Editorial comment: variables affecting the presence of mesenchymal stromal cells in the peripheral blood and their relationship with apheresis product

Paediatric haematology began to establish itself as a speciality in the UK just over 60 years ago. In that time, clinical trials involving all the specialist centres in the country, and based on scientific advances, have dramatically improved the outlook for children with a range of malignant and non-malignant disorders, but particularly acute leukaemia. As in many specialties, multidisciplinary teams have played a major role in delivering these advances. With these structures in place at a national level, perhaps, of all specialities, paediatric haematology is poised to benefit from the new developments in precision medicine, gene editing and immunotherapy.     

Lyophilization Process Design and Development: A Single-Step Drying Approach

High-throughput lyophilization process was designed and developed for protein formulations using a single-step drying approach at a shelf temperature (T_s) of ≥40°C. Model proteins were evaluated at different protein concentrations in amorphous-only and amorphous-crystalline formulations. Single-step drying resulted in product temperature (T_p) above the collapse temperature (T_c) and a significant reduction (of at least 40%) in process time compared to the control cycle (wherein T_p < T_c). For the amorphous-only formulation at a protein concentration of ≤25 mg/mL, single-step drying resulted in product shrinkage and partial collapse, whereas a 50 mg/mL concentration showed minor product shrinkage. The presence of a crystallizing bulking agent improved product appearance at ≤25 mg/mL protein concentration for single-step drying. No impact to other product quality attributes was observed for single-step drying. Vial type, fill height, and scale-up considerations (i.e., choked flow, condenser capacity, lyophilizer design and geometry) were the important factors identified for successful implementation of single-step drying. Although single-step drying showed significant reduction in the edge vial effect, the scale-up considerations need to be addressed critically. Finally, the single-step drying approach can indeed make the lyophilization process high throughput compared to traditional freeze-drying process (i.e., 2-step drying).     

盐制对杜仲治疗去卵巢大鼠骨质疏松症影响的研究

目的：研究杜仲及其盐制品对去卵巢大鼠骨质疏松症的治疗作用,并探讨盐制对其治疗作用的影响。方法40只SD雌性大鼠分为伪手术组、模型对照组、杜仲生品治疗组和杜仲盐制品治疗组,除假手术组施行假手术外,其余均行手术彻底摘除卵巢,术后4周开始杜仲生品及盐制品水提液灌胃给药（4．0 g／kg?d）,实验过程称体质量,连续给药12周后,颈动脉取血,测定血钙（S－Ca）、血磷（S－P）含量,ELISA试剂盒双抗体夹心法测定血清碱性磷酸酶（ALP）、骨钙素（OCN）、雌二醇（E2）含量;动物处死后剥取完整子宫称重,采用HE染色法进行子宫病理学检查,剥离双侧股骨,双能X射线衍射法测定大鼠股骨骨密度。 HE染色法观察股骨骨小梁形态和成骨细胞数量,micro－CT扫描观察股骨骨小梁微体系结构。结果杜仲生品及盐制品能有效抑制去卵巢所致的大鼠体重增加,升高血清钙、雌二醇的含量,降低血磷、碱性磷酸酶和骨钙素的含量。增加大鼠股骨骨密度,改善股骨骨小梁微体系结构,增加股骨骨小梁成骨细胞数量,且长期用药对子宫无明显刺激作用。结论杜仲生品及盐制品对于大鼠去卵巢所引起的骨质疏松症有良好治疗作用,且盐制品效果优于生品。     

Development of a transmission-blocking malaria vaccine: Progress,challenges, and the path forward

New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives.     

A note on implementation of decaying product correlation structures for quasi‐least squares

This note implements an unstructured decaying product matrix via the quasi‐least squares approach for estimation of the correlation parameters in the framework of generalized estimating equations. The structure we consider is fairly general without requiring the large number of parameters that are involved in a fully unstructured matrix. It is straightforward to show that the quasi‐least squares estimators of the correlation parameters yield feasible values for the unstructured decaying product structure. Furthermore, subject to conditions that are easily checked, the quasi‐least squares estimators are valid for longitudinal Bernoulli data. We demonstrate implementation of the structure in a longitudinal clinical trial with both a continuous and binary outcome variable. Copyright © 2014 John Wiley & Sons, Ltd.     

Chemically Accessible Hsp90 Inhibitor That Does Not Induce a Heat Shock Response

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Increased fracture risk in patients with type 2 diabetes mellitus: An overview of the underlying mechanisms and the usefulness of imaging modalities and fracture risk assessment tools

Type 2 diabetes mellitus has recently been linked to an increased fracture risk. Since bone mass seems to be normal to elevated in patient with type 2 diabetes, the increased fracture risk is thought to be due to both an increased falling frequency and decreased bone quality. The increased falling frequency is mainly a result of complications of the disease such as a retinopathy and polyneuropathy. Bone quality is affected through changes in bone shape, bone micro-architecture, and in material properties such as bone mineralization and the quality of collagen. Commonly used methods for predicting fracture risk such as dual energy X-ray absorptiometry and fracture risk assessment tools are helpful in patients with type 2 diabetes mellitus, but underestimate the absolute fracture risk for a given score. New imaging modalities such as high resolution peripheral quantitative computed tomography are promising for giving insight in the complex etiology underlying the fragility of the diabetic bone, as they can give more insight into the microarchitecture and geometry of the bone. We present an overview of the contributing mechanisms to the increased fracture risk and the usefulness of imaging modalities and risk assessment tools in predicting fracture risk in patients with type 2 diabetes.     

Possible ways of reducing dental erosive potential of acidic beverages

Frequent consumption of acidic beverages is related to excessive tooth wear, namely dental erosion. Preventive measures may involve reduction or elimination of acidic drink consumption. However, the success of this approach is difficult to achieve as it is highly dependent on patient compliance. Therefore, a practical way of minimizing the erosive potential of popular acidic drinks may be their chemical modification. The aim of this article was to review the different methods of modification and their shortcomings. The available literature demonstrates that the erosive potential of most acidic beverages could be reduced. To date, the effectiveness of soluble calcium salts supplementation is the best established. However, modification can reduce the sensorial quality of the drink and shorten its shelf‐life. There is also a need to evaluate the lowest effective and safe dose of the additive.     

Advanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP

Advanced glycation end products (AGEs) are associated with the pathogenesis of various diseases. AGEs induce excess accumulation of extracellular matrix and expression of profibrotic cytokines. In addition, studies on receptor for advanced glycation end products (RAGE) have shown that the ligand-RAGE interaction activates several intracellular signaling cascades associated with several fibrotic diseases. We investigated the expression of AGEs and RAGE in samples from patients with idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP). Lung tissues and plasma samples from patients with IPF (n=10), NSIP (n=10), and control subjects (n=10) were obtained. Expression of AGEs and RAGE was determined by immunofluorescence assay of lung tissue. Circulating AGEs were measured by Western blot and enzyme-linked immunosorbent assay. Lungs with IPF showed strong expression for both AGEs and RAGE compared to that in NSIP and controls. However, no difference in AGE or RAGE expression was observed in lungs with NSIP compared to that in the controls. Levels of circulating AGEs also increased significantly in lungs of patients with IPF compared to those with NSIP and normal control. Increased AGE-RAGE interaction may play an important role in the pathogenesis of IPF.