MiR-526b-3p enhances sensitivity of head and neck squamous cell carcinoma cells to radiotherapy via suppressing exosomal LAMP3-mediated autophagy.

Lysosomal associated membrane protein 3 (LAMP3) has been reported to be a tumour promoter in multiple cancer types by modulating tumour cell autophagy. However, the potential mechanism of LAMP3 in radio-resistance of head and neck squamous cell carcinoma (HNSCC) remains unknown. Therefore, our current study aims to detect the impacts of LAMP3 on the resistance of HNSCC cells to radiotherapy and meanwhile explore its functional mechanism. Through RT-Qpcr examination, LAMP3 expression was identified to be expressed at a significantly high level in irradiation-resistant HNSCC cell lines compared with irradiation-sensitive HNSCC cell lines. Functional assays including CCK-8, colony formation and Transwell assays demonstrated that LAMP3 enhanced the radio-resistance through inducing autophagy to promote HNSCC cell growth. Furthermore, irradiation-resistant HNSCC cells could transfer exosomal LAMP3 to elevate LAMP3 expression in irradiation-sensitive HNSCC cells. Mechanistically, microRNA (miRNA) miR-526b-3p could inhibit LAMP3 expression so as to strengthen sensitivity of HNSCC cells to radiotherapy. In a word, exosomal LAMP3 expression promoted radioresistance of HNSCC cells via inducing autophagy, while this effect could be suppressed by miR-526b-3p in a targeted manner.

Exponential Stability of Fractional-Order Switched Systems With Mode-Dependent Impulses and Its Application.

Most exiting results for impulsive switched systems (ISSs) are mainly built on the synchronous switching and impulses case; however, the impulses can not only occur in switched interval including switched instants but also the switched signals may exist between two impulsive points in practical instants. Under asynchronous impulses and switching signals, the main objective of this article is to study the exponential stability of fractional-order hybrid systems. In order to better characterize stability, some novel criteria are presented by adopting the mode-dependent average impulsive interval and induction method. The obtained impulsive switched criteria lead to a tradeoff between fractional-order α and impulsive strength. Especially, the impulsive effects (positive or negative) with the order α are also discussed in detail, which extends the previous integer order results. Moreover, numerical examples are given to interpret and verify the effectiveness of the obtained criteria.

VALD-3 inhibits proliferation and induces apoptosis of colorectal cancer cells via upregulating tumor suppressor activity of p53 to inhibit Wnt/ß-catenin signal pathway.

Colorectal cancer is the third most common malignant tumor and a leading cause of cancer death. Currently lacks effective therapies available to improve the prognosis. In the present study, VALD-3, an important Schiff base ligand from o-vanillin derivatives was evaluated for its anti-cancer activity in vitro and in vivo against colorectal cancer. The effect of VALD-3 on colorectal cancer cells proliferation was assessed using MTT assay and the cell migration was evaluated using wound healing scratch assay. The appearance of apoptotic colorectal cancer cells was detected by flowcytometry analysis. Morphological changes caused by VALD-3 induced apoptosis were also observed by Hoechst 33258 staining. The flow cytometry assay was also used to measure cell cycle arrest. The expression levels of TP53 and Bad were analyzed using quantitative real-time PCR. Protein expression of P53, Wnt/ß-catenin signaling pathway proteins, apoptosis proteins and cell cycle-related protein were viewed by Western blotting. In addition, HT-29 cells xenograft tumor model was used for the study in vivo. Immunohistochemistry (IHC) staining was employed to detect the P53 protein expression. The results showed that VALD-3 obviously inhibited the proliferation and migration for colorectal cancer cells. In addition, flow cytometry analysis demonstrated that VALD-3 markedly increased early and late apoptosis on colorectal cancer cells, respectively. VALD-3 induced cell cycle arrest at the G0/G1 phase. Most importantly, tumor growth in HT-29 xenograft mice was suppressed by VALD-3, but no significant change in body weight. As confirmed by IHC staining from tumor tissue, the P53 proteins expression increased. These results suggested that VALD-3 represses cell proliferation and induces apoptosis associated with upregulating tumor suppressor activity of p53 to inhibit Wnt/ß-catenin signal pathway, and it is a potential anticancer agent for colorectal cancer.

VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, induces cell cycle arrest and apoptosis in breast cancer cells by inhibiting the Wnt/ß-catenin pathway.

