骨形态发生蛋白基因治疗骨缺损

目的:总结骨形态发生蛋白在骨组织工程基因治疗骨缺损中的进展。资料来源:应用计算机检索PubMed数据库1990-01/2007-01相关骨形态发生蛋白基因治疗骨缺损方面的文献,检索词"BMP,tissue engineering,gene therapy,bone defect",限定文献语言种类为English。资料选择:选取包括骨形态发生蛋白基因治疗骨缺损的文献,阅读全部文章的文题和大部分文章的摘要。纳入标准:文章所述涉及骨形态发生蛋白及其基因治疗骨缺损。排除标准:重复性研究和Meta分析类文章。资料提炼:共检索到99篇关于骨形态发生蛋白及基因治疗骨缺损的文献,最终纳入30篇符合标准的文献。资料综合:骨组织工程是组织工程学的重要组成部分,它是指利用组织工程学进行骨组织缺损的修复或重建,包括种子细胞、特定的细胞因子和载体。骨形态发生蛋白是一种疏水性酸性蛋白质,在临床实践中,已证实其能促进骨愈合,被认为是目前最强有力的一种骨诱导因子。基因治疗在许多方面都代表了一种增进骨再生方法的理念。其允许特异的基因产物转移至精确的解剖学部位。运用骨形态发生蛋白基因于骨组织工程领域以治疗骨缺损是目前新的热点。骨组织中的骨形态发生蛋白以及骨形态发生蛋白的表达和功能由于他们显著的生物学作用而被长时间的研究。结论:应用骨形态发生蛋白基因疗法可以成功诱导骨和软骨的发生,为骨缺损的治疗开辟了新的解决途径。     

CLINICAL AUDIT: IS DAY-CASE ADENOTONSILLECTOMY SAFE?

SUMMARY The trend towards day-case procedures is growing, as a consequence not only of improved medical care but the increasing importance of economic considerations in today's healthcare environment. In the largest worldwide study to date to assess the safety of day-case adenotonsillectomy, we reviewed the records of 4386 patients at the otolaryngology department of the Bradford Royal Infirmary. We found a reactionary haemorrhage rate of 0.57%. All patients who underwent surgery in the morning session had presented with haemorrhage and returned to the operating theatre before the end of the afternoon session. We discuss the implications of these findings, and consider that with careful monitoring day-case tonsillectomy and/or adenoidectomy may safely be introduced.     

Patients who develop inflammatory polyarthritis (IP) after immunization are clinically indistinguishable from other patients with IP

Musculoskeletal symptoms may occur following various types of immunization, and it has also been suggested that, like infection, immunization may act as a trigger for rheumatoid arthritis (RA). A total of 48 of 898 (5.3%) patients with early inflammatory polyarthritis (IP) referred to the Norfolk Arthritis Register reported an immunization in the 6 weeks prior to symptom onset. There were no important clinical or demographic differences between the 48 immunized patients and 185 consecutive patients who did not report prior immunization. In addition, the frequencies of HLA-DRB1*01. *04 and the shared epitope in 33 of the immunized patients were similar to those in the 185 non-immunized patients and to those in 136 healthy controls. Further results from a case-control study suggest that the rate of immunization is higher amongst cases (5.5%) than age- and sex-matched controls (2.8%). In a small number of susceptible individuals, immunization may thus act as a trigger for RA.      

Effect of natural killer cells on syngeneic bone marrow: in vitro and in vivo studies demonstrating graft failure due to NK cells in an identical twin treated by bone marrow transplantation

Bone marrow transplantation for severe idiopathic aplastic anemia was undertaken in a patient, using his monozygotic twin brother as the donor. In spite of the use of syngeneic bone marrow, failure of engraftment occurred on two occasions. In vitro studies demonstrated that natural killer (NK) cells from the recipient markedly inhibited the growth of donor bone marrow granulocyte progenitor cells. On a third attempt, successful bone marrow engraftment was achieved following high-dose cyclophosphamide, which has previously been shown to be inhibitory to NK cells. We conclude that NK cell activity may play an important role in bone marrow failure as well as being responsible for at least some cases of aplastic anemia.     

