Construction and validation of a predictive model of pneumonia for ICU patients with traumatic brain injury (TBI).

The incidence of pneumonia in ICU patients with TBI is very high, seriously affecting the prognosis. This study aims to construct a predictive model for pneumonia in ICU patients with TBI and provide help for the prevention of TBI-related pneumonia.Clinical data of ICU patients with TBI were collected from the Medical Information Mart for Intensive Care (MIMIC)-IV database and hospital data. Variables were screened by lasso and multivariate logistic regression to construct a predictive nomogram model, verified in internal validation cohort and external validation cohort by receiver operator characteristic (ROC) curve, calibration curve and decision curve analysis (DCA).A total of 1850 ICU patients with TBI were enrolled in the study from the MIMIC-IV database, including 1298 in the training cohort and 552 in internal validation cohort. The external validation cohort included 240 ICU patients with TBI from hospital data. Nine variables were selected from the training cohort by lasso regression and multivariate logistic regression, and a pneumonia prediction nomogram was constructed. This nomogram has a high discrimination in training, internal validation and external validation cohorts (AUC = 0.857, 0.877, 0.836). The calibration curve and DCA showed that this nomogram had a high calibration and better clinical decision-making efficiency.The nomogram showed excellent discrimination and clinical utility to predict pneumonia, and could identify pneumonia high-risk patients early, thus providing personalised treatment strategies for ICU patients with TBI.

Effects of matrix metalloproteinase inhibitor doxycycline and CD147 antagonist peptide-9 on gallbladder carcinoma cell lines.

Gallbladder carcinoma is the most common and aggressive malignancy of the biliary tree and highly expresses CD147, which is closely related to disease prognosis in a variety of human cancers. Doxycycline exhibited anti-tumor properties in many cancer cells. CD147 antagonist peptide-9 is a polypeptide and can specifically bind to CD147. The effect of these two drugs on gallbladder cancer cells has not been studied. The aim of this study is to investigate the effect of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells and the possible mechanism of inhibition on cancer cell of doxycycline. To investigate the effects of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells (GBC-SD and SGC-996), cell proliferation, CD147 expression, and early-stage apoptosis rate were measured after treated with doxycycline. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were measured after treated with different concentrations of doxycycline, antagonist peptide-9, and their combination. The results demonstrated that doxycycline inhibited cell proliferation, reduced CD147 expression level, and induced an early-stage apoptosis response in GBC-SD and SGC-996 cells. The matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were inhibited by antagonist peptide-9 and doxycycline, and the inhibitory effects were enhanced by combined drugs in gallbladder carcinoma cell lines. Taken together, doxycycline showed inhibitory effects on gallbladder carcinoma cell lines and reduced the expression of CD147, and this may be the mechanism by which doxycycline inhibits cancer cells. This study provides new information and tries to implement the design of adjuvant therapy method for gallbladder carcinoma.

IL-9 antibody injection suppresses the inflammation in colitis mice.

Diverse T help (Th) cells play a crucial role in the processing and maintaining of chronic inflammation as seen in ulcerative colitis (UC). Th9, a novel subset of Th cells that primarily produces interleukin (IL)-9, has recently been associated with the development of inflammatory diseases. In this study, we evaluated the presentation of Th9 cells in inflamed tissues of human and experimental mouse UC, and examined the therapeutic efficiency of anti Th9 cytokine IL-9 in the experimental mouse UC. Using immunohistochemistry (IHC), we evaluated the presentation of Th9 cells labelled by transcriptional factor PU.1 in both human and dextran sulfate sodium (DSS) induced mouse colitis biopsies. The results showed that increased PU.1 positive Th9 cells were mainly located in the lamina propria in relative with the controls, intraepithelial Th9 cells can also be observed but at low density. Double IHCs revealed that most of PU.1 positive cells were CD3 positive lymphocytes in human UC specimens. Anti-IL-9 antibody injection for 2 weeks reduced the severity of inflammation in DSS induced colitis mice. Our results suggest that The Th9/IL-9 is involved in the pathogenesis of UC.