Schiff base compounds and their metal complexes have become important synthetic organic drugs due to their extensive biological activities, which include anticancer, antibacterial and antiviral effects. In this study, we investigated the cytotoxic and apoptotic effects of VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, on human breast cancer cells and the possible underlying mechanisms. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test was used to observe the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells induced by VALD-3. Flow cytometry analysis showed that VALD-3 triggered cell cycle arrest and induced apoptosis of breast cancer cells. Western blot analysis revealed that VALD-3 upregulated pro-apoptotic proteins (Bad and Bax), downregulated anti-apoptotic proteins (Bcl-2, Bcl-xl, survivin and XIAP) and increased the expression of cleaved caspase-3, cleaved caspase-8, Cyto-c and cleaved PARP. VALD-3 also regulated the Wnt/ß-catenin signaling pathway in breast cancer cells, inhibiting the activation of downstream molecules. By xenografting human breast cancer cells into nude mice, we found that VALD-3 significantly suppressed tumor cell growth while showing low toxicity against major organs. In addition, survival analysis showed that VALD-3 can significantly prolong the survival time of mice (P = 0.036). This study is the first to show that VALD-3 induces apoptosis and cell cycle arrest in human breast cancer cells by suppressing Wnt/ß-catenin signaling, indicating that it could be a potential drug for the treatment of breast cancer.

Impact of severe-to-very severe chronic obstructive pulmonary disease on the prognosis of patients with non-small cell lung cancer who received chemotherapy.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. There are limited data about the impact of severe-to-very severe COPD on prognosis in patients with NSCLC receiving first-line chemotherapy. OBJECTIVES: To investigate whether severe-to-very severe COPD impacted survival of patients with NSCLC receiving first-line chemotherapy. METHODS: A retrospective review was performed on 513 consecutive NSCLC patients receiving first-line chemotherapy between February 2014 and May 2018. Prognostic impact of severe-to-very severe COPD was analysed using regression analyses. RESULTS: Totally 258 NSCLC patients (118 non-COPD, 96 mild-to-moderate COPD and 44 severe-to-very severe COPD) were evaluated retrospectively. Kaplan-Meier analysis showed that the median overall survival times in the severe-to-very severe COPD, mild-to-moderate COPD and non-COPD groups were 14.0 months [95% confidence interval (CI): 11.0-17.0], 18 months (95% CI: 14.8-21.2) and 19 months (95% CI: 15.3-22.7), respectively. The difference was significant between patients with severe-to-very severe COPD and those without COPD (χ2  = 6.8, P = 0.009) and between patients with severe-to-very severe COPD and those with mild-to-moderate COPD (χ2  = 4.0, P = 0.045). Multivariate analysis showed that survival time was significantly shorter in the severe-to-very severe COPD group than in the non-COPD group (adjusted hazard ratio: 1.876, 95% CI: 1.161-3.030, P = 0.01) and mild-to-moderate COPD group (adjusted hazard ratio: 1.782, 95% CI: 1.046-3.034, P = 0.033). CONCLUSION: Severe-to-very severe COPD may worsen the prognosis of NSCLC patients who received first-line chemotherapy.

Association between features of COPD and risk of venous thromboembolism.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with risk of venous thromboembolism (VTE) events. A detailed understanding of which clinical features of COPD increase risk of VTE events is needed. OBJECTIVES: To investigate the association between features of COPD and risk of venous thromboembolism. METHODS: A retrospective observational clinical study was conducted on 551 consecutive COPD patients visiting the Department of Respiratory and Critical Care Medicine of Tianjin Chest Hospital between February 2014 and April 2018. Finally, 151 patients were eligible for inclusion. Of these, 29 patients had COPD with VTE and 121 patients had COPD without VTE. Patient informations regarding age, gender, BMI, smoking history, smoking status (package/year), COPD-related symptoms, lung function, number of acute exacerbations and imaging visual emphysema were gathered. RESULTS: Among the 29 VTE patients, 18 patients had PE and five had DVT, while 6 patients had simultaneous PE and DVT. There were statistically significant differences in GOLD grade, Imaging visual emphysema, and frequent acute exacerbations between the two groups. Multivariate logistic regression analysis showed that after adjustment for gender, age, BMI and smoking history, there were statistically significant for visible emphysema (OR = 3.54, 95% CI: 1.13-11.08; P = 0.03) and GOLD grade (OR = 1.77, 95% CI: 1.04-3.01; P = 0.035), but not for frequent acute exacerbations (OR = 1.65, 95% CI: 0.62-4.38; P = 0.31). CONCLUSIONS: Visual emphysema is an independent risk factor for VTE events and the risk of VTE in COPD patients increases with the degree of airway obstruction. However, there is no evidence of an association between exacerbation frequency and VTE events.

