clinical Trial Registry (No. ChiCTR1800017532, date: 2018/08/02).

B cells migrate into remote brain areas and support neurogenesis and functional recovery after focal stroke in mice.

Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including remote areas supporting functional recovery. Stroke induced significant bilateral B cell diapedesis into remote brain regions regulating motor and cognitive functions and neurogenesis (e.g., dentate gyrus, hypothalamus, olfactory areas, cerebellum) in the whole-brain datasets. To confirm a mechanistic role for B cells in functional recovery, rituximab was given to human CD20+ (hCD20+) transgenic mice to continuously deplete hCD20+-expressing B cells following tMCAo. These mice experienced delayed motor recovery, impaired spatial memory, and increased anxiety through 8 wk poststroke compared to wild type (WT) littermates also receiving rituximab. B cell depletion reduced stroke-induced hippocampal neurogenesis and cell survival. Thus, B cell diapedesis occurred in areas remote to the infarct that mediated motor and cognitive recovery. Understanding the role of B cells in neuronal health and disease-based plasticity is critical for developing effective immune-based therapies for protection against diseases that involve recruitment of peripheral immune cells into the injured brain.

The effect of different angle kappa on higher-order aberrations after small incision lenticule extraction.

This study aimed to compare higher-order aberrations (HOAs) after small incision lenticule extraction (SMILE) in patients with different angle kappa. This is a retrospective report in which 341 right eyes of 341 patients who were subjected to SMILE, which used coaxially sighted corneal light reflex (CSCLR) as the treatment zone centered, treated by the same experienced surgeon (LHB) for correction of myopia and myopic astigmatism, preoperative and postoperative spherical equivalent (SE), angle kappa, total higher-order aberrations (total HOA), spherical aberration (SA), vertical coma (VC), horizontal coma (HC), oblique trefoil (OT), and horizontal trefoil (HT), were compared. SMILE showed outstanding performance in terms of safety, efficacy, and predictability. In addition, a comparison of preoperative and postoperative HOAs exhibited the difference of total HOA (P < 0.01), SA (P < 0.01), VC (P < 0.01), and HC (P < 0.01), which was statistically significant; however, for OT and HT with the longer follow-up time, the statistical difference gradually decreased. For stratification of angle kappa into groups based on decantation, angle kappa was divided into three major groups: r < 0.1 mm, 0.1 ≤ r < 0.2 mm, and r ≥ 0.2 mm; the changes of SA (F = 4.127, P = 0.021) and OT (F = 3.687, P = 0.031) exhibited significant difference after 1 year of SMILE. We performed a correlation analysis of all preoperative and postoperative parameters, and the results indicated that the preoperative total HOA was negatively correlated with preoperative cylindrical diopter (DC), and postoperative total HOA, SA, and coma were affected by spherical diopter (DS) and SE. Moreover, we also found a significant difference of SA and VC in the early postoperative with preoperative. SA was positively correlated with Y values and r of 1 year after SMILE. All of the analyzed parameters in the three groups, except for the trefoil, gradually increased over time; however, the trefoil could gradually stabilize over time. We also divided angle kappa into four groups by quadrants; the result showed that the effects of higher-order aberrations were markedly different from the various quadrants. Patients with large angle kappa were able to increase VC and SA postoperatively, and higher HOAs were more significant in patients with high myopia. The differences in quadrants exhibited a diversity of HOAs; this could be attributed to the corneal surface reestablishment and the alteration of angle kappa, but the trend was not apparent. Although all patients displayed increased HOAs after SMILE, the potential application of CSCLR as the treatment zone centered still showed excellent safety, efficacy, and predictability.

Clinical characteristics of virus-related uveitic secondary glaucoma: focus on cytomegalovirus and varicella zoster virus.

