Notch signaling in hematopoietic cell transplantation and T cell alloimmunity

Notch signaling can regulate both hematopoietic progenitors and alloimmune T cells in the setting of allogeneic bone marrow or hematopoietic cell transplantation (allo-HCT). Ex vivo culture of multipotent blood progenitors with immobilized Delta-like ligands induces supraphysiological Notch signals and can markedly enhance progenitor expansion. Infusion of Notch-expanded progenitors shortened myelosuppression in preclinical and early clinical studies, while accelerating T cell reconstitution in preclinical models. Notch also plays an essential role in vivo to regulate pathogenic alloimmune T cells that mediate graft-versus-host disease (GVHD), the most severe complication of allo-HCT. In mouse allo-HCT models, Notch inhibition in donor-derived T cells or transient blockade of Delta-like ligands after transplantation profoundly decreased GVHD incidence and severity, without causing global immunosuppression. These findings identify Notch in T cells as an attractive therapeutic target to control GVHD. In this review, we discuss these contrasting functions of Notch signaling with high translational significance in allo-HCT patients.     

Severe bone defects and reduced mineralization caused by massive metallosis after total knee arthroplasty: histopathologic and bone morphometric findings

Abstract

We encountered a patient who developed metallosis after total knee arthroplasty (TKA), resulting in loosening of the implant, bone resorption, reduced bone formation, and fracture. The implant was replaced with a NexGen modular revision TKA system after autologous bone and hydroxyapatite granule grafting. Histopathologic examination showed accumulation of metallic debris and tartrate-resistant acid phosphatase-positive cells around the trabecular and cortical bone. Examination of hard tissue specimens showed a reduced bone volume (determined by bone histomorphometry) and an increase of all osteoid parameters, indicating disturbance of mineralization in addition to increased bone resorption.     

Effects of air tourniquet on the antibiotics concentration,in bone marrow,injected just before the start of operation

Abstract

Infection is one of the most serious complications after artificial arthroplasty. In order to establish the effective prevention for after operative infection, we measured the serum and bone marrow blood cefmetazole (CMZ) concentration time dependently (1?g CMZ, one shot). Furthermore, we studied the effect of air tourniquet on CMZ transmit into bone marrow blood. Thirteen knees with total knee arthroplasty (TKA) were included in the study. As a control group, 11 hips with total hip arthroplasty (THA) were also included. In TKA, air tourniquet was used during operation in all cases. Just before the start of the operation, 1?g CMZ was injected intravenously (one shot). Subsequently we sampled peripheral blood and bone marrow blood time dependently. Cefmetazole concentration was measured with HPLC. In the THA group, serum and bone marrow blood CMZ concentration showed almost the same time-dependent change. On the other hand, in the TKA group we could not detect CMZ in bone marrow blood in cases where CMZ was injected within 8?min before starting use of an air tourniquet. If CMZ was injected more than 10?min before starting use of the air tourniquet, CMZ concentration in bone marrow blood was much lower than minimum inhibitory concentration (MIC) for Staphylococcus aureus; but after releasing the air tourniquet, CMZ concentration in bone marrow blood was higher than MIC for S. aureus. These data suggested that our injection method is effective for prevention of infection both during and just after operation in the THA but in the TKA, CMZ should be injected more than 10?min before starting to use the air tourniquet.     

qMRI relaxometry of mandibular bone marrow: A monomodal distribution in sickle cell disease

Purpose:

To identify and characterize sickle cell disease (SCD)‐related changes in the composition of mandibular bone marrow using qMRI relaxometry histograms.

Materials and Methods:

Thirteen SCD patients and 17 controls underwent brain MR imaging with the mixed turbo spin‐echo (TSE) pulse sequence at 1.5T. The mandible was manually segmented and divided into body, angle, ramus, and condyle. T1 and T2 histograms of each mandible were modeled with Gaussian functions. The relaxation time histogram peaks were calculated, and the number of monomodal versus bimodal curves was compared.

