A non-invasive artificial intelligence model for identifying axillary pathological complete response to neoadjuvant chemotherapy in breast cancer: a secondary analysis to multicenter clinical trial.

BACKGROUND: This study aims to develop a stacking model for accurately predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) using longitudinal MRI in breast cancer. METHODS: We included patients with node-positive breast cancer who received NAC following surgery from January 2012 to June 2022. We collected MRIs before and after NAC, and extracted radiomics features from the tumour, peritumour, and ALN regions. The Mann-Whitney U test, least absolute shrinkage and selection operator, and Boruta algorithm were used to select features. We utilised machine learning techniques to develop three single-modality models and a stacking model for predicting ALN response to NAC. RESULTS: This study consisted of a training cohort (n = 277), three external validation cohorts (n = 313, 164, and 318), and a prospective cohort (n = 81). Among the 1153 patients, 60.62% achieved ypN0. The stacking model achieved excellent AUCs of 0.926, 0.874, and 0.862 in the training, external validation, and prospective cohort, respectively. It also showed lower false-negative rates (FNRs) compared to radiologists, with rates of 14.40%, 20.85%, and 18.18% (radiologists: 40.80%, 50.49%, and 63.64%) in three cohorts. Additionally, there was a significant difference in disease-free survival between high-risk and low-risk groups (p < 0.05). CONCLUSIONS: The stacking model can accurately predict ALN status after NAC in breast cancer, showing a lower false-negative rate than radiologists. TRIAL REGISTRATION NUMBER: The clinical trial numbers were NCT03154749 and NCT04858529.

Noninvasive Artificial Intelligence System for Early Predicting Residual Cancer Burden during Neoadjuvant Chemotherapy in Breast Cancer.

OBJECTIVE: To develop an artificial intelligence (AI) system for the early prediction of residual cancer burden (RCB) scores during neoadjuvant chemotherapy (NAC) in breast cancer. SUMMARY BACKGROUND DATA: RCB III indicates drug resistance in breast cancer, and early detection methods are lacking. METHODS: This study enrolled 1048 patients with breast cancer from four institutions, who were all receiving NAC. Magnetic resonance images were collected at the pre- and mid-NAC stages, and radiomics and deep learning features were extracted. A multitask AI system was developed to classify patients into three groups (RCB 0-I, II, and III ) in the primary cohort (PC, n=335). Feature selection was conducted using the Mann-Whitney U- test, Spearman analysis, least absolute shrinkage and selection operator regression, and the Boruta algorithm. Single-modality models were developed followed by model integration. The AI system was validated in three external validation cohorts. (EVCs, n=713). RESULTS: Among the patients, 442 (42.18%) were RCB 0-I, 462 (44.08%) were RCB II and 144 (13.74%) were RCB III. Model-I achieved an area under the curve (AUC) of 0.975 in the PC and 0.923 in the EVCs for differentiating RCB III from RCB 0-II. Model-II distinguished RCB 0-I from RCB II-III, with an AUC of 0.976 in the PC and 0.910 in the EVCs. Subgroup analysis confirmed that the AI system was consistent across different clinical T stages and molecular subtypes. CONCLUSIONS: The multitask AI system offers a noninvasive tool for the early prediction of RCB scores in breast cancer, supporting clinical decision-making during NAC.

Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

[Research progress on the manifestations and prognosis of neonatal lupus erythematosus in various systems]. / æ–°ç”Ÿå„¿çº¢æ–‘ç‹¼ç–®å„ç³»ç»Ÿè¡¨çŽ°åŠé¢„åŽç ”ç©¶è¿›å±•.

Neonatal lupus erythematosus (NLE) is caused by the transmission of maternal anti-Ro/SSA antibodies, anti-La/SSB antibodies, and other autoantibodies to the fetus through the placenta. Usually, with the disappearance of autoantibodies in the children's body, abnormal changes in the mucocutaneous, blood system, and digestive system can spontaneously subside, but the damage to various systems caused by autoantibodies may persist for a long time. This article provides a comprehensive review of the manifestations and prognosis of NLE in various systems, including mucocutaneous, blood system, circulatory system, nervous system, digestive system, respiratory system, aiming to provide reference for clinical work.

