Characteristics and Risk Factors of Functional Dyspepsia Fulfilling the Rome IV Criteria Overlapping With Gastroesophageal Reflux Disease, Irritable Bowel Syndrome, and Functional Constipation in South China.

Background/Aims: Functional dyspepsia (FD) overlapping with other gastrointestinal disorders are quite common. The characteristics of FD overlap in Chinese population with latest Rome IV criteria were unclear. This large-scale outpatient-based study assessed the characteristics of FD overlap in South China. Methods: Consecutive FD patients visited the Gastroenterology Clinic at 2 tertiary medical centers in Hangzhou, China who fulfilled the Rome IV criteria were enrolled. Complete questionnaires related to the gastrointestinal symptoms (Rome IV criteria), Reflux Disease Questionnaire, anxiety and depression, quality of sleep and life, and demographic information were collected. Results: Among the total of 3281 FD patients, 50.69% overlapped with gastroesophageal reflux disease, 21.46% overlapped with irritable bowel syndrome, 6.03% overlapped with functional constipation. FD overlap had higher proportion of single/divorced/widowed rate, high education level, being employed, drinking, night shift, unhealthy dietary habit than FD only (P < 0.05). They had higher frequency of consultation and economic burden, as well as lower scores in quality of life (P < 0.001). Multivariate logistic regression showed that increasing age, female, low body mass index, history of gastroenteritis, anxiety, depression, and poor sleep quality were independent risk factors for FD overlap. Conclusions: FD overlap was quite common in China with high economic burden and poor quality of life, FD patients with history of gastroenteritis, anxiety, depression, and poor sleep quality were more likely to have overlap disorders. Awareness of the physical and psychosocial stressors in overlapping condition would help optimize the management of FD overlap in clinical practice.

A proteomic study on gastric impairment in rats caused by microcystin-LR.

Microcystins (MCs) are the most common cyanobacterial toxins. Epidemiological investigation showed that exposure to MCs can cause gastro-intestinal symptoms, gastroenteritis and gastric cancer. MCs can also accumulate in and cause histopathological damage to stomach. However, the exact mechanisms by which MCs cause gastric injury were unclear. In this study, Wistar rats were administrated 50, 75 or 100 µg microcystin-LR (MC-LR)/kg, body mass (bm) via tail vein, and histopathology, response of anti-oxidant system and the proteome of gastric tissues at 24 h after exposure were studied. Bleeding of fore-stomach and gastric corpus, inflammation and necrosis in gastric corpus and exfoliation of mucosal epithelial cells in gastric antrum were observed following acute MC-LR exposure. Compared with controls, activities of superoxide dismutase (SOD) were significantly greater in gastric tissues of exposed rats, while activities of catalase (CAT) were less in rats administrated 50 µg MC-LR/kg, bm, and concentrations of glutathione (GSH) and malondialdehyde (MDA) were greater in rats administrated 75 or 100 µg MC-LR/kg, bm. These results indicated that MC-LR could disrupt the anti-oxidant system and cause oxidative stress. The proteomic results revealed that MC-LR could affect expressions of proteins related to cytoskeleton, immune system, gastric functions, and some signaling pathways, including platelet activation, complement and coagulation cascades, and ferroptosis. Quantitative real-time PCR (qRT-PCR) analysis showed that transcriptions of genes for ferroptosis and gastric function were altered, which confirmed results of proteomics. Overall, this study illustrated that MC-LR could induce gastric dysfunction, and ferroptosis might be involved in MC-LR-induced gastric injury. This study provided novel insights into mechanisms of digestive diseases induced by MCs.

Epidemiology of congenital diaphragmatic hernia among 24 million Chinese births: a hospital-based surveillance study.

