The eye as a model of ageing in translational research – Molecular,epigenetic and clinical aspects

The eye and visual system are valuable in many areas of translational research such as stem cell therapy, transplantation research and gene therapy. Changes in many ocular tissues can be measured directly, easily and objectively in vivo (e.g. lens transparency; retinal blood vessel calibre; corneal endothelial cell counts) and so the eye may also be a uniquely useful site as a model of ageing. This review details cellular, molecular and epigenetic mechanisms related to ageing within the eye, and describes ocular parameters that can be directly measured clinically and which might be of value in ageing research as the translational “window to the rest of the body”. The eye is likely to provide a valuable model for validating biomarkers of ageing at molecular, epigenetic, cellular and clinical levels. A research agenda to definitively establish the relationship between biomarkers of ageing and ocular parameters is proposed.     

Interrogation of gossypol therapy in glioblastoma implementing cell line and patient-derived tumour models

Background:

Glioblastoma (GBM), being a highly vascularised and locally invasive tumour, is an attractive target for anti-angiogenic and anti-invasive therapies. The GBM/endothelial cell response to gossypol/temozolomide (TMZ) treatment was investigated with a particular aim to assess treatment effects on cancer hallmarks.

Methods:

Cell viability, endothelial tube formation and GBM tumour cell invasion were variously assessed following combined treatment in vitro. The U87MG-luc2 subcutaneous xenograft model was used to investigate therapeutic response in vivo. Viable tumour response to treatment was interrogated using immunohistochemistry. Combined treatment protocols were also tested in primary GBM patient-derived cultures.

Results:

An endothelial/GBM cell viability inhibitory effect, as well as an anti-angiogenic and anti-invasive response, to combined treatment have been demonstrated in vitro. A significantly greater anti-proliferative (P=0.020, P=0.030), anti-angiogenic (P=0.040, P<0.0001) and pro-apoptotic (P=0.0083, P=0.0149) response was observed when combined treatment was compared with single gossypol/TMZ treatment response, respectively. GBM cell line and patient-specific response to gossypol/TMZ treatment was observed.

Conclusions:

Our results indicate that response to a combined gossypol/TMZ treatment is related to inhibition of tumour-associated angiogenesis, invasion and proliferation and warrants further investigation as a novel targeted GBM treatment strategy.     

Evaluation of BMP-2 tethered polyelectrolyte coatings on hydroxyapatite scaffolds in vivo

The goal of this in vivo study was to evaluate the osteoinductive and angio-inductive properties of a porous hydroxyapatite (HAp) scaffold with immobilized recombinant bone morphogenetic protein-2 (rhBMP-2) on the surface. It was hypothesized in this study that the use of a rhBMP-2 incorporated polyelectrolyte coating on the HAp scaffold would allow for controlled exposure of rhBMP-2 into the tissue and would provide a sound platform for tissue growth. The scaffolds were characterized for porosity and interconnectivity using pycnometry, scanning electron microscopy and micro-ct. These scaffolds were then divided into the following four groups: (a) HAp scaffold (n-HAp group), (b) rhBMP-2 physically adsorbed on HAp scaffold (HAp-BMP-2 Group), (c) polyelectrolyte coating on HAp scaffold without rhBMP-2 (HAp-PEI Scaffold Group), and (d) polyelectrolyte coating tethered with rhBMP-2 on HAp scaffold (HAp-PEI-BMP-2 Scaffold Group). Using 18 skeletally matured New Zealand white rabbits, these scaffolds were evaluated in a nonload bearing femoral condyle plug model. The negative controls for this study have defects that were left untreated and the positive controls have defects that were filled with autologous bone graft harvested from epsilateral iliac crest. Bone induction, vessel growth, and scaffold-bone contact were analyzed after 8-week implantation using micro-CT and histomorphometry. It was concluded from this study that the use of scaffold with an attached rhBMP-2 increased the vascularization around the implant when compared with the uncoated n-HAp scaffold, a necessary step of bone regeneration. The open-pore HAp scaffold was also concluded to provide a platform for tissue growth, drug loading, and tissue interaction. ? 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012.     