[Factors influencing the occurrence of small for gestational age at different degrees]. / ä¸åŒç¨‹åº¦å°äºŽèƒŽé¾„å„¿å‘ç”Ÿçš„å½±å“å› ç´ åˆ†æž.

OBJECTIVES: To investigate the factors influencing the occurrence of small for gestational age (SGA) at different degrees and provide a basis for early identification of severe SGA cases. METHODS: Neonatal and maternal prenatal information were retrospectively collected from January 2018 to December 2022 at Peking University People's Hospital. The neonates were divided into three groups: severe SGA group (birth weight below the 3rd percentile for gestational age and sex), mild SGA group (birth weight ≥3rd percentile and <10th percentile), and non-SGA group (birth weight ≥10th percentile). An ordered multinomial logistic regression model was used to analyze the factors influencing the occurrence of SGA at different degrees. RESULTS: A total of 14 821 neonates were included, including 258 cases (1.74%) in the severe SGA group, 902 cases (6.09%) in the mild SGA group, and 13 661 cases (92.17%) in the non-SGA group. The proportions of preterm births and stillbirths were higher in the severe SGA group compared to the mild SGA and non-SGA groups (P<0.0125). The proportion of neonatal asphyxia was higher in both the severe SGA and mild SGA groups compared to the non-SGA group (P<0.0125). Ordered multinomial logistic regression analysis showed that maternal pre-pregnancy underweight (OR=1.838), maternal pre-pregnancy obesity (OR=3.024), in vitro fertilization-embryo transfer (OR=2.649), preeclampsia (OR=1.743), connective tissue disease during pregnancy (OR=1.795), nuchal cord (OR=1.213), oligohydramnios (OR=1.848), and intrauterine growth restriction (OR=27.691) were all associated with a higher risk of severe SGA (P<0.05). Maternal parity as a multipara (OR=0.457) was associated with a lower likelihood of severe SGA (P<0.05). CONCLUSIONS: Maternal pre-pregnancy underweight, maternal pre-pregnancy obesity, in vitro fertilization-embryo transfer, preeclampsia, connective tissue disease during pregnancy, oligohydramnios, nuchal cord, and intrauterine growth restriction are closely related to the occurrence of more severe SGA. Maternal parity as a multipara acts as a protective factor against the occurrence of severe SGA.

Matrine Attenuates Lung Injury by Modulating Macrophage Polarization and Suppressing Apoptosis.

INTRODUCTION: Persistent lung inflammation is a characteristic of sepsis-induced lung injury. Matrine, the active ingredient from Sophora flavescens, has exhibited anti-inflammatory activities. This study investigated the effects of prophylactic administration of matrine on macrophage polarization, apoptosis, and tissue injury in a cecal ligation and puncture (CLP)-induced murine lung injury model. METHODS: Mice were randomly allocated into four groups: Sham, CLP, Sham + Matrine, and CLP + Matrine. Lung tissues were collected at 24 h post-CLP. Histopathology and immunofluorescence analysis were performed to evaluate lung injury and macrophage infiltration in the lung, respectively. Caspase-3 activities, TUNEL staining, and anti-apoptotic proteins were examined to assess apoptosis. To determine the mechanism of action of matrine, protein levels of Sirtuin 1 (SIRT1), nuclear factor κB (NF-κB), p53 and the messenger RNA levels of p53-mediated proapoptotic genes were examined to elucidate the associated signaling pathways. RESULTS: Histopathological evaluation showed that matrine prophylaxis attenuated sepsis-induced lung injury. Matrine prophylaxis attenuated sepsis-induced infiltration of the total population of macrophages in the lung. Matrine inhibited M1 macrophage infiltration, but increased M2 macrophage infiltration, thus resulting in a decrease in the proportion of M1 to M2 macrophages in septic lung. Sepsis-induced lung injury was associated with apoptotic cell death as evidenced by increases in caspase-3 activity, TUNEL-positive cells, and decreases in antiapoptotic proteins, all of which were reversed by matrine prophylaxis. Matrine restored sepsis-induced downregulation of SIRT1 and deacetylation of NF-κB p65 subunit and p53, thus inactivating NF-κB pathway and suppressing p53-induced proapoptotic pathway in septic lung. CONCLUSIONS: In summary, this study demonstrated that matrine exhibited pro-M2 macrophage polarization and antiapoptotic effects in sepsis-induced lung injury, which might be, at least partly, due to the modulation of SIRT1/NF-κB and SIRT1/p53 pathways.

