Retinal waves are correlated bursts of spontaneous activity whose spatiotemporal patterns are critical for early activity-dependent circuit elaboration and refinement in the mammalian visual system. ...Three separate developmental wave epochs or stages have been described, but the mechanism(s) of pattern generation of each and their distinct roles in visual circuit development remain incompletely understood. We used neuroanatomical,in vitroandin vivoelectrophysiological, and optical imaging techniques in genetically manipulated mice to examine the mechanisms of wave initiation and propagation and the role of wave patterns in visual circuit development. Through deletion of β2 subunits of nicotinic acetylcholine receptors (β2-nAChRs) selectively from starburst amacrine cells (SACs), we show that mutual excitation among SACs is critical for Stage II (cholinergic) retinal wave propagation, supporting models of wave initiation and pattern generation from within a single retinal cell type. We also demonstrate that β2-nAChRs in SACs, and normal wave patterns, are necessary for eye-specific segregation. Finally, we show that Stage III (glutamatergic) retinal waves are not themselves necessary for normal eye-specific segregation, but elimination of both Stage II and Stage III retinal waves dramatically disrupts eye-specific segregation. This suggests that persistent Stage II retinal waves can adequately compensate for Stage III retinal wave loss during the development and refinement of eye-specific segregation. These experiments confirm key features of the "recurrent network" model for retinal wave propagation and clarify the roles of Stage II and Stage III retinal wave patterns in visual circuit development.
Spontaneous activity drives early mammalian circuit development, but the initiation and patterning of activity vary across development and among modalities. Cholinergic "retinal waves" are initiated in starburst amacrine cells and propagate to retinal ganglion cells and higher-order visual areas, but the mechanism responsible for creating their unique and critical activity pattern is incompletely understood. We demonstrate that cholinergic wave patterns are dictated by recurrent connectivity within starburst amacrine cells, and retinal ganglion cells act as "readouts" of patterned activity. We also show that eye-specific segregation occurs normally without glutamatergic waves, but elimination of both cholinergic and glutamatergic waves completely disrupts visual circuit development. These results suggest that each retinal wave pattern during development is optimized for concurrently refining multiple visual circuits.
Endoscopic submucosal dissection (ESD) is accepted as an established treatment modality for superficial esophageal carcinoma (SEC). The aim of this study was to identify risk factors for ...postoperative stricture after ESD for SEC.
This was a retrospective study at a single institution. A total of 362 patients with SEC treated by ESD at Zhongshan Hospital, Shanghai, were enrolled between January 2007 and February 2012. Demographic and clinical parameters, including patient-, lesion-, and procedure-related factors, were analyzed for postoperative stricture risk factors.
The postoperative stricture rate was 11.6 % (42/362). The mean and median time from ESD to stricture was 58.5 ± 12.3 days (range 21 - 90 days) and 28 days, respectively. Mild, median, and severe stricture were observed in 16.7 % (7/42), 38.1 % (16 /42), and 45.2 % (19/42) of patients, respectively. Multivariate analysis revealed that circumferential extension of > 3/4 (odds ratio OR 44.2, 95 % confidence interval CI 4.4 - 443.6) and the depth of invasion above m2 (OR 14.2, 95 %CI 2.7 - 74.2) were independent risk factors for stricture. The degree of stricture was also related to lesion circumferential extension (relational coefficient φ = 0.47; P < 0.05) and histological depth (relational coefficient φ = 0.647; P < 0.05).
Circumferential extension and histological depth were reliable risk factors for postoperative stricture.
Peroral endoscopic myotomy (POEM) is now a widely used treatment for esophageal achalasia, supported by several large cohort studies. Although major perioperative adverse events (mAE) are rare, ...in-depth investigations of related risks and preventive measures are lacking. The aim of this study was to systematically assess mAEs during POEM by analyzing their incidence, risks, prevention, and management.
This retrospective single-center analysis included all patients (n = 1680) undergoing POEM between August 2010 and July 2015 at Zhongshan Hospital. Major adverse events were defined as: vital-sign instability, intensive care unit (ICU) stay, hospital readmission, conversion to open surgery, invasive postoperative procedure, blood transfusion, or prolonged (> 5 days) hospitalization for functional impairment.