脑卒中简明ICF核心要素信和效度检验的Rasch模型分析

目的 运用多层面Rasch模型检验中国版脑卒中国际功能、残疾与健康分类(ICF)核心要素的信度和效度.方法 由2名评定员对38例脑卒中患者采用中国版简明ICF核心要素的"身体功能"成分包含的20个类目分别进行评分,运用FACETS统计软件计算个人分离指数和信度、拟合分析等检验ICF核心要素的信度和效度.结果 中国版简明ICF核心要素量表中"身体功能"成分类目内部一致性信度好(个人分离指数为6.02,分离信度为0.94,χ2=2158.3,P＜0.01),评定者内信度好(未加权的均方拟合统计量为0.92～1.12),但2位评定员评分时的严格程度有显著差异(χ2=1042.5,P=0.01).该部分量表的结构效度较好(分离指数为1050,分离信度为0.80,χ2=467.3,P=0.01).但是拟合分析表明,b117智力功能处于非拟合状态,而b152情感功能和b755不随意运动反应功能处于过度拟合状态.结论 中国版脑卒中简明ICF核心要素的身体功能成分具有良好的信度和结构效度.多层面 Rasch模型对于检验简明ICF核心要素的信度和效度能够提供更全面的信息,具有良好应用前景.

Abstract：

Objective To test the reliability and validity of the brief International Classification of Functioning, Disability and Health (ICF) core sets for Chinese stroke patients using Rasch model analysis. Methods The body functions of 38 Chinese stroke patients were measured using the brief ICF core sets. The qualifiers of the 20items were measured by two raters and analyzed using FACETS statistical software. The intra-rater reliability and validity were tested by using the separation index and separation reliability and fit analysis. Results The brief ICF core sets had good internal consistency and reliability (person separation index = 6.02, person separation reliability = 0.94 ) with these Chinese patients. The raters showed significantly different strictness in rating, but their ratings had good internal self-consistency. The construct validity was good for the body functions of the ICF component ( separation index = 10.50, separation reliability = 0.80) , but misfitting and overfitting were found in items b117, b152and b755. Conclusion The body function of the brief ICF core sets has good reliability and validity for Chinese stroke patients. A many-facet Rasch measurement model can provide comprehensive information and has good application prospects for testing the reliability and validity of ICF core sets.     

Hypothermia does not increase the risk of infection: a case control study

Introduction  

Hypothermia may improve outcome in patients after traumatic brain injury, especially when hypothermia is maintained for more than 48 hours. In the acute phase, patients with severe brain injury are more vulnerable to infections. Prolonged hypothermic treatment may further enhance the risk of infection. Selective decontamination of the digestive tract (SDD) reduces the risk of respiratory tract infections. The aim of this study was to investigate the incidence of infections in patients treated with hypothermia and normothermia while receiving SDD.     

小脑扁桃体切除联合后颅窝重建术治疗合并脊髓空洞症的Chiari—I畸形患者

目的 探讨手术切除下疝的小脑扁桃体及后颅窝苇建术治疗合并脊髓空洞症的Chiari-I畸形患者的疗效.方法 采用显微神经外科手术将下疝的小脑扁桃体切除联合后颅窝重建术治疗37例合并脊髓空洞症的Chiari-I畸形患者.手术中先行后颅窝充分减压,咬除部分枕骨鳞部、枕大孔后缘和寰椎后弓;在保持软膜完整的前提下将下疝至颈椎管内的小脑扁桃体作软膜下吸除;再将四脑室正中孔处的粘连松解,并将脊髓中央管开口处的隔膜剪开;最后用人工硬膜修补材料减张缝合硬膜.结果 术后随访1~3个月,32例患者的神经症状明显好转,4例患者临床症状改善不明显,1例患者临床症状加重.手术后定期复查头颅MRI,6个月后有11例脊髓空洞完全消失,22例脊髓空洞较术前明显缩小,4例脊髓空洞较术前无变化.结论 利用显微神经手术在软膜下切除下疝的小脑扁桃体及后颅窝重建术是治疗合并脊髓空洞症的Chiari-I畸形的一种有效、安全、创伤小的方法.     

Pancreatic-derived pathfinder cells enable regeneration of critically damaged adult pancreatic tissue and completely reverse streptozotocin-induced diabetes

We demonstrate that intravenous delivery of human, or rat, pancreas-derived pathfinder (PDP) cells can totally regenerate critically damaged adult tissue and restore normal function across a species barrier. We have used a mouse model of streptozotocin (STZ)-induced diabetes to demonstrate this. Normoglycemia was restored and maintained for up to 89 days following the induction of diabetes and subsequent intravenous delivery of PDP cells. Normal pancreatic histology also appeared to be restored, and treated diabetic animals gained body weight. Regenerated tissue was primarily of host origin, with few rat or human cells detectable by fluorescent in situ hybridization (FISH). Crucially, the insulin produced by these animals was overwhelmingly murine in origin and was both types I and II, indicative of a process of developmental recapitulation. These results demonstrate the feasibility of using intravenous administration of adult cells to regenerate damaged tissue. Critically, they enhance our understanding of the mechanisms relating to such repair and suggest a means for novel therapeutic intervention in loss of tissue and organ function with age.