[Research progress on long-term developmental outcomes of offspring of pregnant women with systemic lupus erythematosus]. / å¦Šå¨ åˆå¹¶ç³»ç»Ÿæ€§çº¢æ–‘ç‹¼ç–®æ‚£è€ å­ä»£è¿œæœŸå‘è‚²ç»“å±€çš„ç ”ç©¶è¿›å±•.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that affects multiple organs and systems. It is more common in women of childbearing age. Compared with the general population, pregnant women with SLE are at a significantly increased risk of adverse perinatal outcomes such as preterm birth and intrauterine growth restriction. In addition, the offspring of SLE patients may also be adversely affected by in utero exposure to maternal autoantibodies, cytokines, and drugs. This article summarizes the long-term developmental outcomes of offspring of pregnant women with SLE in terms of the blood system, circulatory system, nervous system, and immune system.

Physiological determinants of biogeography: The importance of metabolic depression to heat tolerance.

A quantitative understanding of physiological thermal responses is vital for forecasting species distributional shifts in response to climate change. Many studies have focused on metabolic rate as a global metric for analyzing the sublethal effects of changing environments on physiology. Thermal performance curves (TPCs) have been suggested as a viable analytical framework, but standard TPCs may not fully capture physiological responses, due in part to failure to consider the process of metabolic depression. We derived a model based on the nonlinear regression of biological temperature-dependent rate processes and built a heart rate data set for 26 species of intertidal molluscs distributed from 33°S to ~40°N. We then calculated physiological thermal performance limits with continuous heating using T 1 / 2 H , the temperature at which heart rate is decreased to 50% of the maximal rate, as a more realistic measure of upper thermal limits. Results indicate that heat-induced metabolic depression of cardiac performance is a common adaptive response that allows tolerance of harsh environments. Furthermore, our model accounted for the high inter-individual variability in the shape of cardiac TPCs. We then used these TPCs to calculate physiological thermal safety margins (pTSM), the difference between the maximal operative temperature (95th percentile of field temperatures) and T 1 / 2 H of each individual. Using pTSMs, we developed a physiological species distribution model (pSDM) to forecast future geographic distributions. pSDM results indicate that climate-induced species range shifts are potentially less severe than predicted by a simple correlative SDM. Species with metabolic depression below the optimum temperature will be more thermal resistant at their warm trailing edges. High intraspecific variability further suggests that models based on species-level vulnerability to environmental change may be problematic. This multi-scale, mechanistic understanding that incorporates metabolic depression and inter-individual variability in thermal response enables better predictions about the relationship between thermal stress and species distributions.

[Perinatal conditions of late preterm twins versus early term twins].

