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Electroacupuncture (EA) is a popular therapeutic therapy for premature ovarian insufficiency (POI). However, little has been known about the underlying processes of EA therapy. To investigate the benefit of EA and reveal the mechanism, thirty SD female rats were allocated into the control, model, sham, EA, and GnRHa groups at random. Vaginal smears were used to monitor the rats’ estrous cycle. Serum liver and renal function (ALT, AST, BUN, and Cr), sex hormone (FSH, E2, and AMH), oxidative stress markers (SOD, GSH, and MDA), and inflammatory cytokine (IL6, IL1β, and TNFα) levels were measured by enzyme-linked immunosorbent assay (ELISA). Their ovary morphology was observed by hematoxylin-eosin staining. Transmission electron microscope was used to remark the ultrastructure of the granulocytes. Protein and gene expressions of Keap1/Nrf2/HO-1 pathway were detected by western blot and RT-PCR. Compared with the model group, in the EA group, the levels of serum sex hormones recovered to normal levels. Moreover, it reduced oxidative stress in rats, as demonstrated by increased SOD and GSH levels and decreased MDA levels. Meanwhile, Keap1 mRNA and protein expression dropped considerably in the EA group, while the mRNA and protein expressions of Nrf2 and HO-1 increased. We found that preventive EA might rescue rats with CTX-induced ovarian dysfunction. The anti-inflammatory and antioxidative stress properties of EA, which elevated the Keap1/Nrf2/HO-1 signaling pathway, might be the underlying mechanism. Furthermore, as compared to GnRHa, electroacupuncture did not raise the burden of the liver (ALT and AST) or the kidney (BUN and Cr). Electroacupuncture has a meaningful impact and a sufficient level of safety, making it useful for therapeutic setting in POI.

Preterm birth is the leading cause of mortality and morbidity in infants. Its etiology is multifactorial with genes and immune homeostasis. The authors investigated whether prostaglandin (PG) synthesis related single nucleotide polymorphisms (SNPs) PLA2G4C rs1366442 and PLA2G4D rs4924618 were associated with the risk of spontaneous preterm birth (SPTB) in a Chinese population of 114 cases of SPTB and 250 controls of term delivery. The risk associations were determined by odds ratios (ORs) and their 95% confidence intervals (CIs) calculated using multivariate logistic regression. Homology modeling was performed to elucidate potential mechanism of the SNP function. The maternal AT/TT genotype of PLA2G4D rs4924618 was associated with a reduced risk of SPTB (OR, 0.61; 95% CI, 0.37‑0.99), while no significant association between PLA2G4C rs1366442 and SPTB risk was identified. Structure and sequence analysis revealed that the amino acid substitution introduced by this SNP located at the conserved central core of the catalytic domain of cytosolic phospholipase A2 δ and was close to the active site. These findings suggested that the polymorphism of PLA2G4D rs4924618 may have a protective influence on the SPTB susceptibility in a Chinese population, supporting a role for genetics in the association between PG synthesis and preterm birth.

This study aims to investigate the relationship between gastrointestinal dysfunction (GD) and cirrhosis severity in cirrhotic patients, to provide evidences for the prevention and treatment of GD in cirrhotic patients. A total of 95 cirrhotic inpatients and outpatients, who were treated in the Department of Gastroenterology of Xinqu Hospital of the First Affiliated Hospital of Henan University of Science and Technology, were enrolled in the present study, and assigned as the experimental group (cirrhosis group). According to Child–Pugh classification, these patients were divided into 3 groups: group A (n = 45), group B (n = 23), and group C (n = 27). Forty healthy adults who received health check-ups during the same period served as the control group. The gastrointestinal (GI) symptoms of cirrhotic patients were scored, and the fasting serum gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) levels were measured in all subjects. The potential correlations of GI symptom scores of patients in these cirrhosis groups with GI hormone levels and cirrhosis severity were analyzed. In cirrhotic patients, the GI symptom scores significantly increased. Furthermore, the symptom scores gradually increased along with the aggravation of liver damage. Moreover, serum GAS and VIP levels were significantly higher in the cirrhosis groups than in the control group, whereas MTL levels were significantly lower. These changes were significantly correlated with cirrhosis severity. The linear correlation analysis revealed that the GI symptom score was positively correlated with GAS and VIP levels, and negatively correlated with MTL level. In addition, the linear correlation analysis revealed that GI symptom score and GAS and VIP levels were positively correlated with cirrhosis severity, whereas MTL level was negatively correlated with cirrhosis severity. Cirrhotic patients have more obvious GI symptoms and higher GI hormone levels, which are closely correlated with the progression of liver cirrhosis and the degree of liver function damage.