Carotid artery plaque intervention with Tongxinluo capsule (CAPITAL): A multicenter randomized double-blind parallel-group placebo-controlled study.

To determine whether the traditional Chinese medicine Tongxinluo (TXL) is efficacious at retarding the progression of carotid atherosclerotic lesions, a total of 1,212 patients with a focal intima-media thickness (IMT) of ≥1.2 mm of the carotid arteries received TXL or placebo capsules in addition to current routine therapy. The primary outcome was between-group differences in annualized change in mean IMT of 12 sites of bilateral carotid arteries over 24 months. The secondary outcomes were between-group differences in plaque area, vascular remodeling index (RI), serum levels of lipids and high-sensitivity C-reactive protein, and a composite of first major cardiovascular events. The results showed that the annualized change in mean IMT in the TXL and placebo groups was -0.00095 (95% CI, -0.00330 to 0.00141) mm and 0.01312 (95% CI, 0.01076 to 0.01548) mm, respectively, with a difference between the two groups of -0.01407 (95% CI, -0.01740 to -0.01073) mm (P < 0.001). Compared with placebo, TXL treatment significantly reduced the change from baseline in the plaque area and RI, as well as the first major cardiovascular events. In conclusion, TXL retarded the progression of mean IMT, plaque area and vascular remodeling of the carotid artery with a good safety profile.

Finite-Time H∞ Filtering for Nonlinear Singular Systems With Nonhomogeneous Markov Jumps.

This paper addresses the finite-time H∞ filtering for a class of nonlinear singular nonhomogeneous Markov jump systems by T-S fuzzy approximation approach, where the transition probabilities (TPs) are time-varying and unknown. First, by considering a stochastic Lyapunov functional and rendering the time-varying TPs inside a polytope, a sufficient condition on singular stochastic H∞ finite-time boundedness (SS H∞ FTB) for the filtering error systems is given. Then, by using the matrix inequality decoupling technique, a novel linear matrix inequality (LMI) condition on the existence of the finite-time H∞ fuzzy filter is presented. The fuzzy filter is developed in terms of LMIs ensuring the filtering error system is SS H∞ FTB. Compared with the previous ones, the proposed design method in this paper has more freedom, leading to less conservative results. A tunnel diode circuit is provided to illustrate the effectiveness and advantage of the design approach proposed in this paper.

Impact of chemotherapy in the prognosis of non-small-cell lung cancer patients with severe to very severe COPD.

BACKGROUND: The aim of the study was to investigate if first-line chemotherapy improves total survival time in non-small-cell lung cancer (NSCLC) patients complicated with severe to very severe COPD. MATERIALS AND METHODS: This retrospective observational clinical study included 267 consecutive NSCLC patients with COPD complications at the Department of Respiratory and Critical Care Medicine of Tianjin Chest Hospital between January 2009 and January 2018. Sixty-nine evaluable patients were included. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients receiving and those not receiving chemotherapy. RESULTS: Forty-five and 24 patients received first-line chemotherapy plus supportive care and supportive care alone, respectively. Kaplan-Meier curves showed that patients receiving chemotherapy had a statistically significant 6-month longer median overall survival (OS) than that of patients receiving supportive care alone (14.0, 95% CI: 8.5-19.5 vs 8.0, 95% CI: 6.4-9.6, respectively) (chi2=8.857, P=0.003). In the multivariate Cox proportional hazard model adjusted for the most relevant variables, the adjusted hazard ratio (HRadj) differed significantly for the receipt of chemotherapy (HRadj=0.4464, 95% CI: 0.2495-0.7988; P=0.0066) but not for gender (HRadj=0.8527, 95% CI: 0.4461-1.6298; P=0.6297), age (HRadj=1.0021, 95% CI: 0.9609-1.0451; P=0.9214), histology (HRadj=1.4422, 95% CI: 0.6959-2.9889; P=0.3247), cancer stage (HRadj=1.9098, 95% CI: 0.8607-4.2375; P=0.1116), performance status score (HRadj=1.5155, 95% CI: 0.7523-3.0529; P=0.2446), lung function (HRadj=1.3856, 95% CI: 0.7149-2.6857; P=0.3341), or respiratory symptoms (HRadj=1.0518, 95% CI: 0.6032-1.8342; P=0.8586). Patients with grade 3/4 adverse reactions accounted for 29% (13/45) of the chemotherapy group. CONCLUSION: The results indicated that chemotherapy may improve the OS of NSCLC patients with severe to very severe COPD.