Differential profile of protumor immunological factors between the tumor site and the tumor-free site - predictive potential of IL-8 and COX2 for colorectal cancer and metastasis.

To study the role of host immune surveillance in the initiation and progression of colorectal cancer (CRC), a set of protumor immunological factors was determined by quantitative real-time PCR (q-PCR) between the primary tumor and the adjacent tumor-free site tissues in 63 patients with colorectal neoplasms. Results showed that expression levels of interleukin (IL)-1ß, IL-6, IL-8, IL-17A, IL-23, and cyclooxygenase 2 (COX2) mRNAs, except transforming growth factor beta (TGFß), in adenoma tissues were significantly higher than that in relative adjacent tissues. Difference of immunological factor levels between adenoma and adjacent tissues (Δ values) was in an order of ΔIL-8 > ΔIL-6 > ΔIL-17A > ΔIL-1ß > ΔCOX2 > ΔIL-23; Analysis showed that the value of ΔCOX2 correlated to the grade of dysplastic degree in patients with adenoma. Notably, levels of all these immunological factors in CRC tissues were continuously increased, the order of values of Δ immunological factors was ΔIL-8 > ΔCOX2 > ΔIL-6 > ΔIL-1ß > ΔIL-17A > ΔIL-23 > ΔTGFß. Further analysis revealed that increased value of Δ IL-1ß was associated with advanced TNM stage, a higher value of Δ COX2 tended to predicate a deeper degree of tumor invasion; and higher values of Δ IL-1ß, IL-6 and COX2 closely correlated to lymph node metastasis in patients with CRC. In addition, the ratio of ΔIL-8/ΔTGFß was most obvious changed factor and associated with node metastasis in patients with CRC. Therefore, we concluded that the difference of protumor immunological factor levels between the primary tumor site and tumor-free site along the adenoma-carcinoma sequence reflects the change of protumor/antitumor force balance, which is associated with CRC initiation and invasion.

Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications.

The majority of colorectal cancers (CRCs) are thought to arise from precancerous adenomas. Upon exposure to diverse microenvironmental factors, precancerous stem cells (pCSCs) undergo complex genetic/molecular changes and gradually progress to form cancer stem cells (CSCs). Accumulative evidence suggests that the pCSC/CSC niche is an inflammatory dominated milieu that contains different cytokines that function as the key communicators between pCSCs/CSCs and their niche and have a decisive role in promoting CRC development, progression, and metastasis. In view of the importance and increasing data about cytokines in modulating pCSCs/CSC stemness properties and their significance in CRC, this review summarizes current new insights of cytokines, such as interleukin (IL)-4, IL-6, IL-8, IL-17A, IL-22, IL-23, IL-33 and interferon (IFN)-γ, involving in the modulation of pCSC/CSC properties and features in precancerous and cancerous lesions and discusses the possible mechanisms of adenoma progression to CRCs and their therapeutic potential.

The presentation and regulation of the IL-8 network in the epithelial cancer stem-like cell niche in patients with colorectal cancer.

BACKGROUND: Accumulative evidence suggests that the biological behavior of cancer stem-like cells (CSCs) is regulated by their surrounding niche, in which cytokines function as one of the main mediators for the interaction between CSCs and their microenvironment in the colorectal cancer (CRC). METHODS: We characterized the presentation of CSCs and the interleukin (IL)- 8 network in the adenoma/CRC epithelium using quantitative real-time PCR (q-PCR), immunohistochemistry (IHC) and double immunofluorescence. In addition, the capacity of IL-1ß to stimulate epithelial IL-8 production in colon cancer Caco-2 cells was examined in vitro and the IL-8 product was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: IHC observation showed increased expression of both CSCs and IL-8 in the adenoma and CRC epithelium, and q-PCR results revealed that increased expression of IL-1ß transcript was strongly correlated with increased IL-8 transcript levels in both adenoma and CRC tissues. Double immunofluorescence images demonstrated the coexpression of the IL-8 receptors IL-8RA and IL-8RB with LGR5 labeled CSCs in CRC tissue sections. Consistently, in vitro experiments showed that coculture of Caco-2 cells with IL-1ß at concentrations of 1, 5, 10 and 20 ng/ml resulted in a dose-dependent release of IL-8, which could be specifically inhibited by cotreatment with the IL-1ß receptor antagonist. CONCLUSIONS: These results demonstrate activation of the IL-8 network in the niche of CSCs from the precancerous adenoma stage to the CRC stage, which is potentially stimulated by IL-1ß in CRC cells.