BACKGROUND: The prevalence of congenital diaphragmatic hernia (CDH) varies across countries, with limited information available on its epidemiology in China. Our study aimed to investigate the prevalence, time trends, and perinatal outcomes of CDH in China, as well as its associated malformations and potential associations with maternal and infant characteristics. METHODS: This study included all birth and CDH cases from the Chinese Birth Defects Monitoring Network between 2007 and 2019, with CDH cases classified as either isolated or associated. We employed the joinpoint regression model to calculate the trends of prevalence and the annual percent change, with Poisson regression used for adjusted prevalence rate ratios. A P value ≤ 0.05 was considered statistically significant. RESULTS: A total of 4397 CDH cases were identified among 24,158,029 births in the study period, yielding prevalence rates of 1.82, 1.13 and 0.69 per 10,000 for overall, isolated, and associated CDH, respectively. The prevalence of each type of CDH increased over time. The prevalence of overall CDH varied significantly by infant sex (male vs. female, 1.91/10,000 vs. 1.63/10,000), maternal residence (urban vs. rural, 2.13/10,000 vs. 1.45/10,000), maternal age (< 20 years, 1.31/10,000; 20-24 years, 1.63/10,000; 25-29 years, 1.80/10,000; 30-34 years, 1.87/10,000; ≥ 35 years, 2.22/10,000), and geographic region (central, 1.64/10,000; east, 2.45/10,000; west, 1.37/10,000). Cardiovascular anomalies were the most common malformations associated with CDH. Infants with associated CDH had a higher risk of premature birth and perinatal death than those with isolated CDH. CONCLUSION: The increasing prevalence and high perinatal mortality rate of CDH highlight the need for further etiological, epidemiological, and clinical studies among the Chinese population. Video Abstract.

Regio- and diastereoselective synthesis of diverse spirocyclic indenes by cyclization with indene-dienes as two carbon building blocks.

We report a base-promoted cyclization with indene-dienes as two carbon building blocks toward diverse spirocyclic indene scaffolds including hexacyclic spiroindenes bearing benzo pyran motifs and pentacyclic spiroindenes containing oxindole units in high yields with excellent diastereoselectivities.

Cyanotoxins, biosynthetic gene clusters, and factors modulating cyanotoxin biosynthesis.

Cyanobacterial harmful algal blooms (CHABs) are a global environmental concern that encompasses public health issues, water availability, and water quality owing to the production of various secondary metabolites (SMs), including cyanotoxins in freshwater, brackish water, and marine ecosystems. The frequency, extent, magnitude, and duration of CHABs are increasing globally. Cyanobacterial species traits and changing environmental conditions, including anthropogenic pressure, eutrophication, and global climate change, together allow cyanobacteria to thrive. The cyanotoxins include a diverse range of low molecular weight compounds with varying biochemical properties and modes of action. With the application of modern molecular biology techniques, many important aspects of cyanobacteria are being elucidated, including aspects of their diversity, gene-environment interactions, and genes that express cyanotoxins. The toxicological, environmental, and economic impacts of CHABs strongly advocate the need for continuing, extensive efforts to monitor cyanobacterial growth and to understand the mechanisms regulating species composition and cyanotoxin biosynthesis. In this review, we critically examined the genomic organization of some cyanobacterial species that lead to the production of cyanotoxins and their characteristic properties discovered to date.

The changing epidemiology of syndactyly in Chinese newborns: a nationwide surveillance-based study.