BACKGROUND: We aimed to analyze the clinical characteristics of secondary glaucoma related to cytomegalovirus (CMV)- and varicella zoster virus (VZV)-positive uveitis. METHODS: In this retrospective study, we enrolled patients with anterior uveitic secondary glaucoma. All the patients underwent aqueous and serum analyses for viral antibody through enzyme-linked immunosorbent assay. Among the 60 included patients, 22 had CMV-negative Posner-Schlossman syndrome (CMV-negative PSS), 25 had CMV-positive PSS, and 13 had VZV-positive anterior uveitis secondary glaucoma (VZV-AUSG). We evaluated the following main indicators: age, disease duration, intraocular pressure (IOP), cup-to-disc ratio, best corrected visual acuity (BCVA), corneal endothelial cell (CEC) count, ocular morphological changes, and medical treatments. RESULTS: We found that 53.2% (25/47) patients with PSS were CMV-positive. Patients with CMV-positive PSS had a larger cup-to-disc ratio (p = .043), lower CEC density (p = .017), more severe CEC loss (p < .001), and more iris depigmentation (p = .006) than CMV-negative PSS patients. Compared with patients with CMV-positive PSS, those with VZV-AUSG were older (p = .003), presented a higher IOP (p = .015), and had poorer BCVA (p < .001). Patients with CMV-positive PSS and VZV-AUSG all accepted ganciclovir treatment, and those with CMV-positive PSS used fewer antiglaucoma agents simultaneously compared with CMV-negative PSS (p = .005) and VZV-AUSG (p < .001). All three groups had a comparable proportion of patients requiring antiglaucoma surgery. CONCLUSIONS: We observed some distinctive clinical features in CMV-positive PSS compared with CMV-negative PSS. Further, we found that patients with VZV-AUSG presented with a higher IOP and worse visual acuity, and required more antiglaucoma medication than those with CMV-positive PSS.

Neutrophil CD64 index for diagnosis of infectious disease in the pediatric ICU: a single-center prospective study.

BACKGROUND: Infection is a major cause of death in children, and it is particularly important to identify biological indicators of early infection. Previous studies showed that the neutrophil CD64 (nCD64) index may be a useful biomarker for infection. The purpose of this study was to investigate use of the nCD64 index to identify infection in children from a pediatric ICU (PICU) in China. METHODS: This prospective observational study enrolled 201 children who were admitted to our PICU and were divided into an infection group and a non-infection group. In each patient, C-reactive protein (CRP), nCD64 index, procalcitonin (PCT), and white blood cell count were measured during the first 24 h after admission. Receiver operating characteristic (ROC) analyses were used to determine the sensitivity, specificity, and diagnostic value of the nCD64 index for infection. RESULTS: Among all 201 children, the infection group had greater levels of CRP, nCD64 index, and PCT (all p < 0.05). ROC analysis indicated the nCD64 index had a sensitivity of 68.8%, specificity of 90.7%, accuracy of 80.5%, and an optimal cut-off value of 0.14, which had better diagnostic value than CRP or PCT. For children with postoperative fever, the nCD64 index also distinguished systemic inflammatory response syndrome (SIRS) from infection with accuracy of 79%. CONCLUSIONS: The nCD64 index is a useful biomarker for the diagnosis of early infection in children admitted to the PICU.

Delayed diapedesis of CD8 T cells contributes to long-term pathology after ischemic stroke in male mice.

OBJECTIVE: Stroke is a debilitating disorder with significant annual mortality and morbidity rates worldwide. Immune cells are recruited to the injured brain within hours after stroke onset and can exhibit either protective or detrimental effects on recovery. However, immune cells, including CD8 T cells, persist in the injured brain for weeks, suggesting a longer-term role for the adaptive immune system during functional recovery. The aim of this study was to determine if the delayed secondary diapedesis of CD8 T cells into the ischemic brain negatively impacts functional recovery after transient ischemic stroke in male mice. RESULTS: Mice exhibited an increased number of leukocytes in the ipsilesional hemispheres at 14 days (3-fold; p < 0.001) and 30 days (2.2-fold; p = 0.02) after transient middle cerebral artery occlusion (tMCAo) compared to 8 days post-tMCAo, at which time acute neuroinflammation predominantly resolves. Moreover, mice with higher ipsilesional CD8 T cells at 30 days (R2 = 0.52, p < 0.01) exhibited worse functional recovery. To confirm a detrimental role of chronic CD8 T cell diapedesis on recovery, peripheral CD8 T cells were depleted beginning 10 days post-tMCAo. Delayed CD8 T cell depletion improved motor recovery on the rotarod (F(1,28) = 4.264; p = 0.048) compared to isotype control-treated mice. CD8 T cell-depleted mice also exhibited 2-fold (p < 0.001) reduced leukocyte infiltration at 30 days post-tMCAo. Specifically, macrophage, neutrophil, and CD4 T cell numbers were reduced in the ipsilesional hemisphere of the CD8 T cell-depleted mice independent of inflammatory status of the post-stroke CNS (e.g. microglial phenotype and cytokine production). RNAseq identified a unique profile for brain infiltrating CD8 T cells at 30 days post-tMCAo, with 46 genes differentially expressed relative to CD8 T cells at 3 days post-tMCAo. CONCLUSION: Our data reveal a role for CD8 T cells in the chronic phase post-stroke that can be therapeutically targeted. We demonstrate long-term CD8 T cell recruitment into the ipsilesional hemisphere that affects both immune cell numbers present in the injured brain and functional recovery through one month after stroke onset.