Exploring Links Between Industrialization, Urbanization, and Chinese Inflammatory Bowel Disease.

Background: Evidence is emerging that the incidence of inflammatory bowel diseases (IBD) is dramatically increased in China, but with a geographic variation. Objectives: We performed a review to summarize the link of accelerated industrialization, urbanization to changing trends in the incidence of IBD over the last three decades. Methods: An electronic database search was performed in PubMed, Medline, EMBASE and Google Scholar (for English literature) and the China Science Periodical Database in Wanfang Data (for Chinese literature) from January 1990 to June 2020. Results: By systematically analyzing the changing trends of gross domestic product (GDP) or GDP per capita, population migration from rural areas to cities and increasing incidence of IBD in parallel in different Chinese regions, an association between accelerated industrialization and urbanization and rising rate of IBD was shown. In which, rates of IBD incidence were higher in provinces with a high value of GDP per capita than those provinces with a low value of GDP per capita. Analysis of available epidemiological data revealed that the incidence of IBD was rising in parallel with increasing trends of both gross products of industry and urban population in Yunnan Province in a 14-year interval. Further evidence suggested that industrialization- and urbanization-induced subsequent changes in environmental factors, e.g., Westernized dietary habits and obesity, and work-related stress, might contribute to the increased risk of IBD in China. In addition, the preliminary results showed that urbanization and Westernized dietary habits might induce significant changes in gut microbiota profile that are possibly to increase the risk for IBD in Chinese. Conclusions: Existing evidence to suggest that accelerated industrialization/urbanization is associated with the increasing incidence of IBD in China, which provides novel insights to study the possible mechanisms for the recent increasing incidence of IBD in newly industrialized and urbanized developing countries. In the future, the interaction between relevant environmental factors e.g., air/water pollution and IBD susceptibility genes in Chinese should be examined.

A multi-institutional retrospective study of hyperthermic plus intravesical chemotherapy versus intravesical chemotherapy treatment alone in intermediate and high risk nonmuscle-invasive bladder cancer.

Objective: To compare the efficacy and safety of hyperthermic intravesical chemotherapy (HIVEC) and intravesical chemotherapy (IVEC) in patients with intermediate and high risk nonmuscle-invasive bladder cancer (NMIBC) after transurethral resection. Methods: We included 560 patients diagnosed with primary or recurrent NMIBC between April 2009 and December 2015 at 1 of 6 tertiary centers. We matched 364 intermediate or high risk cases and divided them into 2 groups: the HIVEC+IVEC group [chemohyperthermia (CHT) composed of 3 consecutive sessions followed by intravesical instillation without hyperthermia] and the IVEC group (intravesical instillation without hyperthermia). The data were recorded in the database. The primary endpoint was 2-year recurrence-free survival (RFS) in all NMIBC patients (n = 364), whereas the secondary endpoints were the assessment of radical cystectomy (RC) and 5-year overall survival (OS). Results: There was a significant difference in the 2-year RFS between the two groups in all patients (n = 364; HIVEC+IVEC: 82.42% vs. IVEC: 74.18%, P = 0.038). Compared with the IVEC group, the HIVEC+IVEC group had a lower incidence of RC (P = 0.0274). However, the 5-year OS was the same between the 2 groups (P = 0.1434). Adverse events (AEs) occurred in 32.7% of all patients, but none of the events was serious (grades 3-4). No difference in the incidence or severity of AEs between each treatment modality was observed. Conclusions: This retrospective study showed that HIVEC+IVEC had a higher 2-year RFS and a lower incidence of RC than IVEC therapy in intermediate and high risk NMIBC patients. Both treatments were well-tolerated in a similar manner.

