In vivo T cell depletion with low-dose rabbit antithymocyte globulin results in low transplant-related mortality and low relapse incidence following unrelated hematopoietic stem cell transplantation

Stem cell transplantation from unrelated donors is associated with an increased risk of graft failure and graft-versus-host disease (GVHD). Addition of pretransplant antithymocyte globulin (ATG), although reducing the risk of graft rejection and GVHD, bears the risk of overimmunosuppression, resulting in an increased relapse rate and transplant-related mortality. Therefore, we evaluated in 21 consecutive patients receiving unrelated stem cell grafts from either HLA-matched (38%) or -mismatched (62%) donors whether low-dose rabbit ATG added to cyclosporin A and methotrexate at a total dose of 3.5 mg/kg for HLA-identical and 5.0 mg/kg for HLA-mismatched transplants given in two divided doses on days -2 and -1 provides sufficient immunosuppression for prevention of GVHD and graft rejection but is associated with an acceptable risk of relapse and transplant-related mortality. Stable leukocyte engraftment was achieved in all patients (100%). Overall survival after a median follow-up of 26 (median, range 14-42) months was 56 +/- 26% (95% confidence interval, CI) and the overall relapse rate at 3 years was 24 +/- 21%. Three-year survival for standard-risk patients, i.e., chronic myeloid leukemia (CML) in first chronic phase or acute leukemia in first complete remission, was 87% +/- 13% versus 40% +/- 31% for patients with more advanced disease. The incidence of acute GVHD II-IV degrees was 55 +/- 22%; that of severe acute GVHD III-IV degrees was 21 +/- 19%. Chronic GVHD was observed in 5/17 (29%) patients surviving more than 100 days post stem cell transplantation. Transplant-related mortality was 16 +/- 15% (95% CI) at day + 100 and 25 +/- 19% (95% CI) at 1 year after the transplant. The data presented show that pretransplant in vivo T cell depletion with low-dose rabbit ATG results in a low transplant-related mortality due to a low incidence of severe acute and chronic GVHD and a low relapse rate. To find out the optimal rabbit ATG dose in the unrelated stem cell transplantation setting, further dose-finding studies comparing high- and low-dose regimens are necessary.     

Microsurgeons do better – tactile training might prevent the age‐dependent decline of the sensibility of the hand

Recent data demonstrate that the normal sensibility of the hand seems to be age‐dependent with the best values in the third decade and a consecutive deterioration afterwards. However, it is not clear if long‐term tactile training might prevent this age‐dependent decline. We evaluated sensibility of the hand in 125 surgeons aged between 26 and 75 years who perform microsurgical operations, thereby undergoing regular tactile training. We examined sensibility of the radial digital nerve of the index finger (N3) and the ulnar digital nerve of the small finger (N10) using static and moving two‐point discrimination (2PD) tests and compared the results to 154 age‐matched individuals without specific long‐term tactile training. We found significantly lower static and moving 2PD values for the sixth, seventh, and eighth decade of life in the microsurgery group compared to the control group (p < 0.05). This study demonstrates that long‐term tactile training might prevent the known age‐dependent decline of the sensibility of the hand.     

Conditioned Medium of Demineralized Freeze‐Dried Bone Activates Gene Expression in Periodontal Fibroblasts In Vitro

Background: Demineralized bone matrix (DBM) is used for the treatment of osseous defects. Conditioned medium from native bone chips can activate transforming growth factor (TGF)‐β signaling in mesenchymal cells. The aim of this study is to determine whether processing of native bone into DBM affects the activity of the conditioned medium. Methods: Porcine cortical bone blocks were subjected to defatting, different concentrations of hydrochloric acid, and various temperatures. DBM was lyophilized, ground, and placed into culture medium. Human gingiva and periodontal fibroblasts were exposed to the respective conditioned medium obtained from DBM (DBCM). Changes in the expression of TGF‐β target genes were determined. Results: DBCM altered the expression of TGF‐β target genes (e.g., adrenomedullin, pentraxin 3, KN motif and ankyrin repeat domains 4, interleukin 11, NADPH oxidase 4, and BTB [POZ] domain containing 11) by at least five‐fold. The response was observed in fibroblasts from both sources. Defatting lowered the activity of DBCM. The TGF‐β receptor type I kinase inhibitor SB431542 [4‐(4‐(benzo[d][1,3]dioxol‐5‐yl)‐5‐(pyridin‐2‐yl)‐1H‐imidazol‐2‐yl)benzamide] but not the inhibitor of bone morphogenetic protein receptor dorsomorphin, blocked the effects of DBCM on gene expression. Moreover, conditioned medium obtained from commercial human DBM modulated the expression of TGF‐β target genes. Conclusion: The findings suggest that the DBCM can activate TGF‐β signaling in oral fibroblasts.     