Results:

SCD patients exhibited monomodal distributions on both T1 and T2 histograms, consistent with a composition of predominantly red hematopoietic marrow. Eighty‐eight percent of mandibles in control subjects exhibited a bimodal distribution in T1 and all showed a bimodal distribution in T2, indicating mixed but predominantly yellow marrow composition. The second peak in control subjects was shorter in T1 and longer in T2, consistent with yellow marrow composition.

Conclusion:

Instead of physiological fatty replacement, SCD patients exhibit red marrow persistence in the mandible, likely due to the increased demand for hematopoiesis. This phenomenon can be manifested by a monomodal curve in both T1 and T2 relaxometric histograms. J. Magn. Reson. Imaging 2013;37:1182–1188. © 2012 Wiley Periodicals, Inc.     

COMPLICATIONS FOLLOWING COMBINED TRANSRECTAL ULTRASOUND-GUIDED PROSTATE NEEDLE BIOPSIES AND TRANSURETHRAL RESECTION OF THE PROSTATE

In order to evaluate safety and morbidity aspects of additional systematic prostate biopsies, we have conducted a retrospective review of patients who had undergone transurethral resection of the prostate (TUR-P) combined with additional systemic prostate needle biopsies at the Chang Gung Memorial Hospital. To this end, the records of 80 men presenting consecutively at our institution between February 2001 and January 2004 inclusively were examined. These 80 individuals included patients experiencing obstructive voiding symptoms and those featuring suspicious screening parameters, all of whom were to undergo transurethral resection of the prostate for symptomatic benign prostatic hyperplasia (BPH), all procedures being performed by a single surgeon. A total of 20 (25%) specimens were found to be positive for prostate cancer. Cancer was detected in the transrectal prostate biopsy specimen of 16 of 57 men (28%) who had not undergone a previous prostate biopsy, and for four of 23 (17%) who had undergone at least one previous (benign) biopsy. Mild complications associated with transurethral prostrate resection, such as hematuria and hemospermia, were reported frequently, featuring rates of 10% and 2.5%, respectively; more severe complications being noted far less frequently. Fever, usually of a low grade, was observed post-operatively for six (7.5%) patients, but a prompt return to normal temperature following antibiotic treatment for one day was revealed. Four (5%) patients remained admitted to the hospital for a prolonged period following surgery. A review of the literature concerning transrectal biopsies and TUR-P has shown that surgery-associated complication rates are slightly lower than was the case for our study. Additional systematic prostate biopsies for patients undergoing TUR-P would appear to be a relatively safe treatment procedure. Identification of risk factors for post-surgery complications might further improve the safety of the screening procedure.     

Estimation of Total Body Calcium from the Bone Mineral Content of the Forearm

The representativity of forearm in bone mineral content (BMC) measurements for estimation of total body calcium is investigated in this article. It is shown that there is a very high correlation between weight and calcium content of examined bone pieces, that there is a high correlation between weight of individual bones and BMC values, that the BMC values from various parts of the skeleton are reasonably well correlated, that the weight of individual bones is highly correlated to the weight of total skeleton, and that there is a reasonably high correlation (r=0.85) between BMC measurements in the distal part of the forearm and total weight of the skeleton. It is concluded that BMC measurements of the distal part of the forearm give an estimate of total body calcium.     

Severe Bone Marrow Depression Induced by an Anticancer Herb Cantharanthus Roseus

We report a 67‐yr‐old woman with hepatitis C–related liver cirrhosis and hepatoma who had developed severe bone marrow suppression after taking Cantharanthus roseus as an alternative anticancer treatment. The patient developed severe pancytopenia with initial presentations of vomiting, diarrhea, oral ulcer, and fever about 1 week after taking 5‐days' course of Cantharanthus roseus. Bone marrow biopsy showed autolysis, which indicated massive necrosis of the hematopoietic cells. There was no malignant cell infiltration. The patient also had severe gastrointestinal disturbances, bacteremia, urinary tract infection, and impaired renal and liver function. Supportive care with broad‐spectrum antibiotics, granulocyte colony‐stimulating factor, repeated blood transfusions, and albumin supplement was given. She recovered and was discharged after 48 days hospitalization. Coadministration of Cantharanthus roseus and cisapride was noted, and these two drugs are both substrates of cytochrome P450 3A4 enzymes (CYP 3A4). Because the vinca alkaloids are extensively metabolized by the liver cytochrome P450 enzymes, poor hepatic function and drug‐herb interaction might predispose the patient to develop the bone marrow toxicity. This case report demonstrated possible effect of oral dose of vinca alkaloids and also hinted that all the substrates and inhibitors of CYP 3A4 have propensity to interfere with metabolism of vinca alkaloids.     

