Serum hydroxycotinine was associated with chronic kidney disease (CKD): a cross-sectional study based on NHANES.

OBJECTIVE: Smoking has been suggested as a modifiable and cardiovascular risk factor for chronic kidney disease (CKD). Although long-term smoking has been associated with CKD, the potential relationship between its metabolite hydroxycotinine and CKD has not been clarified. METHODS: A total of 8,544 participants aged 20 years and above from the National Health and Nutrition Examination Survey (NHANES) 2017 - March 2020 were enrolled in our study. CKD was defined by estimated glomerular filtration rate (eGFR) < 60 mL/(min*1.73 m2). Serum hydroxycotinine was measured by an isotope-dilution high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometric (ID HPLC-APCI MS/MS) method with a lower limit of detections (LLOD) at 0.015 ng/mL. The non-linear relationship was explored with restricted cubic splines (RCS). Pearson's correlation coefficient and a multivariate logistic regression model were used for correlation analysis. RESULTS: Serum hydroxycotinine and eGFR were negatively correlated in both non-CKD group (r= -0.05, p < 0.001) and CKD group (r= -0.04, p < 0.001). After serum hydoxycotinine dichotominzed with LLOD, serum hydroxycotinine ≥ 0.015 ng/mL was negatively correlated with eGFR not only in non-CKD group (r = -0.05, p < 0.001) but also in CKD group (r = -0.09, p < 0.001). After adjusting for comprehensive confounders, results from the multivariate logistic regression analysis showed that participants with serum hydroxycotinine ≥ 0.015 ng/mL had increased odds of CKD (OR = 1.505, p < 0.001). CONCLUSIONS: Serum hydroxycotinine might be positively associated with CKD. Further study is warranted to find the right concentration of hydroxycotinine to measure the CKD.

Development of hypertension models for lung cancer screening cohorts using clinical and thoracic aorta imaging factors.

This study aims to develop and validate nomogram models utilizing clinical and thoracic aorta imaging factors to assess the risk of hypertension for lung cancer screening cohorts. We included 804 patients and collected baseline clinical data, biochemical indicators, coexisting conditions, and thoracic aorta factors. Patients were randomly divided into a training set (70%) and a validation set (30%). In the training set, variance, t-test/Mann-Whitney U-test and standard least absolute shrinkage and selection operator were used to select thoracic aorta imaging features for constructing the AIScore. Multivariate logistic backward stepwise regression was utilized to analyze the influencing factors of hypertension. Five prediction models (named AIMeasure model, BasicClinical model, TotalClinical model, AIBasicClinical model, AITotalClinical model) were constructed for practical clinical use, tailored to different data scenarios. Additionally, the performance of the models was evaluated using receiver operating characteristic (ROC) curves, calibration curves and decision curve analyses (DCA). The areas under the ROC curve for the five models were 0.73, 0.77, 0.83, 0.78, 0.84 in the training set, and 0.77, 0.78, 0.81, 0.78, 0.82 in the validation set, respectively. Furthermore, the calibration curves and DCAs of both sets performed well on accuracy and clinical practicality. The nomogram models for hypertension risk prediction demonstrate good predictive capability and clinical utility. These models can serve as effective tools for assessing hypertension risk, enabling timely non-pharmacological interventions to preempt or delay the future onset of hypertension.

Development of a predictive risk stratification tool to identify the population over age 45 at risk for new-onset stroke within 7 years.

Background and purpose: With the acceleration of the aging process of society, stroke has become a major health problem in the middle-aged and elderly population. A number of new stroke risk factors have been recently found. It is necessary to develop a predictive risk stratification tool using multidimensional risk factors to identify people at high risk for stroke. Methods: The study included 5,844 people (age ≥ 45 years) who participated in the China Health and Retirement Longitudinal Study in 2011 and its follow-up up to 2018. The population samples were divided into training set and validation set according to 1:1. A LASSO Cox screening was performed to identify the predictors of new-onset stroke. A nomogram was developed, and the population was stratified according to the score calculated through the X-tile program. Internal and external verifications of the nomogram were performed by ROC and calibration curves, and the Kaplan-Meier method was applied to identify the performance of the risk stratification system. Results: The LASSO Cox regression screened out 13 candidate predictors from 50 risk factors. Finally, nine predictors, including low physical performance and the triglyceride-glucose index, were included in the nomogram. The nomogram's overall performance was good in both internal and external validations (AUCs at 3-, 5-, and 7-year periods were 0.71, 0.71, and 0.71 in the training set and 0.67, 0.65, and 0.66 in the validation set, respectively). The nomogram was proven to excellently discriminate between the low-, moderate-, and high-risk groups, with a prevalence of 7-year new-onset stroke of 3.36, 8.32, and 20.13%, respectively (P < 0.001). Conclusion: This research developed a clinical predictive risk stratification tool that can effectively identify the different risks of new-onset stroke in 7 years in the middle-aged and elderly Chinese population.