Purification, characterization and immunomodulatory activity of polysaccharides from stem lettuce.

Stem lettuce has a long history of cultivation in China and possesses high nutritional and medicinal value. In our previous studies, extraction optimization, characterization, and bioactivities of stem lettuce polysaccharides (SLP) were investigated. In this study, SLP were further separated into two purified polysaccharides, SLP-1 and SLP-2, by anion exchange chromatography followed by size exclusion chromatography. SLP-1, with a molecular weight of 90 KDa, was mainly composed of galacturonic acid, galactose and arabinose in a molar ratio of 17.6:41.7:33.9. SLP-2, with a molecular weight of 44 KDa, was mainly composed of mannose, galacturonic acid, galactose and arabinose in a molar ratio of 11.5:69.5:9.3:8.2. In addition, both purified polysaccharides contain sulphate radicals, have triple helical structures and can promote macrophage proliferation without cytotoxicity. SLP-2 was better able to stimulate phagocytic and nitric oxide production than SLP-1. The results suggest that polysaccharides from stem lettuce could be explored as immunomodulatory agents in the field of pharmaceuticals and functional foods.

Purification, characterization and immunomodulatory activity of water extractable polysaccharides from the swollen culms of Zizania latifolia.

The swollen culms of Zizania latifolia is a popular vegetable and traditional herbal medicine mainly consumed in some Asian countries. In our previous study, water extractable polysaccharide (ZLPs-W) and alkali extractable polysaccharide (ZLPs-A) was sequentially prepared from the swollen culms of Zizania latifolia. In vitro cell assay revealed that ZLPs-W without cytotoxicity had higher immunomodulatory activity than ZLPs-A. Therefore, in this study, ZLPs-W was further separated to three purified polysaccharides of ZLPs-W1, ZLPs-W2, and ZLPs-W3 by anion exchange chromatography and size exclusive chromatography in sequence. They were found to be homogeneous polysaccharides in ß-type glycosidic linkage. ZLPs-W1 and ZLPs-W2 without triple helix conformation mainly contained Glc in molar percentage of 96.47% and 85.1%, respectively. ZLPs-W3 with triple helix conformation mainly consisted of Man, Rha, GalA, Glc, Gal and Ara in the molar ratio of 10.23:14.14:37.44:17.14:16.54:4.51. In addition, all the three purified polysaccharides could effectively enhanced the proliferation, phagocytosis, and nitric oxide production of murine macrophage RAW 264.7, suggesting that they possessed a potent immunostimulatory activity and could be developed as immunomodulator in medicine or functional food areas.

Tissue metabolomic profiling to reveal the therapeutic mechanism of reduning injection on LPS-induced acute lung injury rats.

Acute lung injury (ALI) is a severe respiratory disease. To date, no medical interventions have been proven effective in improving the outcome. Reduning injection (RDN) showed a potential effect in the therapy of ALI. However, seldom does research concern the holistic pharmacological mechanisms of RDN on ALI. A metabolomic strategy, based on two consecutive extractions of the lung tissue, has been developed to investigate therapeutic mechanisms of RDN on ALI model rat. The extraction procedure was an aqueous extraction with methanol-water followed by organic extraction with dichloromethane-methanol. According to the lipophilicity of extracts, aqueous extracts were analyzed on the T3 column and organic extracts on the C18 column. Partial least-squares discriminant analysis was utilized to identify differences in metabolic profiles of rats. A total of 14 potential biomarkers in lung tissue were identified, which mainly related to phospholipid metabolism, sphingolipid metabolism, nucleotide metabolism and energy metabolism. The combined analytical method provides complementary metabolomics information for exploring the action mechanism of RDN against ALI. And the obtained results indicate metabolomics is a promising tool for understanding the holism and synergism of traditional Chinese medicine.

Optimization of water-soluble polysaccharides from stem lettuce by response surface methodology and study on its characterization and bioactivities.

