Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia associated with dysregulated angiogenesis and arteriovascular malformations. The disease is caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase 1 (ALK1; HHT2) genes, coding for transforming growth factor β (TGF-β) superfamily receptors. Vascular endothelial growth factor (VEGF) has been implicated in HHT and beneficial effects of anti-VEGF treatment were recently reported in HHT patients. To investigate the systemic angiogenic phenotype of Endoglin and Alk1 mutant mice and their response to anti-VEGF therapy, we assessed microvessel density (MVD) in multiple organs after treatment with an antibody to mouse VEGF or vehicle. Lungs were the only organ showing an angiogenic defect, with reduced peripheral MVD and secondary right ventricular hypertrophy (RVH), yet distinctly associated with a fourfold increase in thrombospondin-1 (TSP-1) in Eng ^+/? versus a rise in angiopoietin-2 (Ang-2) in Alk1 ^+/? mice. Anti-VEGF treatment did reduce lung VEGF levels but interestingly, led to an increase in peripheral pulmonary MVD and attenuation of RVH; it also normalized TSP-1 and Ang-2 expression. Hepatic MVD, unaffected in mutant mice, was reduced by anti-VEGF therapy in heterozygous and wild type mice, indicating a liver-specific effect of treatment. Contrast-enhanced micro-ultrasound demonstrated a reduction in hepatic microvascular perfusion after anti-VEGF treatment only in Eng ^+/? mice. Our findings indicate that the mechanisms responsible for the angiogenic imbalance and the response to anti-VEGF therapy differ between Eng and Alk1 heterozygous mice and raise the need for systemic monitoring of anti-angiogenic therapy effects in HHT patients.     

The association between the polymorphism rs2231142 in the ABCG2 gene and gout risk: a meta-analysis

Gout is a common metabolic disorder with high heritability. We tried to explore the association between rs2231142 and gout. We searched “rs2231142 or Q141K and gout” in four databases and scholar searching website until 1 June, 2013 and included data from 52,010 participants in meta-analysis and subgroup analysis. The T allele of rs2231142 was associated with increased gout susceptibility (odds ratio [OR] [95 % confidence interval (95 % CI)]?=?1.73 [1.55–1.91], P?P?P?P?Pacific Islanders with OR (95 % CI)?=?2.94 (1.72–4.15), P?P?=?0.061. No publish or other biases were observed. The T allele of rs2231142 was associated with increased risk of gout.     

Bleeding events and associated factors in a cohort of adult patients taking warfarin in Sarawak,Malaysia

Evidence is emerging that rates of adverse events in patients taking warfarin may vary with ethnicity. This study investigated the rates of bleeds and thromboembolic events, the international normalised ratio (INR) status and the relationship between INR and bleeding events in Malaysia. Patients attending INR clinic at the Heart Centre, Sarawak General Hospital were enrolled on an ad hoc basis from May 2010 and followed up for 1 year. At each routine visit, INR was recorded and screening for bleeding or thromboembolism occurred. Variables relating to INR control were used as predictors of bleeds in logistic regression models. 125 patients contributed to 140 person-years of follow-up. The rates of major bleed, thromboembolic event and minor bleed per 100 person-years of follow-up were 1.4, 0.75 and 34.3. The median time at target range calculated using the Rosendaal method was 61.6 % (IQR 44.6–74.1 %). Of the out-of-range readings, 30.0 % were below range and 15.4 % were above. INR variability, (standard deviation of individuals’ mean INR), was the best predictor of bleeding events, with an odds ratio of 3.21 (95 % CI 1.10–9.38). Low rates of both major bleeds and thromboembolic events were recorded, in addition to a substantial number of INR readings under the recommended target range. This may suggest that the recommended INR ranges may not represent the optimal warfarin intensity for this population and that a lower intensity of therapy, as observed in this cohort, could be beneficial in preventing adverse events.     