This study aims to investigate the gastrointestinal functions of patients with liver failure (LF) based on gastrointestinal dysfunction (GD) scores and serum gastrointestinal hormone levels. The GD in LF patients was scored using the gastrointestinal dysfunction scoring criteria. Serum gastrin (GAS), cholecystokinin (CCK), and motilin (MTL) levels were determined in LF patients. In addition, liver function and prothrombin activity were detected, and ultrasonography was performed. The GD score was significantly higher in the LF groups than in the control group. Compared with the control group, serum GAS, CCK, and MTL levels significantly increased in the LF groups, and was positively correlated with the severity of LF. Furthermore, in the LF groups, GD was positively correlated with the severity of LF. However, the GD score and serum GAS, CCK, and MTL levels in the acute LF group were not statistically different, when compared with those in the subacute LF group, acute-on-chronic LF group and chronic LF group. LF plays a key role in the development of GD, and may be the main cause of obvious gastrointestinal symptoms, such as abdominal distension, nausea, vomiting and anorexia, in LF patients. The severity of GD is not associated with LF type, but is positively correlated with the severity of LF, suggesting that GD in LF patients may have complicated mechanisms.

To the Editor: I read with great interest the study by Shen et al. titled “Alterations of high endothelial venules in primary and metastatic tumors are correlated with lymph node metastasis of oral and pharyngeal carcinoma and congratulate them on their insightful findings and results”.1 They studied high endothelial venules (HEV) in 64 cases of primary oral and pharyngeal squamous cell carcinoma (OPSCC) and demonstrated morphological and functional changes of HEV during OPSCC progression which were correlated with LN metastasis. They also reported the HEV endothelial cell proliferation rate was the highest in metastatic LNs and concluded these tumor-associated remodeled HEV are correlated with LN metastasis of OPSCC and play a crucial role in the metastasis cascade. This observation, in my opinion, is interesting but not novel. We have previously reported in 2012 very similar findings in 65 cases of tongue SCC and their LN basin.2 In addition, we correlated the HEV immunohistochemistry findings and vessel density with the respective patients’ clinical outcome. We had previously proposed and defined the following HEV parameters as an objective and systematic method of analyzing HEV characteristics.3 Definition of the HEV parameters and ratios (Fig. 1): Figure 1. Definitions of the high endothelial venules (HEV) parameters and its ratios (A) and metamorphosis spectrum of HEV in a nodal microenvironment (B). (A) Venn diagram illustrating the relationship between HEV and their different morphological forms. ... • number of all HEV: A • number of dilated HEV (defined as lumen size more than 80 square micron): B • number of dilated HEV with red blood cells (RBC) within its lumen: C The ratios of these abnormal HEV (B and C) with respect to the total number of HEV (A). • Ratio of dilated HEV to the total number of HEV: B/A • Ratio of dilated HEV with RBC within its lumen to total number of dilated HEV: C/B • Ratio of dilated HEV with RBC within its lumen with respect to total number HEV: C/A We demonstrated the total number of HEV in the LN was found to be significantly associated to disease-free interval and there was a similar association comparing the above defined HEV parameters to overall survival. The density of abnormal HEV was significantly higher in patients with established metastases in their lymph nodes and HEV was shown to be a better prognosis factor than conventional tumor staging.3 This is support of their findings in a few aspects, first the total MECA-79+ vessels (defined by us as “total number of HEV”) was higher in LN with metastasis (P = 0.051) and second HEV-like vessels (defined by us as “abnormal HEV”) was also higher in LN with