Warfarin anticoagulation before angioplasty relieves thrombus burden in Budd-Chiari syndrome caused by inferior vena cava anatomic obstruction.

OBJECTIVES: Pulmonary embolism (PE) is one of the major complications after percutaneous balloon angioplasty (PTBA) for Budd-Chiari's syndrome (BCS). The purpose of this study was to investigate the role of warfarin pre-treatment in the prevention of PE after PTBA in patients with large inferior vena cava (IVC) thrombus. PATIENTS AND METHODS: From October 2002 to December 2009, 16 patients with symptomatic membranous or segmental IVC occlusion and large thrombus were treated with warfarin before PTBA. Eleven patients were men and 5 were women. The median age was 36 years, ranging from 21 to 52 years. The median duration of warfarin treatment before PTBA was 7 months, ranging from 3 to 12 months. Fourteen patients had membranous IVC occlusion and 2 had segmental occlusion. All 16 patients had significant thrombi underneath the obstructive lesions. PE diagnosis was based on clinical presentation and pulmonary computerized tomographic angiogram, if indicated. RESULTS: In 14 of 16 patients, IVC thrombus was completely or near-completely resolved based on follow-up cavogram and PTBA was performed. In the other 2 patients, residual thrombus was demonstrated by cavogram at 12 months. PTBA and stent placement were carried out. IVC patency in the 16 patients was confirmed by completion cavogram. No major bleeding complication during warfarin pre-treatment aimed to keep international normalized ratio (INR) 2 to 3. There was no clinically significant PE or death in this group during follow-up, ranging from 6 to 40 months (median 21 months). CONCLUSION: Spontaneous fibrinolysis of IVC thrombus occurs within 1 year in the majority of the patients treated with warfarin. Pre-treatment with warfarin prevents PE after PTBA in the patients with BCS with IVC membranous or segmental occlusion and large thrombus.

Small airway immunoglobulin A profile in emphysema-predominant chronic obstructive pulmonary disease.

BACKGROUND: Due to airway remodeling and emphysematous destruction in the lung, the two classical clinical phenotypes of chronic obstructive pulmonary disease (COPD) are emphysema and bronchiolitis. The present study was designed to investigate the levels of small airway immunoglobulin A (IgA) in COPD with "emphysema phenotype." The study also evaluated the associations between the small airway IgA levels and the severity of disease by the extent of emphysema versus airflow limitation. METHODS: Thirty patients (20 with COPD and ten healthy smokers) undergoing lung resection surgery for a solitary peripheral nodule were included. The study was conducted from January 2015 to December 2018 in the Shanxi Dayi Hospital. The presence of small airway IgA expression was determined in the lung by immunohistochemistry. In vivo, Wistar rats were exposed to silica by intratracheal instillation. Rats were sacrificed at 15 and 30 days after exposure of silica (n = 10 for each group). We also evaluated airway IgA from rats. RESULTS: Small airway secretory IgA (sIgA), dimeric IgA (dIgA), and dIgA/sIgA of Global Initiative for Chronic Obstructive Lung Disease grade 1-2 COPD patients showed no difference compared with smoking control subjects (5.15 ±â€Š1.53 vs. 6.03 ±â€Š0.85; 1.94 ±â€Š0.66 vs. 1.67 ±â€Š0.04; 41.69 ±â€Š21.02 vs. 28.44 ±â€Š9.45, all P > 0.05). dIgA/sIgA level in the lung of COPD patients with emphysema showed higher levels than that of COPD patients without emphysema (51.89 ±â€Š24.81 vs. 31.49 ±â€Š9.28, P = 0.03). The percentage of low-attenuation area below 950 Hounsfield units was positively correlated with dIgA/sIgA levels (r = 0.45, P = 0.047), but not associated with the severity of disease by spirometric measurements (forced expiratory volume in the first second %pred, P > 0.05). Likewise, in the rat study, significant differences in sIgA, dIgA, dIgA/sIgA, mean linear intercept, mean alveoli number, and mean airway thickness of bronchioles (VV airway, all P < 0.01) were only observed between control rats and those exposed for 30 days. However, in the group exposed for 15 days, although the VV airway was higher than that in normal rats (27.61 ±â€Š2.26 vs. 20.39 ±â€Š1.99, P < 0.01), there were no significant differences in IgA and emphysema parameters between the two groups (all P > 0.05). CONCLUSION: Airway IgA concentrations in mild and moderate COPD patients are directly associated with the severity of COPD with "emphysema phenotype" preceding severe airway limitation. This finding suggests that small airway IgA might play an important role in the pathophysiology of COPD, especially emphysema phenotype.