Exendin-4改善胰岛素抵抗的作用机制研究

目的探讨exendin-4（exenatide）对高脂诱导胰岛素抵抗（IR）大鼠胰岛素敏感性（IS）改善的机制及对脂肪细胞因子的影响。方法健康雄性SD大鼠随机分为正常饮食组（NC）、高脂组（HF）和高脂＋Exenatide组（HE）。HE组给予exenatide（2μg／kg，Et二次）腹腔注射6周，用静脉胰岛素耐量试验评价各组IS变化，观察各组肌肉和脂肪组织胰岛素信号传导、脂肪细胞因子表达和血浆浓度变化。结果6周后，HE组Lee＇s指数、空腹血浆FFA、TG、TC均较NC组降低（P均〈0．01），IR明显改善；胰岛素刺激后HE组肌肉和脂肪组织IRS-1酪氨酸磷酸化升高（P〈0．05）；HF和HE组血浆内脏脂肪素（visfatin）水平明显降低（P〈0．05，P〈0．01），但HE组脂联素（APN）血浆水平和脂肪组织mRNA表达明显高于HF和NC组（P均〈0．01）。结论Exenatide明显改善了高脂大鼠IR，其胰岛素增敏机制可能与增强IRS-1酪氨酸磷酸化以及对APN、visfatin等脂肪细胞因子的影响有关。     

Epidemiology and outcome of infections due to Aspergillus terreus: 10-year single centre experience

Aspergillus terreus, a less common pathogen, appears to be an emerging cause of infection at our institution, the Medical University Hospital of Innsbruck. Thus the epidemiology and outcome of A. terreus infections over the past 10 years was assessed. We analysed 67 cases of proven invasive aspergillosis (IA) according to the European Organisation for Research and Treatment of Cancer/Mycoses Study Group criteria, investigated antifungal susceptibility of amphotericin B (AMB), voriconazole and caspofungin and performed molecular typing of A. terreus. Patients with proven IA caused by A. terreus (n = 32) and non-A. terreus (n = 35) were evaluated. The two groups were comparable in terms of age, gender, underlying disease, antifungal prophylaxis and duration of neutropenia (P > 0.05). Leukaemia was the most common underlying malignancy. Fungal dissemination occurred in 63% of the patients. Aspergillus terreus infections were associated with a lower response rate to AMB therapy (20%), compared with 47% for patients with non-A. terreus infections (P < 0.05). In vitro, A. terreus was found to be resistant to AMB and molecular typing discriminated between patients isolates, showing a high strain diversity with 26 distinct types (I-XXVI) identified by combination of three primers. Aspergillus terreus infections displayed evidence of AMB resistance in vitro and in vivo and were associated with a high rate of dissemination and poor outcome; A. terreus causes systemic infections of endemic character in Tyrol, Austria. The onset of A. terreus infection depends not on the degree of immunosuppression but on environmental Aspergillus spp. exposure.     

T-cell precursor frequencies and long-term outcome following unrelated hematopoietic stem cell transplantation

Functional assays measuring alloreactivity of donor cells are desired to detect either cryptic epitopes inducing graft-vs.-host disease (GvHD) after human leukocyte antigen (HLA)-identical hematopoietic stem cell transplantation (HSCT) or permissible HLA mismatches. However, their value in predicting GvHD and survival is still limited. We determined the cytotoxic and helper T-cell precursor (CTLp and HTLp) frequencies by limiting dilution analysis (LDA) in 40 unrelated recipient/donor combinations. The median observation period at the time of this writing was 4.44 years (range from 0.1 to 11.28). Better overall survival was observed in patients with rather low host-specific CTLp and HTLp frequencies, whereas a trend toward high CTLp frequencies was seen in patients with higher incidence of acute GvHD, especially in patients mismatched in HLA-C. CTLp and HTLp frequencies did not correlate with the incidence of chronic GvHD and relapse. In conclusion, we detected a trend toward better overall survival of patient/donor pairs with low CTLp and HTLp frequencies, however, recommend to use LDA as an additional tool for identifying the most suitable donor when more than one fully HLA-matched stem cell donor is available.