Inhibition of mammalian target of rapamycin complex 1 in the brain microvascular endothelium ameliorates diabetic Aß brain deposition and cognitive impairment via the sterol-regulatory element-binding protein 1/lipoprotein receptor-associated protein 1 signaling pathway.

AIMS: Mammalian target of rapamycin complex 1 (mTORC1) is highly activated in diabetes, and the decrease of low-density lipoprotein receptor-associated protein 1 (LRP1) in brain microvascular endothelial cells (BMECs) is a key factor leading to amyloid-ß (Aß) deposition in the brain and diabetic cognitive impairment, but the relationship between them is still unknown. METHODS: In vitro, BMECs were cultured with high glucose, and the activation of mTORC1 and sterol-regulatory element-binding protein 1 (SREBP1) was observed. mTORC1 was inhibited by rapamycin and small interfering RNA (siRNA) in BMECs. Betulin and siRNA inhibited SREBP1, observed the mechanism of mTORC1-mediated effects on Aß efflux in BMECs through LRP1 under high-glucose conditions. Constructed cerebrovascular endothelial cell-specific Raptor-knockout (Raptorfl/+ ) mice to investigate the role of mTORC1 in regulating LRP1-mediated Aß efflux and diabetic cognitive impairment at the tissue level. RESULTS: mTORC1 activation was observed in HBMECs cultured in high glucose, and this change was confirmed in diabetic mice. Inhibiting mTORC1 corrected the reduction in Aß efflux under high-glucose stimulation. In addition, high glucose activated the expression of SREBP1, and inhibiting of mTORC1 reduced the activation and expression of SREBP1. After inhibiting the activity of SREBP1, the presentation of LRP1 was improved, and the decrease of Aß efflux mediated by high glucose was corrected. Raptorfl/+ diabetic mice had significantly inhibited activation of mTORC1 and SREBP1, increased LRP1 expression, increased Aß efflux, and improved cognitive impairment. CONCLUSION: Inhibiting mTORC1 in the brain microvascular endothelium ameliorates diabetic Aß brain deposition and cognitive impairment via the SREBP1/LRP1 signaling pathway, suggesting that mTORC1 may be a potential target for the treatment of diabetic cognitive impairment.

Effects and differences of sleep duration on the risk of new-onset chronic disease conditions in middle-aged and elderly populations.

BACKGROUND: Few longitude cohort studies investigated the risk of the duration of nighttime sleep and naps to the new-onset common chronic disease conditions (CDCs) in middle-aged (45-60) and the elderly (age ≥ 60) populations using an age-stratified strategy. METHODS: The 7025 participants from The China Health and Retirement Longitudinal Study were screened as eligible subjects. Established 13 cohorts with CDCs, acquired their' sleep records in 2011, and obtained new-onset incidents of CDCs during follow-up in 2011-2018. Performed risk association analyses between sleep duration and 13 new-onset CDCs respectively. RESULTS: New-onset risk of four CDCs decreased with increasing nighttime sleep (p-nonlinear>0.05). The risk threshold was approximately 7 hours in middle-aged people and 6 hours in the elderly. For the middle-aged population, compared with 7-9hours sleep, <5hour and 5-7hours nighttime sleep were associated with 1.312∼1.675 times more risk of hypertension, kidney disease, diabetes or high blood sugar status, and multimorbidity; Compared with no nap, a 0-30 min nap was associated with 1.413(1.087∼1.837) times the heart disease risk. In the elderly, < 5 hours of night sleep was a significant risk factor for four CDCs including kidney disease and multimorbidity, etc. A long night's sleep (>9 hours) was connected with 61.2% reduction in risk of memory disease, a >90 min nap increased 62% risk of memory disease, and a 0-30 min nap was associated with higher risks of heart disease, hypertension, and a lower kidney disease risk. CONCLUSIONS: Nighttime sleep and daytime naps may have their own implications for the new-onset CDCs' risk in the aging process.

