Proprotein Convertase Inhibition Results in Decreased Skin Cell Proliferation,Tumorigenesis, and Metastasis

PACE4 is a proprotein convertase (PC) responsible for cleaving and activating proteins that contribute to enhance tumor progression. PACE4 overexpression significantly increased the susceptibility to carcinogenesis, leading to enhanced tumor cell proliferation and premature degradation of the basement membrane. In the present study, we sought to evaluate a novel approach to retard skin tumor progression based on the inhibition of PACE4. We used decanoyl-RVKR-chloromethylketone (CMK), a small-molecule PC inhibitor, for in vitro and in vivo experiments. We found that CMK-dependent blockage of PACE4 activity in skin squamous cell carcinoma cell lines resulted in impaired insulin-like growth factor 1 receptor maturation, diminished its intrinsic tyrosine kinase activity, and decreased tumor cell proliferation. Two-stage skin chemical carcinogenesis experiments, together with topical applications of CMK, demonstrated that this PC inhibitor markedly reduced tumor incidence, tumor multiplicity, and metastasis, pointing to a significant delay in tumor progression in wild-type and PACE4 transgenic mice. These results identify PACE4, together with other PCs, as suitable targets to slow down or block tumor progression, suggesting that PC inhibition is a potential approach for therapy for solid tumors.     

Direct-to-Consumer基因检测是福是祸? 如何应对消费者驱动的基因组时代?

<正>快速发展的基因组技术可以一次检测基因组的数百万个基因变异位点,据此,我们估计每个个体发生肿瘤、糖尿病、心血管病或其他常见疾病的可能风险。这些技术进步集中体现在两方面:消费者驱动型     

No association between nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow: a cross‐sectional general population study

Background In theory, all pigmented make‐up products may contain metal allergens including nickel. Eyelid dermatitis has previously been observed among nickel allergic dermatitis patients following exposure to nickel containing mascara and eye shadow. However, an association between nickel eyelid dermatitis and nickel in make‐up products remains controversial. Objective This cross‐sectional patch test study investigated whether the frequency of self‐reported cosmetic dermatitis from mascara or eye shadow use was higher among nickel allergic Danish women than women without nickel allergy. Methods In 2006, a total of 1843 18–69 year old women completed a postal questionnaire including questions on cosmetic dermatitis and were patch tested with nickel sulphate. Data were analysed by logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Results The prevalence of nickel allergy was similar among women who reported cosmetic dermatitis from eye shadow or mascara and among women who did not report such symptoms. Cosmetic dermatitis was positively associated with self‐reported atopic dermatitis and age. Conclusion Overall, no association between having nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow use was found in the general population. This does not exclude a causal relationship in selected cases.     

Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment

Although treat-to-target strategies are being discussed in osteoporosis, there is little evidence of what the target should be to reduce fracture risk maximally. We investigated the relationship between total hip BMD T-score and the incidence of nonvertebral fracture in women who received up to 10 years of continued denosumab therapy in the FREEDOM (3 years) study and its long-term Extension (up to 7 years) study. We report the percentages of women who achieved a range of T-scores at the total hip or femoral neck over 10 years of denosumab treatment (1343 women completed 10 years of treatment). The incidence of nonvertebral fractures was lower with higher total hip T-score. This relationship plateaued at a T-score between -2.0 and -1.5 and was independent of age and prevalent vertebral fractures, similar to observations in treatment-naïve subjects. Reaching a specific T-score during denosumab treatment was dependent on the baseline T-score, with higher T-scores at baseline more likely to result in higher T-scores at each time point during the study. Our findings highlight the importance of follow-up BMD measurements in patients receiving denosumab therapy because BMD remains a robust indicator of fracture risk. These data support the notion of a specific T-score threshold as a practical target for therapy in osteoporosis. © 2019 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)     

Changes in aortic blood flow induced by passive leg raising predict fluid responsiveness in critically ill patients

Introduction

Esophageal Doppler provides a continuous and non-invasive estimate of descending aortic blood flow (ABF) and corrected left ventricular ejection time (LVETc). Considering passive leg raising (PLR) as a reversible volume expansion (VE), we compared the relative abilities of PLR-induced ABF variations, LVETc and respiratory pulsed pressure variations (ΔPP) to predict fluid responsiveness.