BACKGROUND: Little is known about the epidemiologic features of syndactyly (SD) in Chinese newborns. METHODS: Using 2007-2019 data from the Chinese Birth Defects Monitoring Network, we conducted a prevalence analysis on overall, isolated and associated syndactyly according to birth year, maternal age, maternal residence, geographic region and infant sex, with special interests in time trends, perinatal outcomes and clinical phenotypes. RESULTS: A total of 13,611 SD cases were identified among 24,157,719 births in the study period, yielding the prevalence of 5.63, 4.66 and 0.97 per 10,000 for overall, isolated, and associated SD, respectively. The prevalence of each type of SD exhibited an upward trend over the period. The prevalence of overall SD varied significantly by maternal residence (urban vs. rural, 6.69/10,000 vs. 4.35/10,000), maternal age (< 20 years, 5.43/10,000; 20-24 years, 5.03/10,000; 25-29 year, 5.65/10,000; 30-34 years, 6.07/10,000; ≥ 35 years, 5.76/10,000), geographic region (central, 5.07/10,000; east, 6.75/10,000; west, 5.12/10,000), and infant sex (male vs. female, 6.28/10,000 vs. 4.86/10,000). Newborns with associated SD were more likely to be born prematurely (29.2% vs. 10.6%) or with low birthweight (30.5% vs.9.8%) than those with isolated SD. The bilaterally, and unilaterally affected cases accounted for 18.4% and 76.7%, respectively. The feet were more frequently involved (64.3%) in those bilaterally affected cases, while right side preference (right vs left: 53.8% vs 46.2%) and upper limbs preference (hand vs foot: 50.8% vs 48.0%) were found in unilateral cases. CONCLUSIONS: The prevalence of syndactyly in China is on the rise and notably higher than that in other Asian and European countries, highlighting the importance of investigating the etiology, epidemiology, and clinical implications of this condition in the Chinese population.

A regioselective [3 + 2] cycloaddition reaction of 2-benzylidene-1-indenones with functional olefins to access indanone-fused 2D/3D skeletons.

The regioselective [3 + 2] cycloaddition reaction of 2-benzylidene-1-indenones with functional olefins was established with DABCO as a base under mild conditions. Using this approach, a series of diversely substituted indanone-fused cyclopentane polycycles with highly crowded multiple substituents were synthesized in high yields.

Clinical characteristics of patients with prenatal hydronephrosis in early postnatal period: a single center retrospective study.

BACKGROUND: The study aims to investigate the clinical characteristics of early postnatal period in children with prenatal hydronephrosis (HN) in our single center for 8 years. STUDY DESIGN: The clinical data of 1137 children with prenatal HN from 2012 to 2020 were retrospectively analyzed in our center. Variables of our study mainly included different malformations and urinary tract dilation (UTD) classification, and main outcomes were recurrent hospitalization, urinary tract infection (UTI), jaundice, and surgery. RESULTS: Among the 1137 children with prenatal HN in our center, 188 cases (16.5%) were followed-up in early postnatal period, and 110 cases (58.5%) were found malformations. The incidence of recurrent hospitalization (29.8%) and UTI (72.5%) were higher in malformation, but the incidence of jaundice (46.2%) was higher in non-malformation(P < 0.001). Furthermore, UTI and jaundice were higher in vesicoureteral reflux (VUR) than those in uretero-pelvic junction obstruction (UPJO) (P < 0.05). Meanwhile, Children with UTD P2 and UTD P3 were prone to recurrent UTI, but UTD P0 was prone to jaundice (P < 0.001). In addition, 30 cases (16.0%) of surgery were all with malformations, and the surgical rates of UTD P2 and UTD P3 were higher than those of UTD P0 and UTD P1 (P < 0.001). Lastly, we concluded that the first follow-up should be less than 7 days, the first assessment should be 2 months, and the follow up should be at least once every 3 months. CONCLUSION: Children with prenatal HN have been found many malformations in early postnatal period, and with high-grade UTD were more prone to recurrent UTI, even to surgery. So, prenatal HN with malformations and high-grade UTD should be followed up in early postnatal period regularly.

Acute exposure to microcystins affects hypothalamic-pituitary axes of male rats.