Feasibility and midterm outcomes of percutaneous transhepatic balloon angioplasty for symptomatic Budd-Chiari syndrome secondary to hepatic venous obstruction.

OBJECTIVES: This study evaluated the feasibility and outcomes of percutaneous transhepatic balloon angioplasty (PTBA) of the hepatic vein in the management of Budd-Chiari syndrome (BCS) secondary to hepatic venous outflow obstruction. METHODS: From September 1996 to October 2008, 101 patients (52 males, 49 females) with BCS secondary to occlusion of the hepatic veins were prospectively treated using PTBA of the hepatic vein. Average age was 31.3 years (range, 15-57 years). Nineteen had concurrent inferior vena cava (IVC) obstruction. All the patients presented with symptomatic portal hypertension. PTBA, with or without stenting, was performed after hepatovenography. RESULTS: PTBA was successfully performed in 92 of the 101 patients. Sixty-eight patients underwent PTBA of right hepatic vein, followed by stent placement in two. PTBA was performed in 11 patients with left hepatic vein occlusion and in 13 patients with dominant accessory hepatic vein occlusion. The technical success rate was 92 of 101 (91%). Hepatic venous pressure was significantly decreased after balloon angioplasty/stenting (P < .01, paired t test). Symptoms were significantly improved in the 92 patients who had successful PTBA. Three patients had acute hepatic vein thrombosis during or after PTBA. Two patients sustained intraperitoneal bleeding from the transhepatic puncture track, and one had intrahepatic hematoma. Pulmonary embolism developed in one patient during the operation. All complications were managed nonoperatively. There were no perioperative deaths. Within 1 year, 74 of the 101 patients returned for follow-up, and 51 patients had follow-up at 2 years. The primary patency rates were 84% (62 of 74), 78% (58 of 74), and 76% (39 or 51) at 6, 12, and 24 months after PTBA, respectively. The secondary patency rates were 95% (70 of 74), 92% (68 of 74), and 84% (43 of 51) at 6, 12, and 24 months. CONCLUSIONS: PTBA of the hepatic vein is a safe and effective treatment of BCS. It is currently the most physiologic procedure, and the risk of postoperative encephalopathy is minimized because portal flow is not diverted. Midterm outcomes are satisfactory. Further investigation of the long-term outcomes is needed.

Investigation of miRNA- and lncRNA-mediated competing endogenous RNA network in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a biliary malignancy which is prone to lymphatic metastasis and has a high mortality rate. This disease lacks effective therapeutic targets and prognostic molecular biomarkers. The aim of the current study was to investigate differentially expressed genes and elucidate their association with CCA and the underlying mechanisms of action. mRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) obtained from 36 CCA samples and nine normal samples from The Cancer Genome Atlas were integrated. Subsequently, 1,095 differentially expressed (DE) mRNAs and 75 DE miRNAs were identified using a threshold of |log2 fold change|>2 and an adjusted P<0.01. Weighted gene co-expression network analysis was used to identify the DEmRNAs that could be key target genes in CCA. A total of 12 hub DEmRNAs were identified as targetable genes. Furthermore, the hub DEmRNAs-DElncRNAs pairs were identified using the miRTarBase and miRcode databases. Cytoscape software was used to construct and visualize the protein-protein interactions and the competing endogenous RNA network. Survival time analysis and correlation analysis were used to further evaluate the hub genes. The results obtained in the current study suggested that spalt like transcription factor 3 and OPCML intronic transcript 1 may serve an important role in the development and progression of CCA.