Association between early fluid overload and mortality in critically-ill mechanically ventilated children: a single-center retrospective cohort study.

BACKGROUND: Positive fluid overload (FO) may cause adverse effect. This study retrospectively analyzed the relationship between early FO and in-hospital mortality in children with mechanical ventilation (MV) in pediatric intensive care unit (PICU). METHODS: This study retrospectively enrolled 309 children (ages 28 days to 16 years) receiving invasive MV admitted to the PICU of Xinhua Hospital from March 2014 to March 2019. Children receiving MV for less than 48 h were excluded. The FO in the first 3 days of MV was considered to the early FO. Patients were divided into groups according to early FO and survival to evaluate the associations of early FO, percentage FO(%FO) > 10%, and %FO > 20% with in-hospital mortality. RESULTS: A total of 309 patients were included. The mean early FO was 8.83 ± 8.81%, and the mortality in hospital was 26.2% (81/309). There were no significant differences in mortality among different FO groups (P = 0.053) or in early FO between survivors and non-survivors (P = 0.992). Regression analysis demonstrated that use of more vasoactive drugs, the presence of multiple organ dysfunction syndrome, longer duration of MV, and a non-operative reason for PICU admission were related to increased mortality (P < 0.05). Although early FO and %FO > 10% were not associated with in-hospital mortality (ß = 0.030, P = 0.090, 95% CI = 0.995-1.067; ß = 0.479, P = 0.153, 95% CI = 0.837-3.117), %FO > 20% was positively correlated with mortality (ß = 1.057, OR = 2.878, P = 0.029, 95% CI = 1.116-7.418). CONCLUSIONS: The correlation between early FO and mortality was affected by interventions and the severity of the disease, but %FO > 20% was an independent risk factor for in-hospital mortality in critically ill MV-treated children.

Digital droplet polymerase chain reaction analysis of common viruses in the aqueous humour of patients with Posner-Schlossman syndrome in Chinese population.

BACKGROUND: To compare the detection results consistency of quantitative polymerase chain reaction (qPCR) and digital droplet polymerase chain reaction (ddPCR), and determine the value of ddPCR for viral detection in the aqueous humour. METHODS: A total of 130 aqueous humour samples were collected, including 60 patients with Posner-Schlossman syndrome (PSS) in case group and 70 elderly patients with senile cataract in control group. The target nucleic acid fragments of human cytomegalovirus (HCMV), herpes simplex virus, Epstein-Barr virus and varicella zoster virus in aqueous humour were analysed by qPCR and ddPCR, respectively, for the diagnosis and curative effect monitoring of pathogen-induced PSS. Samples with inconsistent results were verified by next-generation sequencing. RESULTS: There were 27 and 20 HCMV-positive cases detected in the case group by ddPCR and qPCR, respectively. ddPCR increased the sensitivity for the HCMV virus detection from 400 to 100 copies/mL. No other pathogens were found in this study. The results of ddPCR were consistent with that of next generation sequencing. The mean (SD) of Lg (HCMV copies/mL) detected by ddPCR and qPCR were 1.66 (1.92) and 1.10 (1.61), respectively (P < 0.001). Compared with qPCR, results of ddPCR showed better consistency with validity of clinical treatment. All patients with ddPCR-positive results had good validity on antiviral therapy, exhibiting anterior chamber inflammation remission, resolution of corneal oedema and good IOP control within 1 month. CONCLUSIONS: HCMV was the leading cause of pathogen-induced PSS in the Chinese population. ddPCR was a promising tool for early detection, accurate diagnosis and therapeutic validity monitoring of pathogen-induced PSS. The high sensitivity of ddPCR could avoid repeated anterior chamber tap.