Microcystins (MCs) produced by some cyanobacteria can cause toxicity in animals and humans. In recent years, growing evidence suggests that MCs can act as endocrine disruptors. This research systematically investigated effects of microcystin-LR (MC-LR) on endocrine organs, biosynthesis of hormones and positive/negative feedback of the endocrine system in rats. Male, Sprague-Dawley rats were acutely administrated MC-LR by a single intraperitoneal injection at doses of 45, 67.5 or 90 µg MC-LR/kg body mass (bm), and then euthanized 24 h after exposure. In exposed rats, histological damage of hypothalamus, pituitary, adrenal, testis and thyroid were observed. Serum concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT), expressions of genes and proteins for biosynthesis of hormones were lesser, which indicated an overall suppression of the hypothalamus-pituitary-adrenal (HPA) axis. Along the hypothalamus-pituitary-gonadal (HPG) axis, lesser concentrations of gonadotropin-releasing hormone (GnRH) and testosterone (T), but greater concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol (E2) were observed. Except for greater transcription of cyp19a1 in testes, transcriptions of genes and proteins for T and E2 biosynthesis along the HPG axis were lesser. As for the hypothalamus-pituitary-thyroid (HPT) axis, after MCs treatment, greater concentrations of thyroid-stimulating hormone (TSH), but lesser concentrations of free tri-iodothyronine (fT3) were observed in serum. Concentrations of free tetra-iodothyronine (fT4) were greater in rats dosed with 45 µg MCs/kg, bm, but lesser in rats dosed with 67.5 or 90 µg MCs/kg, bm. Transcripts of genes for biosynthesis of hormones and receptors along the HPT axis and expressions of proteins for biosynthesis of tetra-iodothyronine (T4) and tri-iodothyronine (T3) in thyroid were significantly altered. Cross-talk among the HPA, HPG and HPT axes probably occurred. It was concluded that MCs caused an imbalance of positive and negative feedback of hormonal regulatory axes, blocked biosynthesis of key hormones and exhibited endocrine-disrupting effects.

What influences the implementation of kangaroo mother care? An umbrella review.

BACKGROUND: Kangaroo mother care (KMC) is an evidence-based intervention that reduces morbidity and mortality in preterm infants. However, it has not yet been fully integrated into health systems around the world. The aim of this study is to provide a cogent summary of the evidence base of the key barriers and facilitators to implementing KMC. METHODS: An umbrella review of existing reviews on KMC was adopted to identify systematic and scoping reviews that analysed data from primary studies. Electronic English databases, including PubMed, Embase, CINAHL and Cochrane Library, and three Chinese databases were searched from inception to 1 July 2022. Studies were included if they performed a review of barriers and facilitators to KMC. Quality assessment of the retrieved reviews was performed by at least two reviewers independently using the Joanna Briggs Institute (JBI) critical appraisal checklist and risk of bias was assessed with the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool. This umbrella review protocol was documented in the PROSPERO registry (CRD42022327994). RESULTS: We generated 531 studies, and after the removal of duplicates and ineligible studies, six eligible reviews were included in the analysis. The five themes identified were environmental factors, professional factors, parent/family factors, access factors, and cultural factors, and the factors under each theme were divided into barriers or facilitators depending on the specific features of a given scenario. CONCLUSIONS: Support from facility management and leadership and well-trained medical staff are of great significance to the successful integration of KMC into daily medical practice, while the parents of preterm infants and other family members should be educated and encouraged in KMC practice. Further research is needed to propose strategies and develop models for implementing KMC.

IMM-H007 attenuates isoprenaline-induced cardiac fibrosis through targeting TGFß1 signaling pathway.