metastasis (P = 0.037). In their study, they expressed the different morphological forms of HEV as “classic HEVs” and “HEV-like vessels” according to their features. We think the description of “HEV-like vessels” may not be precise as we believe these vessels are in fact originally HEV which have transformed morphologically due to a functional change in the presence of cancer. In my opinion, the term “abnormal or modified HEV” is a more accurate description for these vessels. We also demonstrated similar findings but we believe that the HEV morphological metamorphosis is not in just 2 distinct forms but encompasses a whole morphological spectrum that correlates well with both disease progression and clinical outcome.3 Our hypothesis is that the HEV transformation starts from a normal immunological mediator to a tumor metastasis mediator: this is reflected by morphological changes from a normal appearing HEV, to a dilated HEV, and then to a dilated HEV containing RBC. We believe that this metamorphosis occurs progressively as a spectrum—this process begins with the HEV increasing in absolute numbers, then each becoming more dilated before progressing into a functional vessel carrying blood (Fig. 1B) The authors demonstrated that 12.3% of their cases have HEV-mediated venolymphatic metastases and more than a third (12.3% + 24.7%) of metastasis involves a venolymphatic route. More importantly they have observed that in the cases of HEV-mediated venolymphatic metastases, tumor emboli were situated in the paracortical regions, adjacent to HEVs or just out of the vessels, without any association with lymphatic channels or sinuses. These findings, in addition to the observations that tumor foci were surrounded by abundant HEV, MECA-79+ vessels were observed within the metastatic tumor and that the tumor cells tended to infiltrate to the HEV-rich regions in the front of metastasis, are strongly supportive of our hypothesis that HEV serves as a physical shortcut in the LN for cancer cell metastasis to the systematic vascular system—thereby bypassing the long traditional lymphatic vessel to thoracic duct to subclavian vein route. This is further evident from our observations of the presence of significant abundance of red blood cells within the HEV and significant increase size of its lumen in the presence of a tumor. Our combined findings support the hypothesis that HEV presumably functions like a blood vessel in anticipation to supply the needs for an accelerating growth of a soon-to-arrive tumor deposit, i.e., “preparing the soil”.4,5 As a possible reason for the apparent contradictory findings of high HEV density in primary tumors associated with good prognosis but vice versa when high HEV density are observed in LNs,6 we believe that there is a “point of no return” in this process. HEV proliferate in the primary tumor in response to the cancer, as part of their native and normal immune role, recruiting tumor-associated lymphocytes to combat the tumor and hence, this is reflected and consistent with the findings that high density of HEV and high level of cytotoxic lymphocytes in the primary tumor are often associated with good clinical prognosis.7,8 Once the tumor proliferates beyond the immunotherapy capacity of the tumor-associated T lymphocytes and overwhelms it, tumor cytokines or even single tumor cells escape via lymphatics or tumor HEV themselves to the LN and induces the metamorphosis of the HEV in the LNs from slit-like empty lymphocyte carrier to a large lumen functioning blood vessel. In fact, it was shown that in the presence of cancer, the HEV becomes the predominant blood vessels in the LN.4 Hence, the findings and conclusions of the authors consistently and highly support our previous hypothesis and also provided more evidence that HEV plays a central role in the cancer metastasis cascade. Akin to HEV functioning as a gateway for recruiting lymphocytes in immunological conditions (“lymphocyte trafficking”); in the presence of a cancer, they transformed to that of “tumor cell trafficking” role instead.