Effects of acid and phosphate on arsenic solidification in a phosphogypsum-based cement backfill process

Phosphogypsum (PG) produced during phosphoric acid production contains significant amounts of arsenic and can potentially cause adverse environmental and health effects. Cement backfill technology is an effective management technique that is used to store PG to prevent such problems. The goal of this paper is to study the influencing factors and mechanism of arsenic stabilization in a PG-based cement backfill process. First, a leaching toxicity test was conducted, which showed that the arsenic concentration in PG batches ranged from 129.1 μg L⁻¹ to 407.1 μg L⁻¹, which were all far above the standard limit (10 μg L⁻¹) set by GB/T 14848-93. In addition, the arsenic content was higher in samples with larger PG particles. Secondly, hydrogen and phosphate ions were added to the backfill to investigate how they influenced arsenic solidification, and the results indicated that phosphate ions, rather than hydrogen ions, delayed the arsenic solidification process. This suggests that controlling the soluble phosphate in PG will help reduce arsenic pollution during backfilling. A toxicity leaching test was carried out after backfill samples were cured for 28 d. All arsenic concentrations were below the standard limit, indicating that the cement backfill technology ensured the long-term solidification and stabilization of arsenic.

Phosphogypsum (PG) produced during phosphoric acid production contains significant amounts of arsenic and can potentially cause adverse environmental and health effects.     

A Proposed Complete Methodology to Predict Gravity Flow Obstruction of Pharmaceutical Powders in Drug Product Manufacturing

We present herein a comprehensive methodology to evaluate the risks involved in gravity-driven flow of pharmaceutical powders, including mass flow/funnel flow pattern, arch formation under active stress state (initial discharging) and passive stress state (following initial discharging), and rathole formation. Built on original theories underpinning the hopper design procedure, the methodology was modified to accommodate practices of pharmaceutical powder handling. All data required are generated from conventional ring shear tester. We applied the methodology to evaluate the powder flow risks during drug product manufacturing campaigns, where two powder blends with distinct flow behavior were discharged from a 200-L bin. The predicted results are in agreement with experiments where visual observations were possible, including the flow pattern, arch formation under active stress state, and rathole formation. One notable discovery is that pharmaceutical powders exhibit high risk of arch formation under active stress state, because of the exceeding major principal stress than the passive state. This phenomenon has been so far overlooked and the existing flow function-based classification cannot capture this risk. We propose, through this methodology, that reliable powder flow assessment should consider factors preventing flow (i.e., flow function), as well as factors facilitating flow (i.e., external stress).     

HDL anti-oxidant function associates with LDL level in young adults

Objectives

The primary objective was to evaluate predictors of HDL anti-oxidant function in young adults.

Background

High-density lipoprotein (HDL) cholesterol is considered a protective factor for cardiovascular disease (CVD). However, increased levels are not always associated with decreased cardiovascular risk. A better understanding of the importance of HDL functionality and how it affects CVD risk is needed.

Methods

Fifty non-Hispanic white subjects from the Testing Responses on Youth (TROY) study were randomly selected to investigate whether differences in HDL anti-oxidant function are associated with traditional cardiovascular risk factors, including carotid intima media thickness (CIMT), arterial stiffness and other inflammatory/metabolic parameters. HDL anti-oxidant capacity was evaluated by assessing its ability to inhibit low-density lipoprotein (LDL) cholesterol oxidation by air using a DCF-based fluorescent assay and expressed as a HDL oxidant index (HOI). The associations between HOI and other variables were assessed using both linear and logistic regression.

Results

Eleven subjects (25%) had an HOI ≥ 1, indicating a pro-oxidant HDL. Age, LDL, high sensitivity C-reactive protein (hsCRP), and paraoxonase activity (PON1), but not HDL, were all associated with HOI level in univariate linear regression models. In multivariate models that mutually adjusted for these variables, LDL remained the strongest predictor of HOI (0.13 increase in HOI per 1 SD increase in LDL, 95% CI 0.04, 0.22).Atherogenic index of plasma, pulse pressure, homocysteine, glucose, insulin, CIMT and measurements of arterial stiffness were not associated with HOI in this population.