Upon chronic stress, ß-adrenergic receptor activation induces cardiac fibrosis and leads to heart failure. The small molecule compound IMM-H007 has demonstrated protective effects in cardiovascular diseases via activation of AMP-activated protein kinase (AMPK). This study aimed to investigate IMM-H007 effects on cardiac fibrosis induced by ß-adrenergic receptor activation. Because adenosine analogs also exert AMPK-independent effects, we assessed AMPK-dependent and -independent IMM-H007 effects in murine models of cardiac fibrosis. Continual subcutaneous injection of isoprenaline for 7 days caused cardiac fibrosis and cardiac dysfunction in mice in vivo. IMM-H007 attenuated isoprenaline-induced cardiac fibrosis, diastolic dysfunction, α-smooth muscle actin expression, and collagen I deposition in both wild-type and AMPKα2-/- mice. Moreover, IMM-H007 inhibited transforming growth factor ß1 (TGFß1) expression in wild-type, but not AMPKα2-/- mice. By contrast, IMM-H007 inhibited Smad2/3 signaling downstream of TGFß1 in both wild-type and AMPKα2-/- mice. Surface plasmon resonance and molecular docking experiments showed that IMM-H007 directly interacts with TGFß1, inhibits its binding to TGFß type II receptors, and downregulates the Smad2/3 signaling pathway downstream of TGFß1. These findings suggest that IMM-H007 inhibits isoprenaline-induced cardiac fibrosis via both AMPKα2-dependent and -independent mechanisms. IMM-H007 may be useful as a novel TGFß1 antagonist.

Plasmacytoid dendritic cells mediate the tolerogenic effect of CD8+regulatory T cells in a rat tolerant liver transplantation model.

BACKGROUND: Tolerance is more easily induced in liver transplant models than in other organs; CD8+CD45RClowregulatory T cells (Tregs) have been shown to induce tolerance in heart allografts. Whether CD8+CD45RClowTregs could induce tolerance in a liver transplant model and how dendritic cells (DCs) mediate the CD8+CD45RClowTregs effect remains to be investigated. METHODS: A rat liver transplantation model was established and used to test tolerance and acute rejection compared to control groups. Liver function and histopathological changes of allograft were examined by enzyme-linked immunosorbent assay (ELISA) and haematoxylin and eosin (H&E) staining, respectively. The distribution and proportion of CD8+CD45RClowTregs and plasmacytoid dendritic cells (pDCs) in the allografts and spleen were determined using flow cytometry. Cytokine secretion levels were determined using ELISA and real-time quantitative PCR (qRT-PCR). RESULTS: The rat liver transplantation model was well established, with a success rate of 93.3% (28/30). The mean survival time of the tolerant and acute-rejection rats were 156 and 14 days, respectively. The proportions of CD8+CD45RClowTegs were higher in the allografts of tolerant rats than in those of acute-rejection rats (33.1 ± 4.3 and 12.4 ± 4.6, respectively; P = 0.04). Significant accumulation of pDCs was observed in tolerant liver graft rats compared to that in acute-rejection rats (1.46 ± 0.23 and 0.80 ± 0.20, respectively; P = 0.02). Importantly, CD8+CD45RClowTregs were positively associated with the frequency of pDCs (P = 0.001, r2 = 0.775). The protein and mRNA expression of IL-10 and TGF-ß in the allograft group were increased, possibly being responsible for tolerance induction. CONCLUSION: CD8+CD45RClowT cells interact with pDCs through the induction of IL-10 and TGF-ß expression and are responsible for inducing immune tolerance in rat liver transplantation.

Glibenclamide alleviates ß adrenergic receptor activation-induced cardiac inflammation.

ß-Adrenergic receptor (ß-AR) overactivation is a major pathological factor associated with cardiac diseases and mediates cardiac inflammatory injury. Glibenclamide has shown anti-inflammatory effects in previous research. However, it is unclear whether and how glibenclamide can alleviate cardiac inflammatory injury induced by ß-AR overactivation. In the present study, male C57BL/6J mice were treated with or without the ß-AR agonist isoprenaline (ISO) with or without glibenclamide pretreatment. The results indicated that glibenclamide alleviated ISO-induced macrophage infiltration in the heart, as determined by Mac-3 staining. Consistent with this finding, glibenclamide also inhibited ISO-induced chemokines and proinflammatory cytokines expression in the heart. Moreover, glibenclamide inhibited ISO-induced cardiac fibrosis and dysfunction in mice. To reveal the protective mechanism of glibenclamide, the NLRP3 inflammasome was further analysed. ISO activated the NLRP3 inflammasome in both cardiomyocytes and mouse hearts, but this effect was alleviated by glibenclamide pretreatment. Furthermore, in cardiomyocytes, ISO increased the efflux of potassium and the generation of ROS, which are recognized as activators of the NLRP3 inflammasome. The ISO-induced increases in these processes were inhibited by glibenclamide pretreatment. Moreover, glibenclamide inhibited the cAMP/PKA signalling pathway, which is downstream of ß-AR, by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes. In conclusion, glibenclamide alleviates ß-AR overactivation-induced cardiac inflammation by inhibiting the NLRP3 inflammasome. The underlying mechanism involves glibenclamide-mediated suppression of potassium efflux and ROS generation by inhibiting the cAMP/PKA pathway.