OBJECTIVE: To study the perinatal complications of late preterm twins (LPTs) versus early term twins (ETTs). METHODS: A retrospective analysis was performed for the complications of 246 LPTs, 496 ETTs, and their mothers. The risk factors for late preterm birth were analyzed. According to gestational age, the twins were divided into five groups: 34-34+6 weeks (n=44), 35-35+6 weeks (n=70), 36-36+6 weeks (n=132), 37-37+6 weeks (n=390), and 38-38+6 weeks (n=106). The perinatal complications were compared between groups. RESULTS: Maternal hypertension, maternal thrombocytopenia, placenta previa, and premature rupture of membranes were independent risk factors for late preterm birth in twins (P < 0.05). The LPT group had higher incidence rates of respiratory diseases, feeding intolerance, and hypoglycemia than the ETT group (P < 0.05). The 34-34+6 weeks group had a higher incidence rate of neonatal asphyxia than the 37-37+6 weeks and 38-38+6 weeks groups; and had a higher incidence rate of septicemia than 36-36+6 weeks group (P < 0.0045). The 34-34+6 weeks and 35-35+6 weeks groups had higher incidence rates of neonatal respiratory distress syndrome, neonatal apnea, and anemia than the other three groups; and had higher incidence rates of neonatal pneumonia, hypoglycemia and septicemia than the 37-37+6 weeks and 38-38+6 weeks groups (P < 0.0045). The 35-35+6 weeks group had a higher incidence rate of feeding intolerance than the 36-36+6 weeks, 37-37+6 weeks, and 38-38+6 weeks groups (P < 0.0045). The 36-36+6 weeks group had a lower incidence rate of hypoglycemia than the 34-34+6 weeks group and a higher incidence rate of hypoglycemia than the 37-37+6 weeks group (P < 0.0045). CONCLUSIONS: Compared with ETTs, LPTs have an increased incidence of perinatal complications. The incidence of perinatal complications is associated with gestational ages in the LPTs and ETTs.

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.

OBJECTIVE: The SARS-CoV-2-infected disease (COVID-19) outbreak is a major threat to human beings. Previous studies mainly focused on Wuhan and typical symptoms. We analysed 74 confirmed COVID-19 cases with GI symptoms in the Zhejiang province to determine epidemiological, clinical and virological characteristics. DESIGN: COVID-19 hospital patients were admitted in the Zhejiang province from 17 January 2020 to 8 February 2020. Epidemiological, demographic, clinical, laboratory, management and outcome data of patients with GI symptoms were analysed using multivariate analysis for risk of severe/critical type. Bioinformatics were used to analyse features of SARS-CoV-2 from Zhejiang province. RESULTS: Among enrolled 651 patients, 74 (11.4%) presented with at least one GI symptom (nausea, vomiting or diarrhoea), average age of 46.14 years, 4-day incubation period and 10.8% had pre-existing liver disease. Of patients with COVID-19 with GI symptoms, 17 (22.97%) and 23 (31.08%) had severe/critical types and family clustering, respectively, significantly higher than those without GI symptoms, 47 (8.14%) and 118 (20.45%). Of patients with COVID-19 with GI symptoms, 29 (39.19%), 23 (31.08%), 8 (10.81%) and 16 (21.62%) had significantly higher rates of fever >38.5°C, fatigue, shortness of breath and headache, respectively. Low-dose glucocorticoids and antibiotics were administered to 14.86% and 41.89% of patients, respectively. Sputum production and increased lactate dehydrogenase/glucose levels were risk factors for severe/critical type. Bioinformatics showed sequence mutation of SARS-CoV-2 with m6A methylation and changed binding capacity with ACE2. CONCLUSION: We report COVID-19 cases with GI symptoms with novel features outside Wuhan. Attention to patients with COVID-19 with non-classic symptoms should increase to protect health providers.

Liver Enzyme Elevation in Coronavirus Disease 2019: A Multicenter, Retrospective, Cross-Sectional Study.