Autoreactive CD19+CD20- Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis.

The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein-specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb-treated mice, but they remained detectable in the CD20 mAb-treated mice. Interestingly, residual disease severity in the CD20 mAb-treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19(+)CD20(-) plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19(+)CD20(-) plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19(+)CD20(-) B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.

Comparison of retinal microvascular changes in eyes with high-tension glaucoma or normal-tension glaucoma: a quantitative optic coherence tomography angiographic study.

PURPOSE: The aim of this study is to determine and compare the changes in the retinal vasculature in eyes with high-tension glaucoma (HTG) or normal-tension glaucoma (NTG). METHODS: The right eyes of 43 HTG subjects, 33 NTG subjects, and 51 age- and sex-matched normal subjects were included in this cross-sectional study. Signals were projected from the internal limiting membrane to retinal pigment epithelium. The retinal perfused vessel densities in the peripapillary and parafoveal regions were measured automatically with optic coherence tomography angiography and the split-spectrum amplitude-decorrelation angiography algorithm. RESULTS: Compared with normal eyes, glaucomatous eyes had a smaller retinal nerve fibre layer (RNFL) thickness, smaller full parafoveal retinal thickness, and lower retinal perfused vessel density (PVD) in the peripapillary and parafoveal regions (all P < 0.01). The visual field, RNFL and retinal thicknesses, and PVD in the parafoveal region in the HTG eyes were similar to those in the NTG eyes. However, the NTG eyes had a significantly lower mean PVD than the HTG eyes in the peripapillary region. When the different sectors of the peripapillary region were studied, the difference was still significant in most sectors (all P < 0.05), except the inferotemporal sector (P = 0.676). CONCLUSIONS: The retinal perfused vessel density is significantly reduced in HTG and NTG eyes, and more prominently in the peripapillary region in NTG eyes.

Peripapillary retinal vessel density in eyes with acute primary angle closure: an optical coherence tomography angiography study.

PURPOSE: The purpose was to investigate peripapillary retinal vessel density in resolved acute primary angle closure (APAC) eyes. METHODS: This was a prospective, cross-sectional observational study. Thirty-four eyes of 34 patients with unilateral APAC were included, together with the fellow eyes with primary angle closure suspect (PACS) as controls. Peripapillary retinal vessel density was measured using optical coherence tomography (OCT) angiography. Peripapillary retinal vessel density was compared in both eyes and the potential relationship with visual field (VF) test results was evaluated. RESULTS: After an acute attack, the peripapillary retinal vessel density was lower in the APAC than in the PACS eyes (79.3 ± 8.2 versus 85.6 ± 4.9, respectively; P = 0.001). The VF mean deviation (MD) (-7.7 ± 6.7 versus -3.3 ± 1.8 dB, P = 0.002), and the pattern standard deviation (PSD) (4.6 ± 3.3 versus 2.4 ± 0.9 dB, P = 0.001) were worse for the APAC than the PACS eyes, but both had similar thicknesses of the retinal nerve fiber layer (RNFL) (111.8 ± 9.6 versus 114.1 ± 29.1 µm, P = 0.880) and ganglion cell complex (GCC) (94.7 ± 7.5 versus 91.8 ± 9.3 µm, P = 0.328). The peripapillary retinal vessel density was significantly correlated with the VF MD (vessel density: r = 0.455, P = 0.008) and PSD (vessel density: r = -0.592, P < 0.001) in the APAC eyes. CONCLUSIONS: Even when IOP was normalized after the acute attack, the APAC eyes had a lower peripapillary retinal vessel density, which was correlated with the VF values. OCT angiography is a reliable method for detecting vascular changes in glaucomatous eyes that show no thinning of the RNFL and GCC.

Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms.

Plasma cells and the autoreactive Abs they produce are suspected to contribute to the pathogenesis of multiple sclerosis, but recent attempts to target these components of humoral immunity have failed. MEDI551, an anti-CD19 Ab that depletes mature B cells including plasma cells may offer a compelling alternative that reduces pathogenic adaptive immune responses while sparing regulatory mechanisms. Indeed, our data demonstrate that a single dose of MEDI551, given before or during ongoing experimental autoimmune encephalomyelitis, disrupts development of the disease. Leukocyte infiltration into the spinal cord is significantly reduced, as well as short-lived and long-lived autoreactive CD138(+) plasma cells in the spleen and bone marrow, respectively. In addition, potentially protective CD1d(hi)CD5(+) regulatory B cells show resistance to depletion, and myelin-specific Foxp3(+) regulatory T cells are expanded. Taken together, these results demonstrate that MEDI551 disrupts experimental autoimmune encephalomyelitis by inhibiting multiple proinflammatory components whereas preserving regulatory populations.