Decreased granzyme B+CD19+B cells are associated with tumor progression following liver transplantation.

Lymphocytes play an important role in antitumor immunity following organ transplantation. However, the function of granzyme B+CD19+B cells on the hepatocellular carcinoma cells from liver transplant recipients remains largely unknown; we aimed to analyze the function and elucidate the mechanisms behind it. Blood samples and clinical data from liver transplant recipients and healthy controls at Beijing Chaoyang Hospital as well as from a validation cohort were collected and analyzed. In this study, we found decreased granzyme B+CD19+B cells were correlated with early hepatocellular carcinoma recurrence and could further identify liver transplant recipients with poor tumor differentiation, microvascular invasion, increased total tumor diameter, and tumor beyond Milan criteria. Notably, granzyme B+CD19+B cells directly inhibited the proliferation, migration, and invasion of hepatocellular carcinoma cells. Upon activation regulatory B cells from liver transplant recipients with hepatocellular carcinoma recurrence displayed a CD5+CD38+CD27+CD138+CD19+ granzyme B+ phenotype, but the increased expression of CD5, CD38, and CD138, and the decreased protein level and transcriptional level requiring JAK/STAT signaling. In an independent validation cohort, liver transplant recipients with decreased granzyme B+CD19+B cells had not only early hepatocellular carcinoma cell recurrence but also shorter survival. Our study provides comprehensive data from liver transplant recipients with hepatocellular carcinoma, indicating a critical role of granzyme B+CD19+B cells in preventing cancer progression. Our findings warrant further investigations for the design of future immunotherapies leading to immune responses and improved patient survival.

Therapeutic Effect of Combining Anisodamine With Neostigmine on Local Scar Formation Following Roux-en-Y Choledochojejunostomy in a Novel Rat Model.

Background: The present study aimed to explore the potential effect of combining anisodamine with neostigmine on local scar formation following Roux-en-Y choledochojejunostomy (RCJS) in a novel rat model. Methods: The biliary obstruction model of Sprague Dawley (SD) rats was established in advance, and 54 rats were divided into nine groups randomly (sham operation group, anisodamine group, neostigmine group, combination group, and control group). Anisodamine (25 mg/kg) and neostigmine (50 µg/kg) were injected to the abdominal cavity separately or simultaneously for 1 week since the first day after surgery according to their allocated intervention, while the same amount of saline (0.5 ml) was injected intraperitoneally in the control group. Indexes including body weight, the diameter of the common bile duct, liver function, inflammatory indexes, and the condition of scar formation in different groups at certain time were evaluated in our study. Results: Recovery of liver function (ALT, AST, TB, DB, and GGT) and systematic inflammation indexes (CRP, TNF-α, and IL-1ß) in the combination group was prior to that in the control group (p < 0.05), while no statistical difference in the serum level of IL-10 was observed among groups. Rats in the combination group represented a wider anastomotic diameter and lower expression of α-SMA and TGF-ß1 at anastomotic stoma compared to the control group (p < 0.05). Histopathological staining showed slighter proliferation of collagen and smooth muscle fibers in rats' bile duct wall and less local scar formation at anastomotic stoma compared to the control group. Conclusion: The combination of anisodamine and neostigmine can alleviate local and systemic inflammatory response, promote the recovery of liver function, and reduce scar formation in rats after the RCJS procedure.