Contribution of IL-33 to the Pathogenesis of Colorectal Cancer.

The development of colorectal cancer (CRC) is not only determined by transformed cells per se, but also by factors existing in their immune microenvironment. Accumulating scientific evidence has revealed that interleukin (IL)-33, an IL-1 family member, plays an essential role in the regulation of immune response and is relevant in CRC pathogenesis. Data from both human and experimental studies demonstrated that IL-33 inhibits host anti-tumor immunity, remodels tumor stroma and enhances angiogenesis, thereby promoting the development of CRC. These pro-tumor effects of IL-33 are mainly mediated by IL-33 receptor ST2 (also known as IL-1RL1). Based on those findings, it is currently hypothesized that the IL-33/ST2 pathway is a potential biomarker and therapeutic target for colorectal tumorigenesis. Herein, we summarize the recent discoveries in understanding the critical role of the IL-33/ST2 pathway in contributing to the pathogenesis of colorectal tumorigenesis and discuss its potential implications for the future development of effective anti-tumor strategies.

IL-1ß/IL-6 network in the tumor microenvironment of human colorectal cancer.

OBJECTIVES: Recent studies suggest that the interaction between interleukin (IL)-1ß and IL-6 in the microenvironment might be involved in the development and progression of human colorectal cancer (CRC). However, the expression of IL-1ß/IL-6 network within the CRC microenvironment is not fully understood. MATERIALS AND METHODS: The level of IL-1ß/IL-6 network expression in 40 biopsies of sporadic CRC and 15 biopsies of controls was assessed using quantitative real-time polymerase chain reaction (PCR) assay, immunohistochemistry (IHC) and double immunofluorescence staining. RESULTS: Quantitative results obtained by real-time PCR revealed that both IL-1ß and IL-6 mRNA expressions were increased in CRC tissues compared with expressions in controls. In which, IL-6 mRNA expression in primary CRC tissues showed a statistically significant relationship with tumor invasion depth. IHC observations confirmed that increased expression of IL-1ß and IL-6 immunoreactivities was located in both the CRC epithelium and stroma. Furthermore, IHC results also revealed that increased expression of IL-1ß receptor type 1 (IL-1R1) and IL-6 receptor (IL-6R) were observed in both CRC epithelial and stromal cells. IHCs in serial CRC sections and double immunofluorescence staining revealed a highly co-expression of IL-1R1 immunoreactivity with IL-6 immunoreactivity in the same cells, which confirmed a histological fundament of IL-1ß/IL-6 network. CONCLUSION: The IL-1ß/IL-6 network is highly expressed in the CRC microenvironment, indicating that this network is important in the progression of CRC.

Temporal and spatial changes of cells positive for stem-like markers in different compartments and stages of human colorectal adenoma-carcinoma sequence.

Considerable evidence supports the idea that stem-like cells may play an essential role during the development of colorectal cancer (CRC). To accomplish this aim, we use immunohistochemistry (IHC) and double IHC with different potential stem-like markers, anti-musashi (Msi), anti-CD133, anti- LGR5 and anti-ALDH1 to examine the presentation of stem-like cells in different compartments including adenoma/CRC epithelium, transitional crypts and tumor stroma in colorectal adenoma and CRC. The results showed that cells positive for stem-like markers were remarkably increased in number and frequently observed in the adenoma/CRC epithelium, transitional crypts and tumor stroma. Notably, the population of cells positive for stem-liker markers was expanded from the base to the middle part of the transitional crypt in both adenoma and CRC tissues, reflecting that stem-like cells are likely involved in the process of colorectal tumorigenesis. Counting results showed that the grading scores of cells positive for LGR5 and ALDH1 in the adenoma/CRC epithelium were significantly increased relative with the control epithelium, and associated with the degree of dysplasia in the adenoma and node involvement in the CRC (all P < 0.05). In addition, the density of cells positive for stem-like markers in the adenomatous/cancerous stroma was also increased and paralleled an increase in the density of proliferative stromal cells labeled by PCNA, which were primarily identified as vimentin positive fibroblasts. Our results have revealed a changed temporal and spatial presentation of stem-like markers in different stages of human colorectal adenoma-carcinoma sequence, which might be a hallmark of the adenoma-carcinoma transition.