The mediating effect of depression on new-onset stroke in diabetic population: Evidence from the China health and retirement longitudinal study.

BACKGROUND: Diabetes has a high incidence in China, which may cause stroke and depression. However, the relationship between diabetes and the incidence of new-onset stroke and depression has not been fully studied. METHODS: The data from the China Longitudinal Study on Health and Retirement (CHARLS) from 2013 to 2018 were used. A total of 8530 respondents aged ≥45 years old were included in the follow-up study. Logistic regression model, Cox regression, and Mediation analyses were used to explore the association between diabetes, depression, and new-onset stroke. RESULTS: The depression score of patients with diabetes history was higher (HR,95%CI = 1.02, 1.01-1.04) and were more likely to experience new-onset stroke events (HR, 95%CI = 1.046, 1.02-1.07). With a history of hypertension (HR,95%CI = 1.747, 1.381-2.208), older (HR,95%CI = 1.033, 1.020-1.046) with high BMI (HR,95%CI = 1.056, 1.027-1.086) have a high risk of new-onset stroke. In the combined subgroup analysis, the incidence of new-onset stroke in the subgroup with diabetes depression was higher than in others. The mediating effect of depression on new-onset stroke events in diabetic patients is more pronounced in the medium to long term (>3 years) after adjusting covariates. LIMITATIONS: We defined new-onset stroke by patient self-report, there might be some memory bias. In addition, new-onset stroke was not classified in the CHARLS questionnaire, which would hinder us to evaluate the mediating effect of depression on different types of new-onset stroke. CONCLUSION: Our results showed that depression has a partial mediating effect between diabetes and new-onset stroke in the middle-aged and elderly population in China.

Health Technology Assessment in China's Health Care Sector: Development and Applications.

China's health system is facing severe challenges from social transition and the double burden of population aging and non-communicable diseases. Addressing the tension between the public's increasing demand for health services and the limited availability of medical resources has become a critical issue for health care policymakers and medical insurance fund administrators. In promoting its medical insurance system reform, China is actively developing health technology assessment (HTA) with principles and applications adapted to the Chinese context. This study aims to analyze the evolution of HTA in China with a focus on context, actors, process, content, and challenges encountered through applying a modified verson of Walt and Gilson's policy triangle framework. Currently, HTA plays an indispensable part in the reform of China's health care and medical insurance system, especially in the formulation and adjustment of the National Reimbursement Drug List (NRDL). While HTA is increasingly used in China, there remain challenges, such as the slow development of HTA related disciplines, lack of an independent national HTA authority, and limited scope in the use of HTA. Despite the identified challenges, HTA has the potential to support a wide range of applications in China's health care sector, building on the progress achieved over the last three decades.

Association of the depressive scores, depressive symptoms, and conversion patterns of depressive symptoms with the risk of new-onset chronic diseases and multimorbidity in the middle-aged and elderly Chinese population.

Background: The relationship between depressive symptoms (DS) and their conversion patterns over time and the new-onset risk of diseases in the middle-aged and elderly population has not been extensively studied. Methods: Based on The China Health and Retirement Longitudinal Study participants in 2013, we established 13 cohorts involving 12 types of chronic diseases and multimorbidity, who were identified by face-to-face questionnaires. We retrospectively assessed their DS during 2011 and 2013 through the 10-item Center for Epidemiological Studies Depression Scale (CES-D), which were classified into never, newly developed, relieved, and persistent DS, and these participants were followed from 2013 to 2018. Findings: CES-D scores were new-onset risk factors for 9 diseases. The new-onset risk of diseases increased with higher CES-D scores. When CES-D scores were higher than approximately 6, the hazard ratios (HRs) of emergent diseases were greater than 1. DS was independent new-onset risk factors for 8 diseases, with HRs (95% CI) ranging from 1.2635 (1.0061-1.5867) to 1.5231 (1.0717-2.165). Persistent DS was an independent risk factor for most diseases but might be an independent protective factor for new-onset cancer (HR, 95% CI: 0.276, 0.106-0.723). Interpretation: DS is closely associated with new-onset risk of chronic diseases and multimorbidity, and awareness of the risk associated with pre-DS status (6

Opportunistic osteoporosis screening using chest CT with artificial intelligence.