INTRODUCTION: Elevated liver enzyme levels are observed in patients with coronavirus disease 2019 (COVID-19); however, these features have not been characterized. METHODS: Hospitalized patients with COVID-19 in Zhejiang Province, China, from January 17 to February 12, 2020, were enrolled. Liver enzyme level elevation was defined as alanine aminotransferase level >35 U/L for men and 25 U/L for women at admission. Patients with normal alanine aminotransferase levels were included in the control group. Reverse transcription polymerase chain reaction was used to confirm severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and patients symptomatic with SARS-CoV-2 infection were defined as patients with COVID-19. Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected and compared. RESULTS: Of 788 patients with COVID-19, 222 (28.2%) patients had elevated liver enzyme levels (median [interquartile range {IQR}] age, 47.0 [35.0-55.0] years; 40.5% women). Being male, overweight, and smoking increased the risk of liver enzyme level elevation. The liver enzyme level elevation group had lesser pharyngalgia and more diarrhea than the control group. The median time from illness onset to admission was 3 days for liver enzyme level elevation groups (IQR, 2-6), whereas the median hospitalization time for 86 (38.7%) discharged patients was 13 days (IQR, 11-16). No differences in disease severity and clinical outcomes were noted between the groups. DISCUSSION: We found that 28.2% of patients with COVID-19 presented with elevated liver enzyme levels on admission, which could partially be related to SARS-CoV-2 infection. Male patients had a higher risk of liver enzyme level elevation. With early medical intervention, liver enzyme level elevation did not worsen the outcomes of patients with COVID-19.

Adaptive modal gain controlling for a high-efficiency cylindrical vector beam fiber laser.

We propose and experimentally demonstrate an ytterbium-doped fiber laser emitting the single high-order cylindrical vector beams with a high efficiency and a high modal purity based on adaptive modal gain control. By the combination of a high-order pump with a self-designed ytterbium-ring doped fiber, modal dependent gain was tailored and specific transverse mode can be selected in the laser cavity. A model based on multimode propagation-rate equations is built up to demonstrate the behaviors of transverse mode competition in the fiber laser. Modal dependent gain of high-order mode pump are simulated numerically, which agree well with our experiment results. The slope efficiency of the fiber laser reaches 79.61% with a low threshold of 47.73mw. The purity of the generated high-order CVBs are in excess of 95%. Such a strategy enables the controllability of modal gain in a fiber laser and reveals the potential to offer a new and promising way to achieve a high-power fiber laser with an arbitrary single high-order transverse modes output.

Switching Lamivudine with Adefovir Dipivoxil Combination Therapy to Entecavir Monotherapy Provides Better Viral Suppression and Kidney Safety.

Introduction: Most chronic hepatitis B (CHB) patients in China are primitively treated with a combination of lamivudine (LAM) and adefovir dipivoxil (ADV). Although antiviral resistance can be avoided with this combination therapy, using it can have harmful side effects related to ADV, specifically kidney and bone injury. This study was designed to compare viral suppression and kidney safety when switching LAM and ADV combination therapy de novo to entecavir (ETV) monotherapy in patients with CHB and compensated hepatic cirrhosis. Materials and methods: In total, 360 CHB and compensated liver cirrhosis patients who received treatment of LAM and ADV combination therapy for more than 1 year were included in this study. One hundred and eighty patients continued combination therapy to serve as a control group and the other 180 patients were switched to ETV monotherapy to serve as the experimental group. The total course of therapy was 3 years. Laboratory studies were done every 3 months to measure liver and kidney function. Studies included glomerular filtration rate (eGFR), HBV-DNA, urine ß2-microglobulin (ß2-M) and retinol binding protein (RBP). Results: In the experimental group, an HBV-DNA level below 20 IU/ml was found in 77.65%, 85.88%, and 94.77% in years 1, 2, and 3, respectively. In the control group, HBV-DNA levels were below 20 IU/ml in 69.66%, 75.42%, and 85.80% in years 1, 2, and 3, respectively. Low HBV-DNA levels in the experimental group were significantly less common than in the control group on the second and third year; P values were 0.009 and 0.006 for years 2 and 3, respectively. The cumulative genetic mutation rate was 3.49% in the experimental group and 8.88% in the control group (P=0.044). Decreases in eGFR more than 30% from baseline were found in 0%, 0.56%, and 1.74% of patients in the experimental group and 4.49%, 9.14% and 14.79% in patients in the control group in the first, second, and third year, respectively. Serum creatinine more than 50 µmol/L above baseline was found in 0%, 0% and 1.74% of patients in the experimental group and 1.12%, 4.00% and 5.32% of patients in the control group in years 1, 2, and 3, respectively. The urine ß2-M and RBP levels were abnormal more often in the experimental group than in the control group. Conclusion: Switching to ETV monotherapy can decrease HBV-DNA levels, reduce the genetic mutation rate, and prevent renal damage caused by LAM and ADV combination therapy in patients with CHB and compensated liver cirrhosis. Patients receiving LAM and ADV combination therapy de novo should be switched to ETV monotherapy immediately.