A total of 55 patients (3.3 %, 95 % confidence interval CI 2.5 % - 4.2 %) experienced mAEs: delayed mucosal barrier failure (n = 13, 0.8 %; 95 %CI 0.4 % - 1.3 %), delayed bleeding (n = 3, 0.2 %; 95 %CI 0.04 % - 0.5 %), hydrothorax (n = 8, 0.5 %; 95 %CI 0.2 % - 0.9 %), pneumothorax (n = 25, 1.5 %; 95 %CI 1.0 % - 2.2 %), and miscellaneous (n = 6, 0.4 %; 95 %CI 0.1 % - 0.8 %). Four patients (0.2 %) required ICU admission. No surgical conversion occurred, and 30-day mortality was zero. In stepwise multivariate regression, institution experience of < 1 year (odds ratio OR 3.85, 95 %CI 1.49 - 9.95), air insufflation (OR 3.41, 95 %CI 1.37 - 8.50), and mucosal edema (OR 2.01, 95 %CI 1.14 - 3.53) were identified as related risk factors. After introducing CO
insufflation, the mAE rate declined to 1.9 % (95 %CI 1.2 % - 2.7 %) and seemed to plateau after 3.5 years at ~ 1 %.
In general, POEM appears to be a safe procedure. Major adverse events were rare and could usually be prevented or anticipated, and were all managed effectively.
Background
Achalasia is an esophageal motility disorder with unknown etiology. Previous findings indicate that immune‐mediated inflammatory process causes inhibitory neuronal degeneration. This study ...was designed to evaluate levels of serological cytokines and chemokines in patients with achalasia.
Methods
We collected information from forty‐seven patients with achalasia who underwent peroral endoscopic myotomy. Control samples were collected from forty‐seven age‐ and sex‐matched healthy people. The concentrations of serological cytokines and chemokines were analyzed by Luminex xMAP immunoassay. Serological and clinical data were compared between groups.
Key Results
Compared with healthy controls, achalasia patients had significantly increased concentrations of eleven cytokines and chemokines, namely, TGF‐ß1 (P < .001), TGF‐ß2 (P < .001), TGF‐ß3 (P < .001), IL‐1ra (P < .001), IL‐17 (P = .005), IL‐18 (P < .001), IFN‐γ (P < .001), MIG (P < .001), PDGF‐BB (P < .001), IP‐10 (P = .003), and SCGF‐B (P < .001). Gene ontology (GO) and network functional enrichment analysis revealed regulation of signaling receptor activity and receptor‐ligand activity were the most related pathways of these cytokines and chemokines. Levels of twelve cytokines and chemokines were significantly increased in type III compared with I/II achalasia, namely, TGF‐ß2, IL‐1ra, IL‐2Ra, IL‐18, MIG, IFN‐γ, SDF‐1a, Eotaxin, PDGF‐BB, IP‐10, MCP‐1, and TRAIL.
Conclusions and Inferences
Patients with achalasia exhibited increased levels of serological cytokines and chemokines. Levels of cytokines and chemokines were significantly increased in type III than in type I/II achalasia. Cytokines and chemokines might contribute to the inflammatory development of achalasia.
The possible mechanism of the 11 cytokines and chemokines in the pathogenesis of achalasia. Both pro‐and anti‐inflammatory pathways are activated in achalasia, while proinflammatory pathways dominate in the immune imbalance. Besides, the fibroplasia accelerates the progress of the immune reaction.
Esophageal squamous cell carcinoma (ESCC) causes aggressive and lethal malignancies with extremely poor prognoses, and accounts for about 90% of cases of esophageal cancer. Neuropilin and ...tolloid-like 2 (NETO2) protein coding genes have been associated with various human cancers. Nevertheless, little information is reported about the phenotypic expression and its clinical significance in ESCC progression. Here, our study found that NETO2 expression in ESCC patients was associated with tumor clinical stage and lymph node metastasis status. Gain-of-function and loss-of-function analyses showed that NETO2 stimulated ESCC cell proliferation while suppressing apoptosis
and enhanced tumor growth
. Moreover, knockdown of NETO2 significantly inhibited migration and invasion in combination with regulation of epithelial-mesenchymal transition (EMT) related markers. Mechanistically, overexpression of NETO2 increased the phosphorylation of ERK, PI3k/AKT, and Nuclear factor erythroid-2-related factor 2(Nrf2), whereas silencing NETO2 decreased the phosphorylation of these targets. Our data suggest that Nrf2 was a critical downstream event responsible for triggering the PI3K/AKT and ERK signaling pathways and plays a crucial role in NETO2-mediated tumorigenesis. Taken together, NETO2 acts as an oncogene and might serve as a novel therapeutic target or prognostic biomarker in ESCC patients.