Osteoporosis has a high incidence and a low detection rate. If it is not detected in time, it will cause osteoporotic fracture and other serious consequences. This study showed that the attenuation values of vertebrae on chest CT could be used for opportunistic screening of osteoporosis. This will be beneficial to improve the detection rate of osteoporosis and reduce the incidence of adverse events caused by osteoporosis. INTRODUCTION: To explore the value of the attenuation values of all thoracic vertebrae and the first lumbar vertebra measured by artificial intelligence on non-enhanced chest CT to do osteoporosis screening. METHODS: On base of images of chest CT, using artificial intelligence (AI) to measure the attenuation values (HU) of all thoracic and the first vertebrae of patients who underwent CT examination for lung cancer screening and dual-energy X-ray absorptiometry (DXA) examination during the same period. The patients were divided into three groups: normal group, osteopenia group, and osteoporosis group according to the results of DXA. Clinical baseline data and attenuation values were compared among the three groups. The correlation between attenuation values and BMD values was analyzed, and the predictive ability and diagnostic efficacy of attenuation values of thoracic and first lumbar vertebrae on osteopenia or osteoporosis risk were further evaluated. RESULTS: CT values of each thoracic vertebrae and the first lumbar vertebrae decreased with age, especially in menopausal women and presented high predictive ability and diagnostic efficacy for osteopenia or osteoporosis. After clinical data correction, with every 10 HU increase of CT values, the risk of osteopenia or osteoporosis decreased by 32 ~ 44% and 61 ~ 80%, respectively. And the combined diagnostic efficacy of all thoracic vertebrae was higher than that of a single vertebra. The AUC of recognizing osteopenia or osteoporosis from normal group was 0.831and 0.972, respectively. CONCLUSIONS: The routine chest CT with AI is of great value in opportunistic screening for osteopenia or osteoporosis, which can quickly screen the population at high risk of osteoporosis without increasing radiation dose, thus reducing the incidence of osteoporotic fracture.

Cross-sectional association between body fat percentage and arteriosclerosis assessed by Cardio-Ankle Vascular Index in a Chinese population: a retrospective observational study.

OBJECTIVE: To evaluate arteriosclerosis using Cardio-Ankle Vascular Index (CAVI) and to explore the relation between the body fat percentage (BFP) and CAVI. DESIGN: A retrospective observational study. SETTING AND PARTICIPANTS: A total of 1152 patients admitted to a geriatric unit and general practice at a mega hospital in Wuhan, China, from November 2018 to November 2019 were included in this study. PRIMARY OUTCOME: Association between BFP and CAVI. RESULTS: Multiple linear regression analysis showed that BFP was positively correlated with CAVI after correction for potential confounding variables (ß=0.03; 95% CI: 0.01 to 0.05); this association persisted after BFP was treated by quartile categorical variables and the trend test was statistically significant (p for trend=0.002). Meanwhile, the generalised additive model showed a non-linear association between BFP and CAVI. When BFP<20.6%, BFP is not associated with CAVI for (ß=-0.02; 95% CI: -0.06 to 0.03), but when BFP≥20.6%, there is a linear positive association between BFP and CAVI (ß=0.05; 95% CI: 0.02 to 0.07). Subgroup analysis showed that there was an interaction between BFP and CAVI in the age stratification (p interaction=0.038). CONCLUSION: BFP was non-linearly correlated with CAVI, with a 0.05 increase in CAVI for every 1% increase in BFP when BFP≥20.6% and a 0.03 increase in CAVI in those >65 years of age.

Artificial intelligence measuring the aortic diameter assist in identifying adverse blood pressure status including masked hypertension.