Granzyme B-Producing B Cells Function as a Feedback Loop for T Helper Cells in Liver Transplant Recipients with Acute Rejection.

Granzyme B-producing B cells have been reportedly reported to be an important regulatory B cell subset in the pathogenesis of many diseases. However, its role in liver transplant recipients with acute rejection has never been well elucidated. Seventeen liver transplant recipients with acute rejection and 25 controls with stable liver function were enrolled in this study to determine the function of granzyme B-producing B cells via flow cytometry. Liver transplant recipients with acute rejection had higher expression of granzyme B in CD19+B cells when compared with controls. Following rejection, the granzyme B production was even elevated although comparison failed to reach significance. The percentages of CD27+granzyme B+CD19+B cells and CD138+granzyme B+CD19+B cells were lower than those of CD27-granzyme B+CD19+B cells and CD138-granzyme B+CD19+B cells in patients with acute rejection, respectively. While the production of CD27 and CD138 was not different between liver transplant recipients with and without acute rejection but increased expression of the two surface markers was observed following rejection. Furthermore, the frequency of granzyme B+CD19+B cells correlated with the level of alanine aminotransferase instead of tacrolimus. CD19+B cells could produce granzyme B when stimulated with IgG + IgM and CpG in the presence of the supernatant of activated CD4+CD25-T cells. In return, granzyme B+CD19+B cells could suppress the proliferation of CD4+CD25-T cells in a granzyme B- and contact-dependent manner. The increased expression of granzyme B in CD19+B cells from liver transplant recipients with acute rejection might function as a feedback loop for the activation of the CD4+CD25-T cells.

A combination of the percentages of IFN-γ+CD4+T cells and granzyme B+CD19+B cells is associated with acute hepatic rejection: a case control study.

BACKGROUND: T cells and B cells play a key role in alloimmune responses. We aimed to characterize the shift of T cell subsets and B cell subsets during acute hepatic rejection, and further determine whether they could serve as a prognostic marker. METHODS: Blood samples together with the clinical data from liver transplant recipients with and without acute hepatic rejection were collected and analyzed as well as from a validation cohort. RESULTS: Upon activation the expression of TGF-ß and granzyme B in CD19+B cells, and the expression of IL-2 and IFN-γ in CD4+T cells were higher in acute hepatic rejection. However, only the frequencies of granzyme B+CD19+B cells and IFN-γ+CD4+T cells correlated with liver function in addition to with each other. A combination of the two cell subsets as a novel marker could classify rejection versus non-rejection (area under the curve 0.811, p = 0.001) with the cut-off value of 62.93%, which was more sensitive for worse histological changes (p = 0.027). Moreover, the occurrence rate of acute rejection was higher in the group with the novel marker > 62.93% (p = 0.000). The role of the novel marker was further confirmed in a validation cohort, which was identified to be the only significant independent risk factor for acute rejection (odds ratio: 0.923; 95% CI confidence interval: 0.885-0.964; p = 0.000). CONCLUSIONS: A combination of the percentages of IFN-γ+CD4+T cells and granzyme B+CD19+B cells can distinguish rejection from non-rejection, which can be used as a potential prognostic marker for acute rejection in liver transplant recipients.

Ratio of CA19-9 level to total bilirubin as a novel prognostic indicator in patients with pancreatic head carcinoma following curative resection.