Efficient generation of functional hepatocyte-like cells from mouse liver progenitor cells via indirect co-culture with immortalized human hepatic stellate cells.

BACKGROUND: Differentiation of liver progenitor cells (LPCs) to functional hepatocytes holds great potential to develop new strategies for hepatocyte transplantation and the screening of drug-induced cytotoxicity. However, reports on the efficient and convenient hepatic differentiation of LPCs to hepatocytes are few. The present study aims to investigate the possibility of generating functional hepatocytes from LPCs in an indirect co-culture system. METHODS: Mouse LPCs were co-cultured in Transwell plates with an immortalized human hepatic stellate cell line (HSC-Li) we previously established. The morphology, expression of hepatic markers, and functions of mouse LPC-derived cells were monitored and compared with those of conventionally cultured LPCs. RESULTS: Co-culturing with HSC-Li cells induced differentiation of mouse LPCs into functional hepatocyte-like cells. The differentiated cells were morphologically transformed into hepatocyte-like cells 3 days after co-culture initiation. In addition, the differentiated cells expressed liver-specific genes and possessed hepatic functions, including glycogen storage, low-density lipoprotein uptake, albumin secretion, urea synthesis, and cytochrome P450 1A2 enzymatic activity. CONCLUSIONS: Our method, which employs indirect co-culture with HSC-Li cells, can efficiently induce the differentiation of LPCs into functional hepatocytes. This finding suggests that this co-culture system can be a useful method for the efficient generation of functional hepatocytes from LPCs.

[Absorption mechanism of neobavaisoflavone in Caco-2 cell monolayer mode].

Neobavaisoflavone is one of flavonoids of traditional Chinese medicine Psoralea corylifolial. It has numerous biological properties such as antibacterial, anti-inflammatory, anti-cancer, and anti-osteoporosis effects. This paper aimed to investigate the absorption mechanism of neobavaisoflavone in Caco-2 cell monolayer model. The analyte and osalmide were separated on Thermo Syncronis C18 column with methanol-0.1% formic acid solution (90∶10) as the mobile phase, at a flow rate of 0.2 mL•min⁻¹. The concentration of neobavaisoflavone was determined in eletrospray ionization(ESI) positive ion mode with osalmide as an the internal standard. The effects of time, concentration, P-gp inhibitor verapamil, MRP-2 inhibitor MK-571 and BCRP inhibitor Ko143 on the absorption of neobavaisoflavone were investigated. According to the results, neobavaisoflavone showed a good linearity within the concentration of 10-2 000 µg•L⁻¹, and the results of its specificity, matrix effect, extraction recovery, precision, accuracy and stability all met the requirements. In the Caco-2 cell monolayer model, the transport volume of neobavaisoflavone was correlated positively with the time and concentration. The ER values of 15, 30, 50 µmol•L⁻¹ neobavaisoflavone were 1.64, 1.94,0.99, respectively. As compared with the control group, all of verapamil hyduochloride, MK-571 and Ko143 could promote the transportation of neobavaisoflavone, and the effect was more obvious in verapamil hyduochloride and Ko143. The absorption of neobavaisoflavone may be mainly of active transport in Caco-2 cell monolayer model, and also involve passive transport. Excretion mechanism of intestinal transport protein may be also involved.