Correlation between optic disc perfusion and glaucomatous severity in patients with open-angle glaucoma: an optical coherence tomography angiography study.

PURPOSE: To explore how optic disc perfusion varies in patients with open-angle glaucoma (OAG) and how this correlates with glaucoma severity. METHODS: We performed a prospective and cross-sectional observational study that included 62 eyes from 62 patients with OAG, divided into three groups according to their visual field (VF) results, and 20 eyes from 20 normal control subjects. Optic disc perfusion was studied using optical coherence tomography angiography (angio-OCT), and flow index and vessel density were determined. The VF, mean deviation (MD), pattern standard deviation (PSD), retinal nerve fiber layer (RNFL) thickness, and ganglion cell complex (GCC) thickness were also recorded. The potential associations between disc perfusion and VF defects or structural loss were analyzed. RESULTS: In OAG patients, the disc flow index and vessel density were significantly lower than in normal controls (all p<0.001) and were correlated with the severity of glaucoma. In OAG eyes, the flow index and vessel density were significantly correlated with MD, RNFL, and GCC thickness (all p<0.01), but were not in the normal controls. The receiver operating characteristic (ROC) curve analysis also revealed that disc flow index and vessel density had the power to differentiate normal eyes from eyes with OAG (under the ROC curves: 0.82 and 0.80, respectively). CONCLUSIONS: Angiograms demonstrated a reduced disc flow index and vessel density in glaucoma, and this reduction was closely related to GCC thickness. This indicated that measurement of disc perfusion by angio-OCT might be important for the monitoring of glaucoma.

Repetitive hypoxic preconditioning induces an immunosuppressed B cell phenotype during endogenous protection from stroke.

BACKGROUND: Repetitive hypoxic preconditioning (RHP) creates an anti-inflammatory phenotype that protects from stroke-induced injury for months after a 2-week treatment. The mechanisms underlying long-term tolerance are unknown, though one exposure to hypoxia significantly increased peripheral B cell representation. For this study, we sought to determine if RHP specifically recruited B cells into the protected ischemic hemisphere, and whether RHP could phenotypically alter B cells prior to stroke onset. METHODS: Adult, male SW/ND4 mice received RHP (nine exposures over 2 weeks; 8 to 11 % O2; 2 to 4 hours) or identical exposures to 21 % O2 as control. Two weeks following RHP, a 60-minute transient middle cerebral artery occlusion was induced. Standard techniques quantified CXCL13 mRNA and protein expression. Two days after stroke, leukocytes were isolated from brain tissue (70:30 discontinuous Percoll gradient) and profiled on a BD-FACS Aria flow cytometer. In a separate cohort without stroke, sorted splenic CD19+ B cells were isolated 2 weeks after RHP and analyzed on an Illumina MouseWG-6 V2 Bead Chip. Final gene pathways were determined using Ingenuity Pathway Analysis. Student's t-test or one-way analysis of variance determined significance (P < 0.05). RESULTS: CXCL13, a B cell-specific chemokine, was upregulated in post-stroke cortical vessels of both groups. In the ischemic hemisphere, RHP increased B cell representation by attenuating the diapedesis of monocyte, macrophage, neutrophil and T cells, to quantities indistinguishable from the uninjured, contralateral hemisphere. Pre-stroke splenic B cells isolated from RHP-treated mice had >1,900 genes differentially expressed by microarray analysis. Genes related to B-T cell interactions, including antigen presentation, B cell differentiation and antibody production, were profoundly downregulated. Maturation and activation were arrested in a cohort of B cells from pre-stroke RHP-treated mice while regulatory B cells, a subset implicated in neurovascular protection from stroke, were upregulated. CONCLUSIONS: Collectively, our data characterize an endogenous neuroprotective phenotype that utilizes adaptive immune mechanisms pre-stroke to protect the brain from injury post-stroke. Future studies to validate the role of B cells in minimizing injury and promoting central nervous system recovery, and to determine whether B cells mediate an adaptive immunity to systemic hypoxia that protects from subsequent stroke, are needed.