INTRODUCTION AND OBJECTIVES: Artificial intelligence (AI) made it achievable that aortic dilation could be measured in CT images indirectly, while aortic diameter (AD) has the certain relationship with blood pressure. It was potential that the blood pressure condition be determined by AD measurement using the data obtained from a CT scanning especially in identifying masked hypertension and predicting the risk of poor control of blood pressure (BP) which was easy to elude diagnosis in clinic. We aimed to evaluate the possibility of utilizing AD by AI for predicting the risk of adverse BP status (including masked hypertension or poor BP control) and the optimal thoracic aortic position in measurement as well as the cutoff value for predicting the risk. METHODS: Eight hundred and one patients were enrolled in our study. AI-Rad Companion Cardiovascular (K183268 FDA approved) was used to perform automatic aorta measurement in thoracic CT images at nine key positions based on AHA guidelines. Data was post processed by software from AI-Rad Companion undergone rigorous clinical validation by both FDA and CE as verification of its efficacy and usability. The AD's risk and diagnostic value was assessed in identifying hypertension in the general population, in identifying the poor BP controlled in the hypertension population, and in screening masked hypertension in the general population respectively by multiple regression analysis and receiver operating curve analysis. RESULTS: AD measured by AI was a risk factor for adverse BP status after clinical covariates adjustment (OR = 1.02 ~ 1.26). The AD at mid descending aorta was mostly affected by BP particularly, which is optimal indicator in identifying hypertension in the general population (AUC = 0.73) and for screening masked hypertension (AUC = 0.78). CONCLUSION: Using AI to measure the AD of the aorta, particularly at the position of mid descending aorta, is greatly valuable for identifying people with poor BP status. It will be possible to reveal more clinical information reflected by ordinary CT images and enrich the screening methods for hypertension, especially masked hypertension.PLAIN LANGUAGE SUMMARYHTN has a significant adverse effect on arterial deformation. BP and arterial dilation promote each other in a vicious circle. Arterial dilation may not be restricted by apparent fluctuations in BP and is objective evidence of an undesirable BP state. The accuracy of AD measurements by AI on chest CT images has been verified. There has not been the application of AD measurement by AI in the scene of poor BP status in clinical practice.In this study, we applied AI to measure the diameter of the aorta in nine consecutive positions. We explored the association between AD at various positions and BP levels and the possibility that AD in identifying poor BP status in different populations. We found that the AD at the MD is of great value in screening MH and evaluating the control state of BP in HTN. It will be possible to significantly expand the clinical information reflected by ordinary CT images and enrich the screening methods for HTN, especially MH.

Associations between bone mineral density in different measurement locations and coronary artery disease: a cross-sectional study.

The bone mineral density (BMD) loss is closely related to coronary heart disease (CAD). The BMD measured at different locations differ in BMD values, the risk to CAD, and the capability to identify CAD. An average BMD of the right and left femoral neck being below - 1.70 has the ability to indicate risk of CAD. PURPOSE: Previous studies have reported that low bone mineral density (BMD) is closely related to coronary artery disease (CAD); however, it is not clear that the BMD loss at which location to what extent has the greatest effect in identifying risk of CAD. This study aimed to evaluate the ability of different measurement sites of BMD in identifying CAD and analyze the best measurement sites and the optimal cut-off of BMD for CAD. METHODS: This was a cross-sectional study in which 180 of 817 participants were diagnosed with CAD. All participants in the study were measured by dual-energy X-ray absorptiometry (DEXA) for BMD at 8 locations, and following measurements were derived: the average BMD of lumbar spine (L1-L4), femoral neck (left and right), and total proximal femur (left and right). The association between BMD at different locations and CAD was analyzed using logistic regression. The receiver operating characteristic (ROC) curve was used to select the optimal measurement location and cut-off value of the BMD for identifying CAD. RESULTS: There were significant differences in BMD at 3 different measurement locations. Higher BMD is a protective factor against CAD, which is more pronounced in the femoral neck and total proximal femur (ORs = 0.47 ~ 0.66, P < 0.001) than in the lumbar spine (ORs = 0.74 ~ 0.79, P < 0.001). The optimal site for predicting the risk of CAD by BMD is the femoral neck, with the AUC (area under the ROC curve) is 0.72 (95% CI: 0.67 ~ 0.76) and the cut-off is - 1.70. CONCLUSION: The BMD below particular cut-off of the femoral neck rather than of the lumbar spine may have certain further research value for revealing the risk of CAD.

The Leukocyte Subtype Counts and Ratios Can Effectively Predict the Risk of Arterial Stiffness Assessed by Cardio-Ankle Vascular Index: A Retrospective Study.