No prediction rule is currently available for advanced colorectal neoplasms, defined as invasive cancer, an adenoma of 10 mm or more, a villous adenoma, or an adenoma with high-grade dysplasia, in ...average-risk Chinese. In this study between 2006 and 2008, a total of 7,541 average-risk Chinese persons aged 40 years or older who had complete colonoscopy were included. The derivation and validation cohorts consisted of 5,229 and 2,312 persons, respectively. A prediction rule was developed from a logistic regression model and then internally and externally validated. The prediction rule comprised 8 variables (age, sex, smoking, diabetes mellitus, green vegetables, pickled food, fried food, and white meat), with scores ranging from 0 to 14. Among the participants with low-risk (≤3) or high-risk (>3) scores in the validation cohort, the risks of advanced neoplasms were 2.6% and 10.0% (P < 0.001), respectively. If colonoscopy was used only for persons with high risk, 80.3% of persons with advanced neoplasms would be detected while the number of colonoscopies would be reduced by 49.2%. The prediction rule had good discrimination (area under the receiver operating characteristic curve = 0.74, 95% confidence interval: 0.70, 0.78) and calibration (P = 0.77) and, thus, provides accurate risk stratification for advanced neoplasms in average-risk Chinese.
Objective
Maternal vitamin D deficiency is associated with glucose and lipid metabolism in the mother and offspring. Meanwhile, it can also lead to adverse pregnancy outcomes. The aim of this ...case‐control study was to document maternal, umbilical arterial glucose and lipid metabolic levels and correlations in pregnancies with or without vitamin D deficiency, while also investigating adverse pregnancy outcomes.
Design/Participants/Measurements
A total of 425 pregnant women who received antenatal care and delivered at Wenzhou People's Hospital were enrolled. According to their serum 25‐hydroxyvitamin D 25(OH)D level, the pregnant women were divided into the vitamin D deficiency group 25(OH)D < 20 ng/mL, 185 participants and the control group 25(OH)D ≥ 20 ng/mL, 240 participants. Maternal blood samples were collected at 24‐28 weeks of gestation and delivery for 75‐g oral glucose tolerance test (OGTT), and measurements of glucose and lipid metabolite levels and 25(OH)D levels. Umbilical arterial samples were collected during delivery (33.57‐41.43 gestational weeks).
Results
Compared with control participants, vitamin D deficiency women had significantly higher concentrations of fasting blood‐glucose (P < .01), 1‐h OGTT plasma glucose (P < .01), 2‐h OGTT plasma glucose (P < .01), insulin (P < .01), HOMA‐IR (P < .01), LDL (P < .01) and triglycerides (P = .02) and lower concentrations of HOMA‐S (P < .01). Compared with the control group, vitamin D deficiency women had higher concentrations of triglycerides (P < .01) and lower concentrations of HDL‐C (P < .01) and HOMA‐β (P = .01) in infant umbilical arterial blood. Pearson's correlation analysis demonstrated that the maternal 25(OH)D level was negatively correlated with maternal plasma glucose, insulin, LDL‐C, cholesterol, triglyceride and HOMA‐IR (r = −.38, −.27, −.2, −.11, −.11, −.33 and .11; P < .01, <.01, <.01, <.05, <.05 and <.01, respectively), while there was a positive correlation between maternal serum 25(OH)D and HOMA‐S (r = .11, P < .05). The triglyceride level in the umbilical artery was negatively correlated with maternal serum 25(OH)D concentration (r = −.286, P < .01), while the HDL‐C and HOMA‐β in umbilical artery were positively related (r = .154, .103, P < .01). Compared with the control group, the incidences of pre‐eclampsia 4.8% (9/185) vs 1.25% (3/240), P = .03, gestational diabetes mellitus 19.45% (36/185) vs 12.08% (29/240), P = .04 and premature rupture of membranes 15.68% (29/185) vs 5.42% (13/240), P < .01 were higher in the vitamin D deficiency group.
Conclusion
Vitamin D deficiency during pregnancy is associated with maternal glucose and lipid metabolism and pregnancy outcomes. Therefore, it is worth recommending to maintain vitamin D status at an optimal level in pregnant women to prevent metabolic disorders and pregnancy complications.