Stem lettuce is widely consumed as a vegetable in China. It is also used as a traditional Chinese medicine for a long time. Up to now, no information is available for stem lettuce polysaccharide (SLP). In this study, extraction optimization, characterization, and antioxidant activity of SLP was investigated.The maximum SLP yield of 20.89% was obtained under the optimal extraction conditions as follows: extraction temperature 95°C, extraction time 3.3h and ratio of water to material 25mL/g. The sulfate content of SLP was 5.82% and the main monosaccharides were GalA, Gal, and Ara with a mole ratio of 49.2: 23.3: 22.9. FT-IR spectrum and HPGPC result further indicated that SLP is a sulfated polydisperse heterpolysaccharide. Congo-red test and AFM scan indicated that SLP might be branching and intertwining structure with triple helix conformation. Moreover, SLP exhibited potent antioxidant activity and α-amylase inhibitory activity, hence it could be used as a potential natural antioxidant and hypoglycemic agent in medicine or functional food fields.

Trace determination of five triazole fungicide residues in traditional Chinese medicine samples by dispersive solid-phase extraction combined with ultrasound-assisted dispersive liquid-liquid microextraction and UHPLC-MS/MS.

A novel and reliable method for determination of five triazole fungicide residues (triadimenol, tebuconazole, diniconazole, flutriafol, and hexaconazol) in traditional Chinese medicine samples was developed using dispersive solid-phase extraction combined with ultrasound-assisted dispersive liquid-liquid microextraction before ultra-high performance liquid chromatography with tandem mass spectrometry. The clean up of the extract was conducted using dispersive solid-phase extraction by directly adding sorbents into the extraction solution, followed by shaking and centrifugation. After that, a mixture of 400 µL trichloromethane (extraction solvent) and 0.5 mL of the above supernatant was injected rapidly into water for the dispersive liquid-liquid microextraction procedure. The factors affecting the extraction efficiency were optimized. Under the optimum conditions, the calibration curves showed good linearity in the range of 2.0-400 (tebuconazole, diniconazole, and hexaconazole) and 4.0-800 ng/g (triadimenol and flutriafol) with the regression coefficients higher than 0.9958. The limit of detection and limit of quantification for the present method were 0.5-1.1 and 1.8-4.0 ng/g, respectively. The recoveries of the target analytes ranged from 80.2 to 103.2%. The proposed method has been successfully applied to the analysis of five triazole fungicides in traditional Chinese medicine samples, and satisfactory results were obtained.

Lung Cancer Complicated With Asymptomatic Pulmonary Embolism: Clinical Analysis of 84 Patients.

BACKGROUND AND OBJECTIVE: Pulmonary embolism is potentially life-threatening in patients with lung cancer, but the clinical studies on patients with lung cancer having asymptomatic pulmonary embolism were barely reported. METHODS: Clinical data of patients with lung cancer were obtained from the Department of Respiratory and Critical Care Medicine of Tianjin Chest Hospital during July 2012 and June 2015 and were reviewed retrospectively. A total of 28 patients with lung cancer having pulmonary embolism (LP group) were enrolled, and another 56 cases with lung cancer alone (LC group) were enrolled as controls. RESULTS: Seventeen (60.7%) of 28 patients in the LP group developed adenocarcinoma, which was more frequent than that in the LC group ( P < .01); the LP group displayed lower counts of hemoglobin and albumin than the LC group ( P < .05); the counts of leukocyte (white blood cell) and d-dimer of patients in the LP group were also higher than those in the LC group ( P < .05). The high-incidence period of pulmonary embolism among 17 asymptomatic cases in the LP group was 3.6 months postdiagnosis (95% confidence interval, 3.2-4.0), showing a significant difference with that of other 11 patients with symptomatic pulmonary embolism, which was 10.5 months (95% confidence interval, 8.88-12.12; P < .01). Survival analysis displayed that median survival time of patients with asymptomatic pulmonary embolism was 7.2 months (95% confidence interval, 5.86-8.56), while that of symptomatic pulmonary embolism was 2.8 months (95% confidence interval, 2.48-3.12). Log-rank examination showed that survival time of asymptomatic pulmonary embolism group was statistically longer than that of symptomatic pulmonary embolism group. CONCLUSION: Lung adenocarcinoma, chemotherapy, hyperleukocytosis, and d-dimer increment were the risk factors for lung cancer combined with asymptomatic pulmonary embolism.

The clock drawing test, mortality, incident cardiovascular events and dementia.