High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid.

BACKGROUND: Linezolid is an effective antibiotic reagent for Gram-positive bacterial infection; its most common side effect is thrombocytopenia. However, the incidence of thrombocytopenia in patients with acute-on-chronic liver failure (ACLF) who underwent linezolid therapy was unclear. The present study was to evaluate the incidence of thrombocytopenia in ACLF and non-ACLF patients treated with linezolid and the risk factors of thrombocytopenia in these patients. METHODS: Thirty-five patients with ACLF who had been subjected to intravenous administration of 600 mg linezolid every 12 hours for more than 7 days were categorized as a ACLF treatment (ACLF-T) group, 72 patients without ACLF treated with the same dosage of linezolid were recruited as a non-ACLF treatment (NACLF-T) group, and 70 patients with ACLF without linezolid treatment served as an ACLF control (ACLF-C) group. The incidences of thrombocytopenia in different groups were compared at day 14. Risk factors were investigated using logistic regression analysis. RESULTS: The incidence of thrombocytopenia at day 14 was significantly higher in the ACLF-T group than in the ACLF-C group (20/35 vs 24/70, P=0.025) and in the NACLF-T group (20/35 vs 9/72, P<0.001). Multivariate analysis showed that the ratio of platelet count (day 7/day 0)<1 (OR=10.021; P=0.012) and the baseline platelet count (OR=0.985; P=0.036) were independent risk factors of thrombocytopenia at day 14 of linezolid therapy. CONCLUSIONS: The benefits of linezolid treatment should outweigh the risk of thrombocytopenia in patients with ACLF. Moreover, it is necessary to closely monitor the platelet count during linezolid therapy especially in the patients with decreased platelet count at day 7 of linezolid therapy.

Association of angiotensin II type-1 receptor A1166C gene polymorphism with the susceptibility of immunoglobulin A nephropathy.

Association of angiotensin II type-1 receptor (AT1R) A1166C gene polymorphism with the susceptibility of immunoglobulin A nephropathy (IgAN) is still controversial. This meta-analysis was conducted to evaluate the association of AT1R A1166C gene polymorphism with IgAN susceptibility. The search was performed in the databases of PubMed, Embase, and Cochrane Library as of 1 May 2014. The eligible investigations were recruited for this meta-analysis. Four literatures on the association between AT1R A1166C gene polymorphism and IgAN susceptibility were identified for this meta-analysis. Interestingly, all the included studies were from Asian population. There was no association between AT1R A1166C gene polymorphism and IgAN susceptibility for overall populations (C allele vs. A allele: OR = 1.04, 95% CI: 0.78-1.39, p = 0.76; CC vs. AC + AA: OR = 1.20, 95% CI: 0.48-2.98, p = 0.70; AA vs. AC + CC: OR = 0.97, 95% CI: 0.70-1.34, p = 0.85), and in Asians. In conclusion, AT1R A1166C gene polymorphism was not associated with IgAN susceptibility in Asian population. However, more case-control association investigations on larger, stratified populations are required in the future.

A novel finding of anoctamin 5 expression in the rodent gastrointestinal tract.

Anoctamin 5 (Ano5) belongs to the anoctamin gene family and acts as a calcium-activated chloride channel (CaCC). A mutation in the Ano5 gene causes limb-girdle muscular dystrophy (LGMD) type 2L, the third most common LGMD in Northern and Central Europe. Defective sarcolemmal membrane repair has been reported in patients carrying this Ano5 mutant. It has also been noted that LGMD patients often suffer from nonspecific pharyngoesophageal motility disorders. One study reported that 8/19 patients carrying Ano5 nutations suffered from dysphagia, including the feeling that solid food items become lodged in the upper portion of the esophagus. Ano5 is widely distributed in bone, skeletal muscle, cardiac muscle, brain, heart, kidney and lung tissue, but no report has examined its expression in the gastrointestinal (GI) tract. In the present study, we investigated the distribution of Ano5 in the GI tracts of mice via reverse transcription-polymerase chain reaction (RT-PCR), Western blot and immunofluorescence analyses. The results indicated that Ano5 mRNA and protein are widely expressed in the esophagus, the stomach, the duodenum, the colon and the rectum but that Ano5 immunoreactivity was only detected in the mucosal layer, except for the muscular layer of the upper esophagus, which consists of skeletal muscle. In conclusion, our present results demonstrate for the first time the expression of Ano5 in the GI epithelium and in skeletal muscle in the esophagus. This novel finding facilitates clinical differential diagnosis and treatment. However, further investigation of the role of Ano5 in GI function is required.