骨形态发生蛋白12诱导骨髓间充质干细胞构建组织工程肌腱

背景：以往肌腱损伤的修复方法有端端吻合、自体肌腱移植、同种异体肌腱或人工肌腱移植等,但均有其各自缺点。目的：探讨以家兔骨髓间充质干细胞为种子细胞,骨形态发生蛋白12诱导,聚羟基乙酸复合材料作为支架材料,预构组织工程化肌腱重建家兔跟腱缺损的可能性。方法：家兔抽取股骨近端骨髓,分离所得细胞传代至第2代,加入10μg/L 骨形态发生蛋白12诱导分化,并与Ⅰ型胶原溶液按一定比例移植于预张的聚羟基乙酸缝线上预制组织工程化肌腱备用。将家兔制备成跟腱缺损模型,分别采用不同方法修复跟腱缺损：组织工程化肌腱修复,Ⅰ型胶原-聚羟基乙酸缝线修复,丝线行端端修复。修复12周对各组肌腱行形态学、力学及组织病理学观察。结果与结论：修复12周家兔肌腱组织病理切片：组织工程化肌腱组可见大量梭形纤维母细胞顺应力学方向排列均匀分布于胶原中,纤维细胞明显增多,胶原致密;Ⅰ型胶原-聚羟基乙酸缝线组可见部分纤维组织增生伴少许肉芽组织形成,胶原纤维呈松散网丝状,细胞排列紊乱分布不均;丝线组可见纤维组织旁见大量肉芽组织形成。修复12周家兔肌腱生物力学强度：骨形态发生蛋白12+聚羟基乙酸重建肌腱的力学强度明显优于Ⅰ型胶原-聚羟基乙酸组,与丝线缝合组差异无显著性意义;但骨形态发生蛋白12+聚羟基乙酸重建肌腱的力学强度低于正常肌腱。提示以自体骨髓间充质干细胞作为种子细胞,骨形态发生蛋白12诱导,以聚羟基乙酸为支架,可望构建组织工程化肌腱。构建的组织工程肌腱具有一定的生物力学特性,能用于修复跟腱缺损。     

Clinical Assessment of the 1/3 Radius Using a New Desktop Ultrasonic Bone Densitometer

The objectives of this study were to evaluate the capability of a novel ultrasound device to clinically estimate bone mineral density (BMD) at the 1/3 radius. The device rests on a desktop and is portable, and permits real-time evaluation of the radial BMD. The device measures two net time delay (NTD) parameters, NTD_DW and NTD_CW. NTD_DW is defined as the difference between the transit time of an ultrasound pulse to travel through soft-tissue, cortex and medullary cavity, and the transit time through soft tissue only of equal overall distance. NTD_CW is defined as the difference between the transit time of an ultrasound pulse to travel through soft-tissue and cortex only, and the transit time through soft tissue only again of equal overall distance. The square root of the product of these two parameters is a measure of the radial BMD at the 1/3 location as measured by dual-energy X-ray absorptiometry (DXA). A clinical IRB-approved study measured ultrasonically 60 adults at the 1/3 radius. BMD was also measured at the same anatomic site and time using DXA. A linear regression using NTD produced a linear correlation coefficient of 0.93 (p < 0.001). These results are consistent with previously reported simulation and in vitro studies. In conclusion, although X-ray methods are effective in bone mass assessment, osteoporosis remains one of the largest undiagnosed and under-diagnosed diseases in the world today. The research described here should enable significant expansion of diagnosis and monitoring of osteoporosis through a desktop device that ultrasonically assesses bone mass at the 1/3 radius.