OBJECTIVE: The purpose of this study is to examine the association of the clock drawing test (CDT) with incident dementia, cardiovascular events and mortality in very elderly hypertensive patients. METHOD: All participants were hypertensive and aged 80 years and over. The CDT was administered at baseline and annually thereafter. Data on incident cardiovascular, fatal events and dementia were collected over follow-up. RESULTS: There were 3845 participants recruited and followed up for a mean of 2.1 years. Of these, 2701 completed a CDT with 2259 available at baseline. Of this group, 6.6% had a cardiovascular event, 6.1% died, and 10% were diagnosed with dementia. There was no relationship between baseline CDT score and subsequent cardiovascular events or mortality. For incident dementia, the hazard ratio was 0.88 (95% confidence intervals 0.83-0.94) suggesting that better performance on the baseline CDT was associated with a lower risk of dementia. CONCLUSION: These results provide tentative support for the CDT alongside other cognitive screening tools in a hypertensive elderly population.

Improved blood pressure control with nifedipine GITS/valsartan combination versus high-dose valsartan monotherapy in mild-to-moderate hypertensive patients from Asia: results from the ADVISE study, a randomized trial.

AIMS: ADVISE was a 12-week, multicenter, randomized, prospective, open-label, parallel-group study comparing combination therapy of nifedipine GITS 30 mg plus valsartan 80 mg (N + V) with high-dose valsartan (160 mg) monotherapy (V160) in Asian patients with hypertension. METHODS: Patients with hypertension inadequately controlled with valsartan 80 mg for at least 4 weeks were randomized. The coprimary endpoints were the mean changes in clinic systolic and diastolic blood pressures (SBP and DBP, respectively) at Week 12. Other endpoints included blood pressure (BP) control rate, response rate, and adverse events. RESULTS: The full analysis set (FAS) comprised 359 patients. Least squares (LS) mean changes in SBP were -18.3 mmHg (N + V; n = 177) and -16.5 mmHg (V160; n = 182) (difference: -1.9 mmHg; P = 0.0998). DBP LS mean changes were -9.8 mmHg (N + V) and -7.4 mmHg (V160) (difference: -2.4 mmHg; P = 0.0011). BP control rates were significantly higher in the N + V group (Week 4: 51.2% vs. 38.4%, P = 0.0138; Week 8: 68.3% vs. 50.3%, P = 0.0004; and Week 12: 71.2% vs. 55.5%, P = 0.0024). Similar findings were observed when patients were stratified according to smoking status, SBP baseline quartiles, and ESC/ESH guideline-defined added-risk category. The BP response rate was also higher in the N + V group compared with the V160 group. Rates of adverse drug reactions (all mild-to-moderate) were similar: 4.5% (N + V) and 4.4% (V160). CONCLUSIONS: Although one of the coprimary endpoints did not reach statistical significance, combination treatment with N + V provided a greater early and more consistent BP-lowering effect than monotherapy with V160, including superior reduction in DBP and BP control rates.

Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial.

BACKGROUND: Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia; however, the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting, and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence. The Hypertension in the Very Elderly trial (HYVET) was designed to assess the risks and benefits of treatment of hypertension in elderly patients and included an assessment of cognitive function. METHODS: Patients with hypertension (systolic pressure 160-200 mm Hg; diastolic pressure <110 mm Hg) who were aged 80 years or older were enrolled in this double-blind, placebo-controlled trial. Participants were randomly assigned to receive 1.5 mg slow release indapamide, with the option of 2-4 mg perindopril, or placebo. The target systolic blood pressure was 150 mm Hg; the target diastolic blood pressure was 80 mm Hg. Participants had no clinical diagnosis of dementia at baseline, and cognitive function was assessed at baseline and annually with the mini-mental state examination (MMSE). Possible cases of incident dementia (a fall in the MMSE score to <24 points or a drop of three points in 1 year) were assessed by standard diagnostic criteria and expert review. The trial was stopped in 2007 at the second interim analysis after treatment resulted in a reduction in stroke and total mortality. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00122811. FINDINGS: 3336 HYVET participants had at least one follow-up assessment (mean 2.2 years) and were included: 1687 participants were randomly assigned to the treatment group and 1649 to the placebo group. Only five reports of adverse effects were attributed to the medication: three in the placebo group and two in the treatment group. The mean decrease in systolic blood pressure between the treatment and placebo groups at 2 years was systolic -15 mm Hg, p<0.0001; and diastolic -5.9 mm Hg, p<0.0001. There were 263 incident cases of dementia. The rates of incident dementia were 38 per 1000 patient-years in the placebo group and 33 per 1000 patient-years in the treatment group. There was no significant difference between treatment and placebo groups (hazard ratio [HR] 0.86, 95% CI 0.67-1.09); however, when these data were combined in a meta-analysis with other placebo-controlled trials of antihypertensive treatment, the combined risk ratio favoured treatment (HR 0.87, 0.76-1.00, p=0.045). INTERPRETATION: Antihypertensive treatment in elderly patients does not statistically reduce incidence of dementia. This negative finding might have been due to the short follow-up, owing to the early termination of the trial, or the modest effect of treatment. Nevertheless, the HYVET findings, when included in a meta-analysis, might support antihypertensive treatment to reduce incident dementia.