Background: Arterial stiffness was the pathological basis and risk factor of cardiovascular diseases, with chronic inflammation as the core characteristic. We aimed to analyze the association between the arterial stiffness measured by cardio-ankle vascular index (CAVI) and indicators reflecting the inflammation degree, such as count of leukocyte subtypes, platelet, and monocyte-to-lymphocyte ratio (MLR), etc. Methods: The data of inpatients from November 2018 to November 2019 and from December 2019 to September 2020 were continuously collected as the training set (1,089 cases) and the validation set (700 cases), respectively. A retrospective analysis of gender subgroups was performed in the training set. The association between inflammatory indicators and CAVI or arterial stiffness by simple linear regression, multiple linear regression, and logistic regression was analyzed. The effectiveness of the inflammation indicators and the CAVI decision models to identify arterial stiffness by receiver operating curve (ROC) in the training and validation set was evaluated. Results: The effect weights of MLR affecting the CAVI were 12.87% in men. MLR was the highest risk factor for arterial stiffness, with the odds ratio (95% confidence interval) of 8.95 (5.04-184.79) in men after adjusting the covariates. A cutpoint MLR of 0.19 had 70% accuracy for identifying arterial stiffness in all participants. The areas under the ROC curve of the CAVI decision models for arterial stiffness were >0.80 in the training set and validation set. Conclusions: The MLR might be a high-risk factor for arterial stiffness and could be considered as a potential indicator to predict arterial stiffness.

Thoracic Aorta Diameter Calculation by Artificial Intelligence Can Predict the Degree of Arterial Stiffness.

Background: Arterial aging is characterized by decreased vascular function, caused by arterial stiffness (AS), and vascular morphological changes, caused by arterial dilatation. We analyzed the relationship of pre-AS and AS, as assessed by cardio ankle vascular index (CAVI), with arterial diameters (AD) at nine levels, from the aortic sinus to the abdominal aorta, as measured by artificial intelligence (AI) on non-enhanced chest computed tomography (CT) images. Methods: Overall, 801 patients who underwent both chest CT scan and arterial elasticity test were enrolled. Nine horizontal diameters of the thoracic aorta (from the aortic sinuses of Valsalva to the abdominal aorta at the celiac axis origin) were measured by AI using CT. Patients were divided into non-AS (mean value of the left and right CAVIs [M.CAVI] < 8), pre-AS (8 ≤ M.CAVI < 9), and AS (M.CAVI ≥ 9) groups. We compared AD differences among groups, analyzed the correlation of age, ADs, and M.CAVI or the mean pressure-independent CAVI (M.CAVI0), Furthermore, we evaluated the risk predictors and the diagnostic value of the nine ADs for pre-AS and AS. Results: The AD at mid descending aorta (MD) correlated strongest with CAVI (r = 0.46, p < 0.001) or M.CAVI0 (r = 0.42, p < 0.001). M.CAVI was most affected by the MD AD and by age. An increase in the MD AD independently predicted the occurrence of pre-AS or AS. For MD AD, every 4.37 mm increase caused a 14% increase in the pre-AS and AS risk and a 13% increase in the AS risk. With a cut-off value of 26.95 mm for the MD AD, the area under the curve (AUC) for identifying the risk of AS was 0.743. With a cut-off value of 25.15 mm, the AUC for identifying the risk of the stage after the prophase of AS is 0.739. Conclusions: Aging is associated with an increase in AD and a decrease in arterial elasticity. An increase in AD, particularly at the MD level is an independent predictor of AS development.

Structure-Based Development of (1-(3'-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-ß-lactamases.

The emergence and spread of bacterial pathogens acquired metallo-ß-lactamase (MBL) and serine-ß-lactamase (SBL) medicated ß-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2'S)-(1-(3'-mercapto-2'-methylpropanamido)methyl)boronic acid (MS01) as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural optimization yielded new, more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2 and showed selectivity across serine hydrolyases in E. coli and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL enzymes.

[Effects and mechanism of the long-snake moxibustion on ankylosing spondylitis based on Th17/Treg/Th1 immune imbalance].