Background Given the high morbidity and mortality rates for surgery and the diminishment of quality of life caused by operative resection of the gastric cardia, a minor invasive treatment without ...loss of curability is desirable for submucosal tumors (SMTs) of the esophagogastric junction (EGJ). Endoscopic submucosal dissection (ESD) has been used successfully for the removal of esophageal or gastric SMTs; however, the EGJ has been regarded as a difficult location for ESD because of its narrow lumen and sharp angle. Objective To evaluate the clinical impact of ESD for SMTs of the EGJ arising from the muscularis propria layer. Design Single-center, prospective study. Setting Academic medical center. Patients 143 patients with 143 SMTs of the EGJ originating from the muscularis propria layer. Interventions ESD. Main Outcome Measurements Complications, en bloc resection rate, local recurrence, and distant metastases. Results The average maximum diameter of the lesions was 17.6 mm (range 5 - 50 mm). The en bloc resection rate was 94.4% (135/143). All en bloc resection lesions showed both lateral and deep tumor-free margins, including 20 GI stromal tumors. Perforations occurred in 6 patients (4.2%, 6/143), and metal clips were used to occlude the defect. Four pneumoperitoneum and 2 pneumothorax caused by perforations were resolved with nonsurgical treatment. Local recurrence and distant metastasis have not occurred during a 2-year follow-up. Limitations Single-center, short follow-up. Conclusions ESD appears to be a safe, feasible, and effective procedure for providing accurate histopathologic evaluations, as well as curative treatments for SMTs of the EGJ originating from the muscularis propria layer.
Background
An increasing number of studies have been conducted on the use of endoscopic ultrasound (EUS)-guided needle sampling for upper gastrointestinal subepithelial lesions (SEL). However, ...reported diagnostic efficacy varies greatly.
Objective
To summarize up current evidences on the diagnostic efficacy of EUS-guided needle sampling for upper GI SEL.
Method
A reproducible strategy was used to search four databases. Search results were evaluated for eligibility, and the quality of eligible studies was assessed by QUADAS-2. Pooled efficacy of EUS-guided needle sampling in upper GI SEL was calculated. Procedure-related complications, diagnostic errors, and independent factors related to a higher success rate were also recorded and analyzed.
Results
Seventeen studies, comprising 978 attempts of EUS-guided needle sampling, were included in a meta-analysis. Pooled diagnostic rate of EUS-guided needle sampling was 59.9 %, with a heterogeneity
I
2
of 55.2 %. Subgroup analysis showed no difference in diagnostic rate among fine needle aspiration (FNA), trucut needle biopsy (TCB), and fine needle biopsy (FNB), or among 19-, 22-, and 25-G needles. Subgroup analysis and meta-regression suggested that the cell block method might be correlated with a higher diagnostic rate. Few severe complications were reported. Diagnosis errors were rare.
Conclusion
EUS-guided needle sampling is a safe, but only moderately effective method for pathology diagnosis of upper GI SEL. Choice of FNA/TCB/FNB, or 19 G/22 G/25 G does not seem to alter the overall diagnostic rate.
Local recurrence of esophageal squamous cell carcinoma (ESCC) after endoscopic resection does not have an established treatment. The efficacy and safety of repeat endoscopic submucosal dissection ...(ESD) for recurrent ESCC were determined in the study.
Forty-three consecutive patients with 45 locally recurrent superficial ESCC lesions undergoing repeat ESD and 909 first ESD lesions for propensity score matching (PSM) at Zhongshan Hospital between January 2011 and January 2020 were retrospectively enrolled. After PSM (1:2), operation-related parameters were compared between repeat ESD and first ESD. In the repeat ESD group, the Kaplan-Meier method and log-rank tests were used for identification of risk factors for local recurrence after repeat ESD.
As compared with propensity score–matched first ESD, rates of complete resection (86.7% vs 97.8%, P = .02) and curative resection (86.7% vs 96.7%, P = .06) were lower and procedure duration (54.8 ± 21.7 minutes vs 46.2 ± 20.6 minutes, P = .67) and hospital stay (4.3 ± 1.8 days vs 2.9 ± 1.4 days, P = .25) were longer in the repeat ESD group. The en-bloc resection rate (93.3% vs 98.8%, P > .11) remained comparable. Adverse events including bleeding (4.4% vs 0%, P = .11), perforation (.0% vs .0%, P > .99), and stricture (6.7% vs 2.2%, P = .33) presented with no difference. The 5-year overall survival rate and recurrence-free survival rate for repeat ESD was 100% and 86.0%, respectively. Multiplicity was significantly associated with recurrence after repeat ESD (P = .01).
Repeat esophageal ESD showed favorable short- and long-term outcomes and thus provides an alternative choice for recurrent superficial ESCC.
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