Age at menarche and risk of major cardiovascular diseases: Evidence of birth cohort effects from a prospective study of 300,000 Chinese women.

BACKGROUND: Previous studies of mostly Western women have reported inconsistent findings on the association between age at menarche and risk of cardiovascular disease (CVD). Little is known about the association in China where there has been a large intergenerational decrease in women's mean age at menarche. METHODS: The China Kadoorie Biobank recruited 302,632 women aged 30-79 (mean 50.5)years in 2004-8 from 10 diverse regional sites across China. During 7years follow-up, 14,111 incident cases of stroke, 14,093 of coronary heart disease (CHD), and 3200 CVD deaths were reported among 281,491 women who had no prior history of CVD at baseline. Cox regression yielded adjusted hazard ratios (HRs) relating age at menarche to CVD risks. RESULTS: The mean (SD) age of menarche was 15.4 (1.9)years, decreasing from 16.2 (2.0) among women born before 1940 to 14.7 (1.6) for those born during the 1960s-1970s. The patterns of association between age at menarche and CVD risk appeared to differ between different birth cohorts, with null associations in older generations but U-shaped or weak positive associations in younger women, especially those born after the 1960s. After minimizing the potential confounding effects from major CVD risk factors, both early and late menarche, compared with menarche at age 13years, were associated with increased risk of CVD morbidity and mortality, which was more pronounced in younger generations. CONCLUSION: Among Chinese women the associations between age at menarche and risk of CVD differed by birth cohort, suggesting other factors may underpin the association.

Accumulation of FoxP3+ T regulatory cells in the tumor microenvironment of human colorectal adenomas.

OBJECTIVES: T regulatory cells (Tregs) play a critical important role for the occurrence and development of human tumors. Most human colorectal cancers (CRCs) develop from the preformed adenomas, this study is therefore designed to evaluate forkhead box P3 (FoxP3)+ Tregs in human colorectal adenomas. MATERIALS AND METHODS: FoxP3+ Tregs in human colorectal adenomas were evaluated with immunohistochemistry (IHC) and real-time PCR, and compared to CRCs and normal tissues. In addition, the change of Treg immunosuppressive cytokine interleukin (IL)-10 was examined with IHC and real-time PCR. RESULTS: increased FoxP3+Tregs were observed in the adenomatous stroma/epithelium and the density in colorectal adenomas, which was similar to that in the CRCs, significantly increased as compared to normal tissues. Numerous IL-10+cells were observed in the adenomatous stroma, but not in adenomatous epithelium, as compared with the controls. The density grading score of IL-10+ cells in the adenomas confirmed an increased density of IL-10+cells in the adenomatous/CRC stroma. Double IHCs with CD4/CD25 and IL-10/FoxP3 antibodies confirmed above observations and revealed that IL-10 was at least partially released from increased Tregs. Quantitative real-time PCR results confirmed that the expression levels of FoxP3 and IL-10 mRNAs in the adenomas were increased, which equivalent to that in the CRCs. CONCLUSION: accumulation of FoxP3+ Tregs in the tumor microenvironment is an early event along the adenoma-carcinoma sequence, and might play a role in the regulation of host immune response to the initiation of CRC.

Regional variations in the prevalence and misdiagnosis of air flow obstruction in China: baseline results from a prospective cohort of the China Kadoorie Biobank (CKB).