OBJECTIVE: To explore the effects and mechanisms of the long-snake moxibustion on ankylosing spondylitis (AS) based on Th17/Treg/Th1 immune imbalance. METHODS: A total of 60 AS patients were randomized into an observation group and a control group, 30 cases in each one. In the observation group, the long-snake moxibustion therapy was used on the acupoints of the governor vessel from Dazhui (GV 14) to Yaoshu (GV 2) as well as the bilateral Jiaji (EX-B 2) alternatively. The moxibustion was given once a day, for 7 days continuously as one course. There were 3 days at the interval between the courses and 4 courses were required. In the control group, the routine western medication was provided, the salazosulfapyridine combined with non-steroidal anti-inflammatory drugs were used, for 7 days continuous as one course. A total of 4 courses of medication were required. The enzyme linked immunosorbent assay (ELISA) was adopted to determine the levels of interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23) and tumor necrosis factor-α (TNF-α). The real-time quantification polymerase chain reaction (RT-PCR) was used to determine the mRNA expressions of the specific transcription factors, FoxP3 and T-bet of the helper 17 cells (Th17), regulatory T cells (Treg) and T helper 1 cells (Th1). The flow cytometry was applied to determine the rates of Treg, Th1 and Th17, as well as the changes of the inflammatory reaction index, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The therapeutic effects were compared between the two groups. RESULTS: After treatment, the total effective rate was 93.3% (28/30) in the observation group, which was better than 86.7% (26/30) in the control group (P<0.05). After treatment, the levels of CRP, ESR, IL-6, IL-17, IL-23 and TNF-α, as well as the rate of Th17 were reduced significantly as compared with those before treatment in the observation group (all P<0.05). The mRNA expressions of FoxP3 and T-bet and the rates of Treg and Th1 were increased as compared with those before treatment (all P<0.05). The change degree in the observation group was significant as compared with the control group (all P<0.05). In the control group, the levels of CRP, ESR, IL-6, IL-17, IL-23 and TNF-α, as well as the rate of Th17 were reduced, and the mRNA expressions of FoxP3 and T-bet and the rates of Treg and Th1 were increased after treatment. But the changes were not significant as compared with those before treatment (all P>0.05). CONCLUSION: The long-snake moxibustion effectively relieves the clinical symptoms in AS patients and regulates the Th17/Treg/Th1 immune imbalance. Its effect target is probably related to the modulation of the AS immune derangement and the inflammatory responses induced by immune derangement so as to achieve the dual-positive regulatory effect.

Phenotypic characterization and anticancer capacity of CD8+ cytokine-induced killer cells after antigen-induced expansion.

Cytokine-induced killer cells (CIK) have been used in clinic for adoptive immunotherapy in a variety of malignant tumors and have improved the prognosis of cancer patients. However, there are individual differences in the CIK cell preparations including the obvious differences in the ratio of effector CIK cells among different cancer patients. Infusion of such heterogeneous immune cell preparation is an important factor that would affect the therapeutic efficacy. We report here the enrichment and expansion of CD8+ cells from CIK cells cultured for one week using magnetic activated cell sorting (MACS). These enriched CD8+ CIK cells expressed T cell marker CD3 and antigen recognition receptor NKG2D. Phenotypic analysis showed that CD8+ CIK cells contained 32.4% of CD3+ CD56+ natural killer (NK)-like T cells, 23.6% of CD45RO+ CD28+, and 50.5% of CD45RA+ CD27+ memory T cells. In vitro cytotoxic activity assay demonstrated that the enriched CD8+ CIK cells had significant cytotoxic activity against K562 cells and five ovarian cancer cell lines. Intriguingly, CD8+ CIK cells had strong cytotoxic activity against OVCAR3 cells that has weak binding capability to NKG2D. Flow cytometry and quantitative RT-PCR analysis revealed that OVCAR3 cells expressed HLA-I and OCT4 and Sox2, suggesting that CD8+ CIK cells recognize surface antigen via specific T cell receptor and effectively kill the target cells. The results suggest that transplantation of such in vitro enriched and expanded OCT4-specific CD8+ CIK cells may improve the specific immune defense mechanism against cancer stem cells, providing a novel avenue of cancer stem cell targeted immunotherapy for clinical treatment of ovarian cancer.

First synthesis of 22-oxa-chenodeoxycholic acid analogue.

In this study, we report the first synthesis of 22-oxa-chenodeoxycholic acid analogue via androstenedione and progesterone, in 11 and 8 steps with overall yields of 6.4% and 12.7%, respectively. We anticipate this will help to facilitate the development of new drugs.

Investigation of medical waste management in Gansu Province, China.

