Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease.

Reduced bone mineral density (BMD) occurs frequently in children after hematopoietic cell transplantation (HCT), but therapy for this complication is undefined. To determine the impact of bisphosphonate therapy on reduced BMD after HCT, we compared baseline and follow-up dual energy X-ray absorptiometry (DEXA) scans of 48 patients (controls) who received calcium and vitamin D to 18 patients who also received bisphosphonate therapy. Among the controls, median annualized increase in standardized BMD (sBMD) was 10% (range, -26% to +41%), but the deviation of sBMD from normal, as indicated by the Z-score, did not improve from baseline, -2.46 (range: -5.15 to -1.16) compared to follow-up, -2.79 (range: -5.76 to +0.07). For the bisphosphonate-treated patients, the median annualized increase in sBMD was 33% (range 3% to 147%, P = .0002) and the median Z-score improved from -3.57 (range: -5.13 to -0.86) at baseline, to -1.80 (-4.89 to +0.47) at follow-up (P = .06). The annualized median change in BMD Z-scores per year was +0.12 (-2.28 to +4.24) among the controls and +1.43 (-0.29 to +3.72) for the bisphosphonate group (P = .0002). The greatest improvement in BMD was observed in children who received therapy with bisphosphonates.     

Prevention of early onset group B streptococcal sepsis in the newborn

: There is an urgent need for strategies to prevent early onset group B streptococcal sepsis in the newborn. The most effective mechanism is the identification of maternal carriers of the organism and interruption of transmission during labour. Vaginal culture is currently the most reliable method for the identification of carriers. Antibiotic prophylaxis for known carriers in labour has been demonstrated to be effective as standard management practice in a number of Australian institutions and is the best available strategy at this stage.     

Optimale Thrombozytenaggregationshemmung nach koronarer Stentimplantation

Percutaneous coronary intervention (PTCA, PCI) is the most frequently used therapy for the treatment of stenoses or occlusions of coronary arteries. In Germany, six PCIs are performed for every coronary bypass surgery. Today, stents are implanted in over 80% of PCIs to improve the acute and long-term results. The most feared complication after stent implantation is the acutely occurring stent thrombosis, which usually leads to a myocardial infarction with its relatively high mortality. The introduction of platelet inhibition (acetylsalicylic acid [ASA] and ticlopidine/clopidogrel) decreased the rate of early ( 30 days to 1 year) or very late (> 1 year) stent thromboses after BMS, but they do occur. Whereas a dual platelet inhibition of 4 weeks is sufficient after BMS, it must be performed longer after DES due to its prolonged period of endothelialization. In the randomized DES versus BMS studies, the rates of late and very late stent thromboses were increased with DES in the range of approximately 1 per thousand annually - but without affecting the mortality. DES may prevent myocardial infarctions by reducing restenoses, thus offsetting the possibly negative effects of late stent thrombosis. In patients with more extensive disease, previously sent to bypass surgery, the rate of late and very late stent thromboses is in the range of 0.6% per year. Since there is no control group from major randomized studies for these patients, more data have to be awaited.The optimal duration of dual platelet inhibition after DES is unknown, since no prospective, randomized trials have addressed this question. Based on the presently available data, clopidogrel must be given in addition to ASA for at least 6 months. Depending on the individual risk of stent thrombosis and the individual risk of bleeding, clopidogrel can be administered for 1 year or longer. Although a diminished effect of ASA and/or clopidogrel is known to be present in some patients, laboratory testing of platelet aggregation cannot be recommended for clinical decision- making at the present time due to missing standards and lack of pivotal studies. For clopidogrel, an increased platelet inhibition has been described with double dose (75 mg bid), but the clinical relevance is unknown. Whether new thienopyridine derivatives, like prasugrel, will also be superior to clopidogrel under "everyday" conditions has still to be shown. In patients with proven indication for chronic anticoagulation, the use of DES should be restricted or avoided. If a DES was nevertheless implanted, triple therapy (coumadin, ASA, and clopidogrel) is recommended - with an INR (International Normalized Ratio) target of 2.0, possibly adding a proton pump inhibitor. In case of nondeferrable surgery, dual platelet inhibition should be continued, if possible (like dental extractions), or perioperatively converted to a small-molecule glycoprotein IIb/IIIa inhibitor - under in-hospital survey. Further developments of next-generation DES with different drugs, modified release kinetics, specifically abluminal drug release or bioabsorbable polymers or absorbable stents are necessary, in order to reduce the duration of dual platelet inhibition to the range of BMS - but maintaining the well-established antiproliferative effects of DES.     