BACKGROUND: Despite the great burden of chronic respiratory diseases in China, few large multicentre, spirometry-based studies have examined its prevalence, rate of underdiagnosis regionally or the relevance of socioeconomic and lifestyle factors. METHODS: We analysed data from 512 891 adults in the China Kadoorie Biobank, recruited from 10 diverse regions of China during 2004-2008. Air flow obstruction (AFO) was defined by the lower limit of normal criteria based on spirometry-measured lung function. The prevalence of AFO was analysed by region, age, socioeconomic status, body mass index (BMI) and smoking history and compared with the prevalence of self-reported physician-diagnosed chronic bronchitis or emphysema (CB/E) and its symptoms. FINDINGS: The prevalence of AFO was 7.3% in men (range 2.5-18.2%) and 6.4% in women (1.5-18.5%). Higher prevalence of AFO was associated with older age (p<0.0001), lower income (p<0.0001), poor education (p<0.001), living in rural regions (p<0.001), those who started smoking before the age of 20 years (p<0.001) and low BMI (p<0.001). Compared with self-reported diagnosis of CB/E, 88.8% of AFO was underdiagnosed; underdiagnosis proportion was highest in 30-39-year olds (96.7%) compared with the 70+ age group (81.1%), in women (90.7%), in urban areas (89.4%), in people earning 5K-10 K ¥ monthly (90.3%) and in those with middle or high school education (92.6%). INTERPRETATION: In China, the burden of AFO based on spirometry was high and significantly greater than that estimated based on self-reported physician-diagnosed CB/E, especially in rural areas, reflecting major issues with diagnosis of AFO that will impact disease treatment and management.

The expression of non-mast histamine in tumor associated microvessels in human colorectal cancers.

Angiogenesis is essential for the growth, expansion and metastasis of human colorectal cancers (CRCs). Histamine produced by mast cells is a potent proangiogenic factor. However, the significance of non-mast cell expressing histamine in the tumor microenvironment remains unknown. In this study, we evaluated the histamine positive microvessels with the specific marker for biosynthesis of histamine L-histidine decarboxylase (HDC) in the CRC tumor microenvironment. The relationship between HDC positive microvessel density (HDC-MVD) and clinical pathological parameters was assessed. The results revealed that HDC-MVD in the tumor microenvironment of CRCs was significantly increased as compared with the controls. CRC patients with lymph node invasion had a particularly higher density of HDC-MVD than those without. The density of HDC-MVD accounted for ~79 % of CD34 positive MVD in CRCs and double IHC analysis demonstrated that these HDC positive microvessels were mostly CD34 positive microvessels and with a high proliferative activity. Our results suggest that histamine expressed in microvessels could be an additional cellular source and involved in the cancer invasion through promoting angiogenesis in human CRCs.

Exhaled carbon monoxide and its associations with smoking, indoor household air pollution and chronic respiratory diseases among 512,000 Chinese adults.

BACKGROUND: Exhaled carbon monoxide (COex) level is positively associated with tobacco smoking and exposure to smoke from biomass/coal burning. Relatively little is known about its determinants in China despite the population having a high prevalence of smoking and use of biomass/coal. METHODS: The China Kadoorie Biobank includes 512,000 participants aged 30-79 years recruited from 10 diverse regions. We used linear regression and logistic regression methods to assess the associations of COex level with smoking, exposures to indoor household air pollution and prevalent chronic respiratory conditions among never smokers, both overall and by seasons, regions and smoking status. RESULTS: The overall COex level (ppm) was much higher in current smokers than in never smokers (men: 11.5 vs 3.7; women: 9.3 vs 3.2). Among current smokers, it was higher among those who smoked more and inhaled more deeply. Among never smokers, mean COex was positively associated with levels of exposures to passive smoking and to biomass/coal burning, especially in rural areas and during winter. The odds ratios (OR) and 95% confidence interval (CI) of air flow obstruction (FEV1/FVC ratio<0.7) for never smokers with COex at 7-14 and ≥14 ppm, compared with those having COex<7, were 1.38 (1.31-1.45) and 1.65 (1.52-1.80), respectively (Ptrend<0.001). Prevalence of other self-reported chronic respiratory conditions was also higher among people with elevated COex (P<0.05). CONCLUSION: In adult Chinese, COex can be used as a biomarker for assessing current smoking and overall exposure to indoor household air pollution in combination with questionnaires.