Characteristics of the Chinese subjects entered the hypertension in the very elderly trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The baseline characteristics of patients in a multinational trial are possibly related to cardiovascular outcome. This study compared the baseline characteristics of patients recruited in China with those recruited in other countries.</p><p><b>METHODS</b>A total of 508 Chinese hypertensive men and 728 women over the age of 80 years who entered the Hypertension in the Very Elderly Trial (HYVET) were compared with those in 860 men and 1348 women who entered the trial in other countries.</p><p><b>RESULTS</b>The Chinese subjects were slightly younger, had less previous hypertension but more previous strokes than the subjects from other countries. The Chinese subjects smoked more than those from other countries, but drank less alcohol. They had less previous episodes of myocardial infarction and were, on average, lighter and shorter. The Chinese had lower mean concentrations of blood urea, uric acid and creatinine as well as higher concentrations of high density lipoprotein (HDL) cholesterol. The concentration of total cholesterol was, on average, lower in the Chinese subjects as was blood glucose. The levels of serum sodium and potassium, blood hematocrit and hemoglobin were all, on average, lower in the Chinese subjects.</p><p><b>CONCLUSIONS</b>Calorie restriction, compared with the rest of the world, may have resulted in lower stature and weight, and recent increases in calorie intake have not changed the metabolic profile of the very elderly hypertensive patients in China. Some of these biochemical differences may reflect different dietary lifestyle in the Chinese.</p>

The catecholamine-beta-adrenoreceptor-cAMP system and prediction of cardiovascular events in hypertension.

Although the importance of elevated circulating plasma catecholamines on cardiac structural and functional remodelling of hypertension is well documented, it is unclear whether the catecholamine-beta-adrenoreceptor (beta AR)-cAMP system can predict different cardiovascular events. 2. A total of 601 identified hypertensive patients with baseline and follow-up plasma levels of noradrenaline (NA) and adrenaline (Adr), lymphocyte beta AR density (B(max)) and intra-lymphocyte cAMP levels in peripheral blood (last examination 60+/-26 months apart) were followed up for an additional 24+/-12 months. 3. After the last follow up, a composite end-point of cardiovascular death, non-fatal myocardial infarction (MI) and stroke occurred in 139 patients (23.1%). In Cox analyses, adjusting for other standard factors as well as treatment effect, NA (hazard ratio 1.22; 95% confidence interval (CI) 1.17-1.28; P=0.0008), Adr (hazard ratio 1.53; 95% CI 1.18-2.00; P=0.002), beta AR (hazard ratio 1.12; 95% CI 1.06-1.17; P=0.007) and cAMP (hazard ratio 1.15; 95% CI 1.09-1.21; P=0.005) separately predicted cardiovascular mortality. Noradrenaline, Adr, beta AR and intra-lymphocyte cAMP separately predicted fatal/non-fatal MI; NA and Adr predicted fatal/non-fatal stroke, whereas B(max) and intra-lymphocyte cAMP levels were not a significant predictor of fatal/non-fatal stroke. When stratifying the study population by NA or Adr (median 4 nmol/L), B(max) (median 600 fmol/10(7) cells) and cAMP (median 5.0 pmol/mg protein) above and below the median values in both parameters categories, patients above the median had composite cardiovascular end-point (all P<0.001) and high cardiovascular death (all P<0.01, log-rank test). 4. These results suggest that plasma NA and Adr are significant predictors of cardiovascular mortality, MI and stroke. The B(max) and intra-lymphocyte cAMP levels are significant predictors of cardiovascular mortality and MI, but not stroke.