A strategy to improve treatment‐related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays

Background

Treatment‐related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world.

Procedure

A collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper‐middle income country, and Dana‐Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced‐intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact.

Results

The Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995–2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P = 0.005), abandonment (32% to 9%; P < 0.001), and event‐free survival with abandonment considered an event (47% to 65% at 2 years; P = 0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy ≥4 weeks delayed predicted markedly inferior disease‐free survival (P = 0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high‐income countries.

Conclusions

Implementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. Pediatr Blood Cancer 2015;62:1395–1402. © 2015 Wiley Periodicals, Inc.     

养老机构老年人综合健康评估及其影响因素的研究

目的 通过对上海市属养老机构内老年人综合健康评估及其影响因素的研究,为指导养老机构有针对性的提供个性化服务,提升养老机构的照护水平提供数据支持。方法 应用《老年人综合健康功能评估表》对上海市属第一、第三、第四社会福利院内60岁及以上的认知、思维、表达能力正常的老年人综合健康及其影响因素进行调查。资料统计采用SpSS 19.0软件进行分析。结果 老年人健康状况与日常生活能力和躯体健康最为密切。老年人精神健康优良者比例最高(43.5%),躯体健康优良者比例最低(33.9%)。老年人综合健康状况优良者占22.6%,一般者占23.9%,较差者占 53.5%。就受教育程度而言,大学、中学文化程度的老年人综合健康功能最好,文盲者综合健康功能损害最严重。月收入越低,综合健康功能的损害越大。老年慢性病患病率为91.0%,平均患病2.3种,居前五位的疾病是高血压、冠心病、脑卒中、糖尿病、慢性支气管炎。结论 躯体健康、日常活动能力的损害是老年人中最主要的问题。年龄、文化程度、职业、经济收入等是影响老年人综合健康的因素,养老机构应针对不同老人的综合健康状况提供差异化的专业服务,提高老年人生活质量,提升机构服务水平。     

Metabolomics analysis of multidrug-resistant breast cancer cells in vitro using methyl-tert-butyl ether method

The comprehensive characterization of metabolome and lipidome to reveal unknown pathological conditions, are being used to investigate the molecular mechanisms of cancer, especially in the field of early diagnosis, treatment, and prognosis. The multidrug resistance (MDR) of tumor cells limits the therapeutic effect of anti-cancer drugs and is the main obstacle for chemotherapy. Here, we adopted a methyl-tert-butyl ether (MTBE)-based extraction method to simultaneously extract small polar molecules and lipophilic metabolites for nontargeted metabolomics of multidrug-resistant breast cancer cell line MCF-7/ADR and its parental cell line MCF-7/S by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Distinctly different metabolic features were shown between MCF-7/ADR cells and MCF-7/S on the basis of multivariate analyses. 17 potential biomarkers were identified. And these potential biomarkers were mainly correlated with cell membrane lipids composition, cell signaling regulated by lipids, and anti-oxidation ability. The studies of cellular ultrastructure and morphology by in situ atomic force microscopy (AFM) also demonstrated the cellular membrane changed along with the MDR. We expect that this study could provide a new method for monitoring drug resistance during clinical chemotherapy and be useful for the development of drugs to overcome the MDR.

MTBE-based cellular lipidomics to investigate the mechanisms of multidrug resistance of breast cancer.     

Positional accommodative intraocular lens power error induced by the estimation of the corneal power and the effective lens position

Purpose:

To evaluate the predictability of the refractive correction achieved with a positional accommodating intraocular lenses (IOL) and to develop a potential optimization of it by minimizing the error associated with the keratometric estimation of the corneal power and by developing a predictive formula for the effective lens position (ELP).

Materials and Methods:

Clinical data from 25 eyes of 14 patients (age range, 52–77 years) and undergoing cataract surgery with implantation of the accommodating IOL Crystalens HD (Bausch and Lomb) were retrospectively reviewed. In all cases, the calculation of an adjusted IOL power (P_IOLadj) based on Gaussian optics considering the residual refractive error was done using a variable keratometric index value (n_kadj) for corneal power estimation with and without using an estimation algorithm for ELP obtained by multiple regression analysis (ELP_adj). P_IOLadj was compared to the real IOL power implanted (P_IOLReal, calculated with the SRK-T formula) and also to the values estimated by the Haigis, HofferQ, and Holladay I formulas.

Results:

No statistically significant differences were found between P_IOLReal and P_IOLadj when ELP_adj was used (P = 0.10), with a range of agreement between calculations of 1.23 D. In contrast, P_IOLReal was significantly higher when compared to P_IOLadj without using ELP_adj and also compared to the values estimated by the other formulas.