Conclusions

These results suggest LDL, hsCRP and DBP might predict HDL anti-oxidant function at an early age.     

浓缩生长因子对上颌前牙区种植骨增量术后反应的影响

目的 研究浓缩生长因子（CGF）对种植骨增量患者术后疼痛和肿胀的作用。方法 选择28例单颗上颌前牙缺失伴唇侧骨板缺损可同期植入种植体的患者,随机分为2组,每组14例,试验组应用CGF行引导骨再生术,对照组应用胶原膜行引导骨再生术,分析对比两组患者术后疼痛和肿胀程度。术后疼痛采用视觉模拟评分（VAS）法测定,肿胀程度根据肿胀范围划分4个等级。采用SPSS 23.0软件包对结果进行统计分析。结果 试验组和对照组患者疼痛VAS评分分别为35.1±22.5和47.0±20.3,术后疼痛持续时间分别为（2.1±1.5）、（2.8±1.0） d,组间差异无统计学意义（P>0.05）。试验组无肿胀、轻度肿胀、中度肿胀、重度肿胀的百分比分别为21.4%、57.1%、21.4%、0,对照组依次为7.1%、35.7%、35.7%和21.4%,术后肿胀持续时间分别为（2.4±1.4）、（4.2±2.2） d,差异存在统计学意义（P<0.05）。结论 CGF的应用可以减轻患者术后肿胀程度,缩短术后肿胀时间,但对疼痛无明显作用。     

富血小板纤维蛋白衍生物的研究进展

富血小板血浆和富血小板纤维蛋白（PRF）目前已成熟地应用于口腔医学领域,随着制备技术与基础研究的不断深入,PRF的衍生物也相继出现并应用于口腔临床中。本文就PRF衍生物的演变、制备技术、生物学特性及医学研究进展作一综述。     

Effects of LaCoO3 perovskite nanoparticle on Daphnia magna: accumulation,distribution and biomarker responses

Perovskite nanomaterials (PNMs) have been shown to be promising materials for the effective replacement of conventional energy source materials. With the increasing use of PNMs, they will inevitably enter aquatic environments, giving rise to concerns regarding the environmental impact of PNMs. To fill up the gap in information about the environmental effect of PNMs, Daphnia magna was exposed to a typical PNM LaCoO₃ for 48 h, to assess temporal patterns in PNM bioaccumulation and distribution. Synchrotron radiation based micro X-ray fluorescence spectroscopy (μ-XRF) was used to investigate the time dependent spatial distribution of LaCoO₃. Reactive oxygen species (ROS), superoxide dismutase (SOD) and Na⁺/K⁺-adenosine triphosphatase (ATPase) were measured as key biomarkers. The results showed that oxidative stress was observed at both LaCoO₃ concentrations and Na⁺/K⁺-ATPase was inhibited by high levels of LaCoO₃. The mode of action of LaCoO₃ was mainly dependent on the metal forms. At low LaCoO₃ levels, food ingestion was the main entry pathway into organisms and LaCoO₃ nanoparticle aggregates accumulated in the gut area. At high LaCoO₃ levels, both waterborne and dietary uptake was observed and the gut and thoracic limbs were the main target sites for LaCoO₃ nanoparticle aggregates and dissolved ions, respectively. LaCoO₃ was not found to translocate in daphnids during the 48 h exposure period at either concentration, suggesting that internalization did not occur. These findings help further our understanding of the fate of PNMs in aquatic organisms, as well as the associated biological responses to PNM exposure.

The instability of PNMs in water is of environmental concern. This study shows that in daphnids over 48 h, the mode of action of a representative PNM LaCoO₃ is dependent on Co species, which results in the differences in uptake, accumulation, distribution and toxicity.