Leukemia inhibitory factor upregulates cytokine expression by a murine stromal cell line enabling the maintenance of highly enriched competitive repopulating stem cells

Attempts to maintain or expand primitive hematopoietic stem cells in vitro without the concomitant loss of their differentiative and proliferative potential in vivo have largely been unsuccessful. To investigate this problem, we compared the ability of three cloned bone marrow (BM) stromal cell lines to support the growth of primitive Thy- 1lo Sca-1+H-2Khi cells isolated by fluorescence-activated cell sorting from the BM of Ly-5.2 mice treated 1 day previously with 5-fluo- rouracil. Sorted cells were highly enriched in cobblestone area-forming cells (CAFC), but their frequency was dependent on the stromal cell lines used in this assay (1 per 45 cells on SyS-1; 1 per 97 cells on PA6). In the presence of recombinant leukemia inhibitory factor (LIF), CAFC cloning efficiency was increased to 1 per 8 cells on SyS-1 and 1 per 11 cells on PA6, thus showing the high clonogenicity of this primitive stem cell population. More primitive stem cells with competitive repopulating potential were measured by injecting the sorted cells into lethally irradiated Ly-5.1 mice together with 10(5) radioprotective Ly-5.1 BM cells whose long-term repopulating ability has been "compromised" by two previous cycles of marrow transplantation and regeneration. Donor-derived lymphocytes and granulocytes were detected in 66% of animals injected with 50 sorted cells. To quantitate the maintenance of competitive repopulating units (CRU) by stromal cells, sorted cells were transplanted at limiting dilution before and after being cultured for 2 weeks on adherent layers of SyS-1, PA6, or S17 cells. CRU represented 1 per 55 freshly sorted cells. CRU could be recovered from cocultures supported by all three stromal cell lines, but their numbers were approximately-sevenfold less than on day 0. In contrast, the addition of LIF to stromal cultures improved CRU survival by 2.5-fold on S17 and PA6 cells (approximately two-fold to threefold decline), and enabled their maintenance on SyS-1. LIF appeared to act indirectly, because alone it did not support the proliferation of Thy- 1lo Sca-1+H-2Khi cells in stroma-free cultures. Polymerase chain reaction (RT-PCR) analysis revealed that Interleukin-1beta (IL-1 beta) IL-2, IL-6, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, transforming growth factors, LIF, and Steel Factor (SLF) mRNAs were upregulated in SyS-1 within 1 to 6 hours of LIF-stimulation. To determine if increased expression of SLF by LIF-stimulated SyS-1 cells could account for their capacity to support stem cells, sorted calls were cocultured on simian CV-E cells that were transfected with an expression vector encoding membrane-bound SLF, or supplemented with soluble SLF. In both cases, SLF synergized with IL-6 produced endogenously by CV-E cells enabling CAFC growth equivalent to that on LIF-stimulated SyS-1. CAFC development on LIF- stimulated SyS-1 could also be completely abrogated by an anti-SLF antibody. These data provide evidence for a role of LIF in the support of long-term repopulating stem cells by indirectly promoting cytokine expression by BM stroma. Furthermore, we have used quantitative assays to show a maintenance of CRU numbers, with retention of in vivo function following ex vivo culture.     

The safety of anticholinergic bronchodilators for the treatment of chronic obstructive pulmonary disease

Introduction: Poorly absorbable quaternary ammonium-inhaled muscarinic antagonists both as the short-acting ipratropium and as long-acting (12 – 24 h) agents (tiotropium, glycopyrronium, aclidinium and umeclidinium) have all demonstrated statistically and clinically significant efficacy in chronic obstructive pulmonary disease compared with placebo. However, controversy has arisen concerning the safety of this class of agents principally regarding their association with both fatal and nonfatal cardiovascular toxicity.

Areas covered: The safety of both ipratropium and the long-acting muscarinic antagonists is reviewed with a major emphasis on potential cardiovascular toxicity, based on published clinical trials data and results of analyses of pooled data, meta-analyses, and observational studies. Since glycopyrronium, aclidinium, and umeclidinium have become available only relatively recently, more emphasis will be placed on the more extensive literature concerning the safety of the older anticholinergic compounds, the short-acting ipratropium, and the long-acting tiotropium in its dry powder formulation, as well as its newer soft mist inhaler delivery device.