Association between prolonged vancomycin infusion and trough concentrations in children. Retrospective study. / Asociación entre infusión prolongada de vancomicina y concentración valle en niños. Estudio retrospectivo.

Introduction: This study investigated the serum concentration of vancomycin during prolonged infusion in children. Population and methods: This retrospective cohort study included pediatric patients who received vancomycin from June 2017 to June 2020 at a tertiary referral hospital. The patients were divided into two groups according to infusion strategy, the SII (standard intermittent infusion) group and the PI (prolonged infusion) group. Demographic details, infusion period, serum creatinine, duration of vancomycin therapy, trough concentration of vancomycin, and pediatric intensive care unit stay were reviewed. Differences of the concentrations were measured. Results: Sixty-eight patients were included: 31 in the SII group and 37 in the PI group. The trough concentration of vancomycin was significantly higher in the PI group than in SII group (11.2 mg/L [5.9-13.7] vs. 7 mg/L [3.5- 9.3]; p = 0.02). The target attainment rate was higher in the PI group than in the SII group (59.4% and 19.3%, respectively; p = 0.001). There were no significant differences between the SII and PI groups regarding the peak concentrations of vancomycin, final creatinine and peak creatinine. There were no differences between the SII and PI groups regarding the failure events, PICU stay and duration of vancomycin therapy. The multivariable analysis showed that PI was significantly associated with higher trough serum concentrations of vancomycin (OR = 2.27; p = 0.005). Conclusion: Compared to the SII strategy, the PI strategy may be an optimized option to children with severe infection, as it can achieve higher trough concentrations and target concentration attainment.

Introducción: Este estudio investigó la concentración plasmática de vancomicina en los niños, durante la infusión prolongada. Población y métodos: Estudio retrospectivo de una cohorte que incluyó pacientes pediátricos tratados con vancomicina desde junio de 2017 hasta junio de 2020, en un hospital de referencia de nivel III. Los pacientes se dividieron en dos grupos sogún el tipo de infusión: el grupo de infusión intermitente estándar (IIE) y el grupo de infusión prolongada (IP). Se registraron detalles demográficos, periodo de infusión, creatinina plasmática, duranción del tratamiento con vancomicina, concentración valle de vancomicina y permanencia en la unidad de cuidados intensivos pediátricos (UCIP). Se midieron las diferencias entre concentraciones. Resultados: Se incluyeron 68 pacientes, 31 en el gruop IIE y 37 en el grupo IP. La concentración valle de vancomicina fue significativamente más alta en el grupo IP en comparación con el grupo IIE (11,2mg/L [5,9-13,7] vs. 7 mg/L [3,5-9,3]; p = 0,02). La tasa de logro del objetivo fue más alta en el grupo IP que en el grupo IIE (59,4 % y 19,3 % repectivamente; p = 0,001). No hubo diferencias significativas entre ambos grupos en las concentraciones pico de vancomicina, valor de creatinina final, pico de creatinina, fracaso terapéutico, duración de la estadía en la UCIP y duración del tratamiento con vancomicina. El análisis multivariado mostró que la IP se asoció en forma significativa con concentraciones valle más altas de vancomicina (OR: 2,27, p = 0,005). Conclusión: En comparación con la estrategia de IIE, la infusión prolongada puede ser una opción optimizada para los niños con infección grave, porque puede alcanzar concentraciones valle más altas y mejorar la obtención de la concentración objetivo.

Outcomes of Filtering Surgery Versus Clear Lens Extraction in Young Patients With Angle-Closure Glaucoma.