Methods

We studied 22 critically ill patients in acute circulatory failure in the supine position, during PLR, back to the supine position and after two consecutive VEs of 250 ml of saline. Responders were defined by an increase in ABF induced by 500 ml VE of more than 15%.

Results

Ten patients were responders and 12 were non-responders. In responders, the increase in ABF induced by PLR was similar to that induced by a 250 ml VE (16% versus 20%; p = 0.15). A PLR-induced increase in ABF of more than 8% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 83%. Corresponding positive and negative predictive values (PPV and NPV, respectively) were 82% and 91%, respectively. A ΔPP threshold value of 12% predicted fluid responsiveness with a sensitivity of 70% and a specificity of 92%. Corresponding PPV and NPV were 87% and 78%, respectively. A LVETc of 245 ms or less predicted fluid responsiveness with a sensitivity of 70%, and a specificity of 67%. Corresponding PPV and NPV were 60% and 66%, respectively.

Conclusion

The PLR-induced increase in ABF and a ΔPP of more than 12% offer similar predictive values in predicting fluid responsiveness. An isolated basal LVETc value is not a reliable criterion for predicting response to fluid loading.     

Normalization of echocardiographically derived paediatric cardiac dimensions to body surface area: time for a standardized approach

The quantification of cardiac dimensions derived from echocardiographyis important in paediatric cardiac practice. Evaluation of thesize and growth of cardiac chambers, valves, and great vesselsplays a key role in the management of congenital heart disease,from the initial decision-making in the neonatal period to thenature and timing of subsequent interventions. It may also beimportant in the assessment and risk stratification of childrenwith ‘acquired’ heart disease such as hypertrophiccardiomyopathy or coronary artery involvement in Kawasaki disease.Body size and cardiac dimensions change dramatically duringnormal growth and development. Therefore, it is necessary toplace in context the measured size of a given cardiac structureby correcting for body size, through the process of normalization.     

乳突根治术后用贝复济的临床疗效

1 临床资料慢性化脓性中耳炎58例(62耳), 男19例(20耳),女39例(42耳). 年龄9～71岁,病程4 mo～35 a. 主要症状有耳内闷胀、堵塞感28耳,耳漏46耳,听力下降52耳,耳鸣18耳,耳疼31耳,眩晕6例,患侧头闷胀痛19例, 均全身和耳部应用抗生素保守治疗无效.     

支气管败血鲍特氏菌致肾脓肿1例

1 病例报告患者,男,49岁,因头部撞地后意识障碍进行性加重6 h入唐都医院神经外科,临床症状: 呕吐频繁,躁动不安,深昏迷,呼吸困难,右侧瞳孔散大,对光反射消失,双侧巴氏征( ),双肺布满湿性罗音.CT示右额颞部硬膜外血肿、中线左移2.5 cm.急诊开颅清除血肿及气管切开.术后意识障碍渐好转,但第10日开始持续高热,呼吸道分泌物多,痰培养见支气管败血杆菌生长.多次尿检均未见明显异常.血常规: WBC 19.6×109/L,中性0.99,淋巴0.01,核左移.反复动脉血培养均为阴性.按肺部感染给予抗炎及雾化吸入等治疗,肺部感染得到控制,但仍发热.术后28 d发现患者左腹部一压痛包块,B超提示左肾体积增大,内有液性暗区.肾穿刺放出灰白色粘稠无臭味脓液约2500 mL,细菌培养为支气管败血杆菌.引流5 d后体温便恢复正常,后行左肾切开造瘘术并置造瘘管引流,2 mo后痊愈.     

P-矩阵分光光度法同时测定复方降压片中六种组分的含量

本文应用P-矩阵分光光度法同时测定十组分的复方降压片中维生素B₁、维生素B₆、利眠宁、盐酸异丙嗪、硫酸双肼肽嗪及氢氯噻嗪等六种组分的含量,并应用“条件数”原理来选择最佳测定波长,同时就实验误差,测定点数、“条件数”、组分浓度对处方量的偏差等因素对该法计算结果的影响进行了较为深入的探讨。被测组分的平均回收率均在97～10?%范围之内,变异系数(CV%)均小于或等于9.5(n=11)。