BACKGROUND: Ratio of carbohydrate antigen 19-9 level to total bilirubin (CA19-9/TB) is used to reduce the influence of obstructive jaundice on the concentration of CA19-9, thereby determining the correlation between CA19-9/TB and tumor recurrence or long-term prognosis of patients with pancreatic head cancer (PHC). METHODS: In this study, a total of 339 patients were enrolled. The optimal cut-off value of CA19-9/TB was determined by ROC curve based on preoperative CA19-9/TB and 1-year survival, and the patients were divided into low-ratio group (Group 1) and high-ratio group (Group 2) accordingly. Univariate and multivariate analyses were performed to screen out the risk factors affecting postoperative recurrence and long-term prognosis of PHC. RESULTS: The best cut-off value of CA19-9/TB was 7.7. [area under curve (AUC), 0.599, 95% CI: 0.533-0.666] Compared with Group 1, Group 2 had lower CA19-9, higher TB and lymph node metastasis rate (P<0.05). The 1-, 2- and 3-year disease-free survival (DFS) rates of patients in Group 1 and Group 2 were 70.1%, 44.3% and 30.8%, 39.9%, 17.1% and 13.6%, respectively (P=0.000), and the 1-, 2- and 3-year overall survival (OS) rates were 81.5%, 52.1% and 31.5%, 53.7%, 20.5% and 14.2%, respectively (P=0.000). Multivariate analysis showed that CA19-9/TB, portal vein invasion and lymph node metastasis were independent risk factors for postoperative tumor recurrence and long-term survival of PHC. CONCLUSIONS: Compared with CA19-9 alone, CA19-9/TB is more valuable in judging postoperative tumor recurrence and long-term survival of PHC. The lower the ratio, the better the long-term prognosis.

Pneumocystis pneumonia in liver transplant recipients.

The clinical course of Pneumocystis pneumonia in liver transplant recipients has not been well investigated. Therefore, we collected and analyzed the clinical, epidemiological, and molecular data from patients with Pneumocystis pneumonia as well as paired controls (Chinese Clinical Trial Registry, ChiCTR2100046028; www.chictr.org.cn). There were a total of ten patients diagnosed with Pneumocystis pneumonia containing prospectively included six patients and retrospectively collected four patients, of which seven were transferred to the surgical intensive care unit and four died. The transmission map revealed that inter-patient transmission of Pneumocystis jirovecii was impossible; P. jirovecii detection was negative in all air samples. It was positive only in one sample from the twelve healthcare workers who had close contact with diseased patients. Five out of 79 liver transplant recipients during the outbreak were colonized with Pneumocystis jirovecii compared to 2 out of 94 after the outbreak upon admission (P>0.05). Liver transplant recipients with Pneumocystis pneumonia had totally different genotypes based on multilocus sequence typing. Additionally, we found an unreported mutation in the cytochrome b gene. The absolute CD19+ B-cell counts (odds ratio: 1.028; 95% confidence interval: 1.000-1.057; P=0.049) were defined to be the only significant independent risk factor. At a cut-off value of 117.16/µL, the sensitivity and specificity were 100% and 70%, respectively. Pneumocystis pneumonia is a severe complication following liver transplantation. The outbreak may not be caused by nosocomial transmission. A decrease in absolute CD19+ B-cell counts may be associated with the development of Pneumocystis pneumonia.

α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation.

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by ß-adrenergic receptors (ß-ARs). However, α1-adrenergic receptors (α1-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α1-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α1-AR agonist phenylephrine (PE, 5 or 10 mg/kg, s.c.) with or without pretreatment with α-AR antagonist prazosin (5 mg/kg, s.c.). PE injection caused cardiac dysfunction and cardiac inflammation, evidenced by the increased expression of inflammatory cytokine IL-6 and chemokines MCP-1 and MCP-5, as well as macrophage infiltration in myocardium. These effects were blocked by prazosin pretreatment. Furthermore, PE injection significantly increased the expression of NOD-like receptor protein 3 (NLRP3) and the cleavage of caspase-1 (p20) and interleukin-18 in the heart; similar results were observed in both Langendorff-perfused hearts and cultured cardiomyocytes following the treatment with PE (10 µM). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3-/- mice compared with wild-type mice. In conclusion, α1-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.