PURPOSE: To compare the effect of filtering surgery versus clear lens extraction in young patients with medically uncontrolled angle-closure glaucoma (ACG). DESIGN: Retrospective, nonrandomized, comparative, interventional study. METHODS: We reviewed the medical charts of patients with the following scenarios: (1) age ≤40 years; (2) diagnosis of ACG without cataract, including primary angle-closure glaucoma (PACG), nanophthalmic ACG, and ACG combined with retinal dystrophies; and (3) ACG undergoing filtering surgery or clear lens extraction. The main outcomes including intraocular pressure (IOP), number of medications, best-corrected visual acuity, and severe complications were extracted at the postoperative early (within 1 week) and late stage (>3 months) follow-up. RESULTS: Data from 160 eyes of 130 young patients with ACG were available. Eyes with 76 PACG, 12 nanophthalmic ACG, and 26 ACG with retinal diseases underwent filtering surgery, whereas eyes with 22 PACG, 12 nanophthalmic ACG, and 12 ACG with retinal diseases received clear lens extraction. Overall, filtering surgery and clear lens extraction resulted in significant but comparable IOP and drug reductions at the postoperative late stage in each ACG subgroup, with similar complete success rates between 2 treatments (all P > .05). Regarding the safety, filtering surgery and patients with retinal diseases were independent factors associated with postoperative malignant glaucoma (P < .05 in both multivariable logistic regression models). CONCLUSIONS: This study highlights that the efficacy of clear lens extraction is comparable to that of filtering surgery in medically uncontrolled ACG in young patients, but clear lens extraction is safer, especially for young patients with ACG comorbid with retinal diseases.

A meta-analysis of randomized controlled trials evaluating the effectiveness and safety of the repeated low-level red light therapy in slowing the progression of myopia in children and adolescents.

PURPOSE: The aim of this study was to evaluate the effectiveness and safety of repeated low-level red light (RLRL) therapy in controlling myopia progression in children through a meta-analysis. METHODS: We searched several databases including PubMed, Embase, The Cochrane Library, Web of Science, CNKI, WANFANG, CBM, and VIP with languages restricted to both Chinese and English. The search was conducted from the establishment of the databases to March 23, 2023. We collected randomized controlled trials and controlled experiments to evaluate changes in axial length (AL) and spherical equivalent (SE) before and after RLRL intervention. Two researchers performed literature screening and data extraction, and RevMan software (Ver 5.3) and StataMP 17.0 were used for meta-analysis. RESULTS: A total of 141 articles were retrieved, and finally, six randomized controlled trials met the inclusion and exclusion criteria, including 820 eyes (RLRL group: 411 eyes, control group: 409 eyes). The meta-analysis results showed that the RLRL group was significantly better than the control group in controlling AL, and the difference between the two groups was statistically significant (mean difference [MD] = -0.22, 95% confidence interval [CI] [ - 0.28, -0.16]; P < 0.001). The RLRL group was also better than the control group in terms of SE, and the difference between the two groups was statistically significant (MD = 0.46, 95% CI [0.32, 0.6]; P < 0.001). Five studies reported adverse reactions in the RLRL group, and two cases stopped treatment due to the feeling of too bright light, while the others had no significant side effects in the short term. CONCLUSION: RLRL therapy is a safe and effective method for controlling myopia, which can inhibit the growth of AL and slow down the progression of myopia. However, further research and validation are needed to determine its treatment efficacy and course.

Expression of Matrix Metalloproteinase-3 in the Aqueous Humor of Patients with Posner-Schlossman Syndrome.

PURPOSE: To explore the expression of matrix metalloproteinase-3 (MMP-3) in the aqueous humor of patients with Posner-Schlossman syndrome (PSS), and the association between MMP-3 and PSS. METHODS: Peripheral blood and aqueous humor were routinely collected from 29 patients with PSS (PSS group) and 30 patients with age-related-cataract (ARC) (control group). The content of MMP-3 in serum and aqueous humor was measured by immunoturbidimetry. The correlation between MMP-3 and ophthalmic examination results were verified by Spearman's correlation analysis. RESULTS: The MMP-3 level in the aqueous humor of the PSS group was (25.86 ± 13.4)ng/ml, significantly higher than that in the control group (3.9 ± 2.7)ng/ml(p < 0.001), while there was no significant difference in serum MMP-3 level between the two groups (p = 0.125). The endothelial cell density (ECD) in the aqueous humor of the PSS group was (2078 ± 440) cell/mm2, intraocular pressure (IOP) in the aqueous humor of the PSS group was (33 ± 12) mmHg. The correlation analysis of aqueous humor MMP-3 and various ophthalmic examination results showed that aqueous humor MMP-3 had a moderate correlation with IOP and the difference in ECD between the affected eye and the fellow eye. CONCLUSIONS: MMP-3 level is elevated in the aqueous humor of PSS patients, and it may play an important role in the pathogenesis of PSS.