Altered expression of dopamine receptors in cholinergic motoneurons of the hypoglossal nucleus in a 6-OHDA-induced Parkinson's disease rat model.

Parkinson's disease (PD) is a common neurodegenerative disorder that is often associated with weak tongue motility. However, the link between the degenerated dopaminergic neurons in the substantia nigra (SN) and lingual dysfunction remains unclear. In the present study, we investigated the localization of dopamine receptor 1 (D1) and dopamine receptor 2 (D2) and alternations in their expression in cholinergic motoneurons of the hypoglossal nucleus (HN) using double-label immunofluorescence, Western blotting and semi-quantitative reverse transcription and polymerase chain reaction (SqRT-PCR) in rats that received microinjections of 6-hydroxydopamine bilaterally into the SN (6-OHDA rats). The results revealed that a large population of choline acetyltransferase immunoreactive (ChAT-IR) neurons was distributed throughout HN and that almost all of the ChAT-IR motoneurons were also D1-IR and D2-IR. Several tyrosine hydroxylase (TH)-IR profiles were observed in a nonuniform pattern near the ChAT-IR, D1-IR or D2-IR somas, suggesting potent dopaminergic innervation. In the 6-OHDA rats, TH immunoreactivity in the SN was significantly decreased, but food residue was increased and treadmill occupancy time was shortened. In the HN, protein expression of TH and D2 was increased, whereas that of ChAT and D1 was decreased. A similar pattern was observed in mRNA levels. The present study suggests that dopamine may modulate the activity of cholinergic neurons via binding with D1 and D2 in the HN. Changes in the expression of ChAT, TH, D1 and D2 in the HN of 6-OHDA rats might be associated with the impaired tongue motility in PD. These findings should be further investigated.

Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men--the role of gut microbiota composition: study protocol for the AELC randomized controlled trial.

BACKGROUND: Pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether individualized aerobic exercise (AEx) and low carbohydrate diet (LCh) intervention affect hepatic fat content (HFC) in pre-diabetes via modification of gut microbiota composition and other post-interventional effects. METHODS/DESIGN: A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50-65 year-old with pre-diabetes and NAFLD. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1 = AEx, 2 = LCh, 3 = AEx + LCh, and 4 = control. In addition, two age-matched reference groups (5 = pre-diabetes without NAFLD (n = 50) and 6 = Healthy without pre-diabetes or NAFLD (n = 50)) are included. The exercise program consists of progressive and variable aerobic exercise (intensity of 60 to 75% of initial fitness level, 3-5 times/week and 30-60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (30%). The control and reference groups are advised to maintain their habitual habits during the intervention. The primary outcome measures are HFC, serum metabolomics and gut microbiota composition. The secondary outcome measures include body composition and cytokines. In addition, socio-psychological aspects, social support, physical activity and diet will be performed by means of questionnaire and interview. DISCUSSION: Specific individualized exercise and diet intervention in this study offers a more efficient approach for liver fat reduction and diabetes prevention via modification of gut microbiota composition. Besides, the study explores the importance of incorporating fitness assessment and exercise in the management of patients with pre-diabetes and fatty liver disorders. If our program is shown to be effective, it will open new strategies to combat these chronic diseases. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN42622771.