Expert opinion: Pooled analyses and meta-analyses of randomized controlled trials (RCTs) of tiotropium in both its dry powder and soft mist formulations, as well as some observational studies, have implicated this agent as increasing the risk of nonfatal and fatal cardiovascular events. However, the most robust evidence based on large-scale randomized controlled trials (RCTs) of relatively long duration specifically designed to evaluate the cardiovascular safety of tiotropium have not confirmed these safety concerns. Because of the relatively limited amount of safety data for the newer long-acting muscarinic antagonists compared to the far more extensive experience with tiotropium, it will be important to accumulate additional safety information from post-marketing pharmacovigilance for these newer agents.     

Evaluation of N‐Terminal Prohormone B‐Type Natriuretic Peptide in Patients With Acute Coronary Syndromes and Percutaneous Coronary Intervention

J Clin Hypertens (Greenwich). ©2010 Wiley Periodicals, Inc.The aim of this research was to describe N‐terminal part of the prohormone B‐type natriuretic peptide (NT‐proBNP) levels over time in patients with acute coronary syndrome (ACS) before and after percutaneous coronary intervention (PCI). NT‐proBNP, troponin I (Tn‐I), creatine kinase (CK), CK MB isoenzyme (CKMB), fibrinogen, D‐dimers, and C‐reactive protein (CRP) were measured in 300 consecutive patients with ACS before undergoing successful reperfusion with PCI in the first 48 hours, 2 days after, and at the end of the 1st, 3rd, 6th, 12th, 18th, and 24th month. The concentration of NT‐proBNP was cross‐correlated with the levels of NT‐proBNP in 300 patients without ACS and was significantly increased before and after PCI and at the end of the 3rd month, contrasting with the fast conversion to normal levels of Tn‐I, CK, CKMB, fibrinogen, D‐dimers, and CRP. In patients with ACS undergoing successful PCI, NT‐proBNP shows slow kinetics, especially in patients with an increased thrombolysis in myocardial infarction risk score, hypertension, and diabetes. Nevertheless, cardiac neurohormonal activation may be a unifying feature among patients at high risk for cardiovascular events after ACS and PCI. J Clin Hypertens (Greenwich). 2010;12:861–868.

Brain (B‐type) natriuretic peptide (BNP) is a peptide hormone released primarily from the cardiac ventricles in response to myocyte stretch. It is synthesized as an inactive prohormone that is split into the active hormone BNP and the inactive N‐terminal fragment (NT‐proBNP). BNP has a number of systemic effects, including vasodilation, increases in urinary volume and sodium output, and inhibition of the sympathetic nervous system and the renin‐angiotensin‐aldosterone system. ^{1 , 2} Elevated BNP and NT‐proBNP levels may not only reflect increased left ventricular wall stress but may also result directly from cardiac ischemia. ³ The prognostic importance of BNP and NT‐proBNP has been extensively studied in patients with heart failure as well as in patients with acute coronary syndrome (ACS), and both markers have been shown to be strong predictors of morbidity and mortality. ^{4 , 5 , 6} Data from the Framingham Heart Study identified BNP as a strong predictor of morbidity and mortality in the general population even when BNP levels were below the threshold of 100 pg/mL, which is normally used to identify patients with heart failure. ⁷ BNP has been shown to provide valuable prognostic information in patients with ACS. ^{6 , 8 , 9} However, the prognostic importance of natriuretic peptides in patients with acute coronary artery disease (CAD) and percutaneous coronary intervention (PCI) is unclear. Biochemical markers, including troponin I (Tn‐I), ¹⁰ high‐sensitivity C‐reactive protein (CRP), and NT‐proBNP, have become available for the additional evaluation of risk stratification in ACS patients. An association between the level of these biomarkers and the risk of future cardiovascular events has been discussed in patients with ACS. ^{11 , 12 , 13} Therefore, we undertook the present study to evaluate the effect of the level of NT‐proBNP on 24‐month follow‐up and studied the prognostic implications of elevations especially in Tn‐I, NT‐proBNP, and CRP across the spectrum of ACS. A combined prediction for analysis of cardiac events was also carried out to evaluate a multi‐marker strategy for the individualization of risk stratification.