Medical waste is a special category of waste with potential health and environment risks. The present study aimed to explore the current status of medical waste management in western China. Seventy-four healthcare facilities were selected to assess the general status of medical waste management based upon a designed questionnaire survey. The surveyed results showed that the quantities of average medical waste generation were 0.79, 0.59 and 0.61 kg bed(-1) day(-1) in tertiary, secondary and primary hospitals, respectively. The incomplete segregation of domestic and medical waste generated a higher quantity of medical waste in primary hospitals (0.61 kg bed(-1) day(-1)) than that in secondary hospitals. Furthermore, the effective implementation of the medical waste management system depended on national regulations, occupational safety, internal policies and administration and the qualifications and competence of the directors of the waste management department in the healthcare facilities. Therefore, sufficient training programmes and protective measures should be provided by healthcare facilities to all relevant personnel and adequate financial support and effective administrative monitoring should be performed by local authorities.

[Predictive value of umbilical cord blood bilirubin level for subsequent neonatal jaundice].

OBJECTIVE: To investigate the predictive value of umbilical cord serum (UCS) bilirubin for subsequent jaundice in healthy term newborns. METHODS: Five hundred and twenty-three healthy term newborns (275 boys, 248 girls) were selected. The cord blood total serum bilirubin concentration and the serum albumin concentration were determined. All the infants were assessed for jaundice daily by measurement of transcutaneous bilirubin (TCB). When the infant's TCB was >or= 18 within the first 24 h after birth, >or= 21 at 48 h, >or= 25 at or after 72 h, the venous total serum bilirubin (TSB) was determined and treatment against jaundice was applied as needed. The infants were aligned into four groups according to their UCS bilirubin levels, starting from < 30 micromol/L(group 1); >or= 30 micromol/L(group 2); >or= 36 micromol/L(group 3); >or= 42 micromol/L(group 4). The frequency of hyperbilirubinemia and phototherapy (PT) were compared among the four groups. An analysis of UCS bilirubin as a predictor of later development of jaundice was performed. The characteristics of the infants who became jaundiced (jaundiced group) were compared with the normal infants (non-jaundiced group). RESULTS: A clear correlation between UCS bilirubin level and the development of hyperbilirubinemia was found in all populations of the four groups. Only eight of the 194 infants in group 1 showed a TCB index >or= 25. TSB values > 205 micromol/L but < 257 micromol/L were observed in 2 newborns. None of the infants in this group showed TSB > 257 micromol/L or needed PT. Thirty-two infants in group 2 showed TCB >or= 25, 12 infants had TSB > 205 micromol/L but < 257 micromol/L, 2 infants had TSB > 205 micromol/L and received PT. In group 3, one infant developed hyperbilirubinemia at 48 h after birth and received PT. Thirty-nine infants showed TCB >or= 25, 16 infants TSB > 205 micromol/L but < 257 micromol/L, 2 infants had TSB > 205 micromol/L and also received PT. In group 4, 4 infants showed a range of TSB from 200 to 215 micromol/L at 48 h and received PT. Twenty-two infants showed TCB >or= 25, 17 of them showed TSB > 205 micromol/L but < 257 micromol/L, and 5 of them had TSB > 205 micromol/L and received PT. The frequency of TSB > 205 micromol/L increased from 1.03% in group 1, 5.77% in group 2, 19.75% in group 3 and to 42.5% in group 4. None of the 194 newborns in group 1 needed phototherapy, whereas 0.96%, 3.70% and 22.5% of the newborns in groups 2 - 4, needed PT. The frequency of patients with hyperbilirubinemia or phototherapy increased with increasing UCS bilirubin levels. For the prediction of TCB >or= 25 using a UCS bilirubin cut-off level, such as >or= 35 micromol/L, we found a positive predictive value of 45.68% and sensitivity of 68.27%. It is significant to predict neonatal jaundice by UCS bilirubin levels (P < 0.001). In the jaundiced group (TCB >or= 25) UCS bilirubin levels were significantly higher than those in the non-jaundiced group (t = 10.96, P < 0.001). No significant differences were found in the cord blood serum albumin concentration (t = 2.38, P > 0.05), the gestational age (t = -0.90, P > 0.05), and birthweight (t = 0.10, P > 0.05) between the jaundiced and non-jaundiced groups. CONCLUSIONS: UCS bilirubin level is useful in predicting the subsequent jaundice in healthy term infants. The use of UCS bilirubin values may help detect infants at low or high risk for hyperbilirubinemia and minimize an unnecessary prolongation of hospitalization.