Conclusions:

Predictable refractive outcomes can be obtained with the accommodating IOL Crystalens HD using a variable keratometric index for corneal power estimation and by estimating ELP with an algorithm dependent on anatomical factors and age.     

Regulator of G‐protein signalling 5 protects against atherosclerosis in apolipoprotein E‐deficient mice

Background and Purpose

Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.

Experimental Approach

RGS5^−/− apolipoprotein E (ApoE)^−/− and ApoE ^−/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.

Key Results

Atherosclerotic phenotypes were significantly accelerated in RGS5^−/− ApoE ^−/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.

Conclusions and Implications

RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

ApoE

apolipoprotein E

CHD

coronary heart disease

H&E

haematoxylin‐eosin

ICAM‐1

intercellular adhesion molecue‐1

LDL

low‐density lipoprotein

MEK

MAPK/ERK kinase

RGS

regulator of G‐protein signalling

SMC

smooth muscle cell

VCAM‐1

vascular cell adhesion molecule‐1

Tables of Links

Application of the enabling occupation II guidelines in a non-Canadian context

Abstract

Background. The Canadian Enabling Occupation II guidelines contain theory and examples of how to apply client-centredness in occupation-based practice. Little information is available about the feasibility of the guidelines in other contexts. For 18 months, nine Dutch occupational therapists participated in a community of practice to explore, together with three researchers, their experiences with the application of the Enabling Occupation II guidelines. Purpose. To understand the experiences of Dutch occupational therapists with the application of the Enabling Occupation II guidelines. Method. A qualitative study using four focus group discussions and content analysis. Findings. Four themes emerged: (1) an indication that the guidelines of Enabling Occupation II are in line with values and norms of Dutch occupational therapists, (2) the meaningfulness of an intensive process of studying, discussing, applying and reflecting, (3) the struggles faced by the occupational therapists with translating English and getting a grip on concepts and (4) the challenges to implementing the guidelines in practice. Implications. Findings indicate that Enabling Occupation II embody values and norms of Dutch occupational therapists. They experience many benefits in their doing, thinking and being when applying the guidelines in practice. Struggles with reading English, getting a grip on concepts and theories, and difficulties in handling obstacles indicate that the application of the guidelines takes effort. An understanding of the philosophy, application, and reflection on professional identity may be prerequisites for appraising the feasibility of adoption of client-centred guidelines cross-culturally.     

GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineurin-dependent mechanism

The use of GH to treat heart failure has received considerable attention in recent years. Although the mechanisms of its beneficial effects are unknown, it has been implicated in the regulation of apoptosis in several cell types, and cardiomyocyte apoptosis is known to occur in heart failure. We therefore decided to investigate whether GH protects cardiomyocytes from apoptosis. Preliminary experiments confirmed the expression of the GH receptor (GHR) gene in primary cultures of neonatal rat cardiomyocytes (PC), the specific binding of GH by HL-1 cardiomyocytes, and the GH-induced activation of GHR and its classical downstream effectors in the latter. That GH prevented the apoptosis of PC cells deprived of serum for 48 h was shown by DNA electrophoresis and by Hoechst staining assays in which GH reduced the percentage of cells undergoing apoptosis. Similarly, the TUNEL-evaluated pro-apoptotic effect of cytosine arabinoside (AraC) on HL-1 cells was almost totally prevented by pre-treatment with GH. Fluorescence-activated cell sorter (FACS) analysis showed apoptosis in 9.7% of HL-1 cells growing in normal medium, 21.1% of those treated with AraC and 13.9% of those treated with AraC+GH, and that GH increased the percentage of AraC-treated cells in the S/G(2)/M phase from 36.9% to 52.8%. GH did not modify IGF-I mRNA levels or IGF-I secretion in HL-1 cells treated with AraC, and the protection afforded by GH against AraC-induced apoptosis in HL-1 cells was not affected by the presence of anti-IGF-I antibodies, but was largely abolished by the calcineurin-inhibiting combination cyclosporin+FK506. GH also reduced AraC-induced phosphorylation of mitogen-activated protein kinase p38 (MAPK p38) in HL-1 cells. In summary, GH protects PC and HL-1 cells from apoptosis. This effect is not mediated by IGF-I and may involve MAPK p38 as well as calcineurin.     

A randomized study comparing two guidewire strategies for angioplasty of chronic total coronary occlusion

Chronic total coronary occlusions were more frequently crossed using the Crosswire as a primary guidewire strategy than with the conventional strategy. This strategy resulted in a lower number of guidewires being used, a trend toward shorter procedural and fluoroscopy times, and decreased use of contrast media.     

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.