大鼠骨髓基质干细胞定向分化为成骨细胞及体外增殖过程中地塞米松的抑制性干预

目的:地塞米松在体外诱导骨髓基质干细胞向成骨细胞分化过程中起着关键性作用。验证骨髓基质干细胞向成骨细胞分化的能力,观察成骨细胞分化早期地塞米松对骨髓基质干细胞体外增殖的抑制效果。方法:实验于2006-09/12在南方医科大学组织工程研究中心完成。①实验方法:取5周龄雄性SD大鼠10只,经颈椎脱位法处死后取股骨,去除双侧干骺端,用DMEM高糖完全培养基冲洗骨髓腔,收集骨髓细胞,离心后按(1～2)×107L-1密度接种,加入条件培养液(DMEM高糖完全培养基,体积分数为0.1的标准胎牛血清,50mg/L维生素C,10mmol/L的B-甘油磷酸钠,100U/mL青霉素、100U/mL链霉素)进行体外培养。分别于细胞传代培养后第0,2,4天向培养基中加入1μmol/L地塞米松1mL,并设立仅加入等量培养基的空白对照组。②实验评估:以2d为间隔,倒置显微镜下观察细胞生长情况。采用CellTiter96试剂盒各组细胞增殖情况。结果:①骨髓基质干细胞向成骨细胞的分化:原代培养中贴壁细胞多呈长梭形,少数呈小圆形或三角形。原代培养六七天后进行传代,多数细胞在加入地塞米松后逐渐呈均一的长梭形,随着时间延长呈叠形多层排列,细胞外基质明显增多,并逐渐形成多个小结样结构。空白对照组细胞形态欠均一,少数细胞呈多边形或三角形,细胞外基质明显少于地寒米松组,罕见小结样结构。传代后10～12d可达80%～90%致密层,细胞生长速度较原代细胞明显增快,至第10代细胞仍未出现衰老现象。②骨髓基质干细胞的增殖检测:与空白对照组比较,细胞传代培养后第0,2,4天加入地塞米松,干预处理8,10,12d时的细胞数量均明显下降(t=5.0445～11.3795,P均<0.01)。结论:①传代的骨髓基质干细胞经地塞米松处理后,细胞形态趋于成熟,生长速度加快,可定向分化为成骨细胞。②在向成骨细胞分化早期,地塞米松能够抑制骨髓基质干细胞的体外增殖。     

Incidental congenital coronary artery vascular fistulas in adults: Evaluation with adenosine-~(13)N-ammonia PET-CT

AIM To assess the functionality of congenital coronary artery fistulas(CAFs) using adenosine stress ~(13)N-ammonia positron emission tomography computed tomography(PET-CT).METHODS Congenital CAFs were incidentally detected during coronary angiography(CAG) procedures in 11 adult patients(six males and five females) with a mean age of 64.3 years(range 41-81). Patients were collected from three institutes in the Netherlands. The characteristics of the fistulas(origin, pathway and termination), multiplicity of the origins and pathways of the fistulous vessels were assessed by CAG. Five patients underwent adenosine pharmacologic stress ~(13)N-ammonia PET-CT to assess myocardial perfusion and the functional behavior of the fistula. RESULTS Eleven patients with 12 CAFs, 10 unilateral and one bilateral, originating from the left anterior descending coronary artery(n = 8), right coronary artery(n = 2) and circumflex(n = 2). All fistulas were of the vascular type, terminating into either the pulmonary artery(n = 11) or coronary sinus(n = 1). The CAG delineated the characteristics of the fistula(origin, pathway and termination). Multiplicity of the origins and pathways of the fistulous vessels were common in most fistulas(8/12, 67% and 9/12, 75%, respectively). Multiplicity was common among the different fistula components(23/36, 64%). Adenosine pharmacologic stress ~(13)N-ammonia PET-CT revealed normal myocardial perfusion and ejection fraction in all but one patient, who showed a reduced ejection fraction.CONCLUSION PET-CT may be helpful for assessing the functional status of congenital CAFs in selected patients regarding clinical decision-making. Studies with a larger patient series are warranted.     

Dissection of the CMV specific T-cell response is required for optimized cardiac transplant monitoring

Despite the success of antivirals in preventing clinically overt CMV disease in cardiac allograft recipients, sub-clinical active CMV infection remains a major concern because of its association with allograft rejection and vasculopathy. The measurement of CMV specific T-cell responses is a promising approach to assessing this situation. For simplicity, class-I MHC/peptide-multimers staining CD8 T-cells directly are often used but this ignores a much wider range of responses including the whole CD4 T-cell compartment. CD4 T-cells, however, were recently shown to be critical to reducing CMV load early after transplantation. To determine how extensive T-cell responses to CMV are, the responses to two dominant CMV proteins, IE-1 and pp65, were dissected in detail accounting for T-cell lineage, frequencies, epitope recognition and changes over time in more than 25 heart transplant recipients. Cross-sectional results from over 30 healthy CMV-carriers were analyzed for comparison. Responses were unexpectedly complex, with considerable inter-individual variation in terms of dominance, breadth, and recognized epitopes. Whereas the use of MHC/peptide-multimers for clinical CD8 T-cell response monitoring alone can be justified in some situations, short term T-cell activation combined with intracellular cytokine staining was clearly found to be of more general usefulness. The performance of IFN-gamma, TNF-alpha, or IL-2 as single read-outs in identifying activated T-cells was examined and confirmed that the frequently used IFN-gamma was best suited. These results should be used to inform the design of clinically applicable and diagnostically useful approaches to monitoring CMV specific responses in heart transplant recipients.     

A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment

Background  

About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.