Simultaneous control of the Dzyaloshinskii-Moriya interaction and magnetic anisotropy in nanomagnetic trilayers.

Magneto-optical Kerr effect (MOKE) microscopy measurements of magnetic bubble domains demonstrate that Ar^{+} irradiation around 100 eV can tune the Dzyaloshinskii-Moriya interaction (DMI) in Pt/Co/Pt trilayers. Varying the irradiation energy and dose changes the DMI sign and magnitude separately from the magnetic anisotropy, allowing tuning of the DMI while holding the coercive field constant. This simultaneous control emphasizes the different physical origins of these effects. To accurately measure the DMI, we propose and apply a physical model for a poorly understood peak in domain wall velocity at zero in-plane field. The ability to tune the DMI with the spatial resolution of the Ar^{+} irradiation enables new fundamental investigations and technological applications of chiral nanomagnetics.

Cardiac allograft vasculopathy in Dutch heart transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a multifactorial disease and a major cause of graft failure after heart transplantation. However, the impact of CAV may vary according to the definition and the regional differences in transplantation settings. OBJECTIVES: We sought to assess CAV prevalence, predictors and prognosis in Dutch heart transplant recipients based on coronary angiography, following the 2010 standard nomenclature of the International Society for Heart and Lung Transplantation. METHODS: Patients ≥18 years who underwent heart transplantation at our centre with at least one coronary angiography during follow-up were included in the analysis. Clinical variables were collected prospectively. RESULTS: Among 495 analysed recipients, there were 238 (48 %) with CAV. The prevalence of CAV was 18, 47 and 70 % at 4, 12 and 20 years, respectively. In the multivariable proportional hazards regression analysis, only male donor gender and increasing donor age were significantly associated with the risk of CAV. The long-term prognosis of the patients with CAV at fourth-year angiography was significantly worse as compared with that of CAV-free patients, independently of the severity of CAV (p < 0.001). CONCLUSION: The prevalence of CAV increased gradually over time, with a similar trend as in other registries. Post-transplant survival is decreased in patients with any degree of early CAV, indicating that management strategies should start with donor selection and preventive measures immediately after transplantation.

Measurements of nanoscale domain wall flexing in a ferromagnetic thin film.

We use the high spatial sensitivity of the anomalous Hall effect in the ferromagnetic semiconductor Ga(1-x)Mn(x)As, combined with the magneto-optical Kerr effect, to probe the nanoscale elastic flexing behavior of a single magnetic domain wall in a ferromagnetic thin film. Our technique allows position sensitive characterization of the pinning site density, which we estimate to be ∼10(14) cm(-3). Analysis of single site depinning events and their temperature dependence yields estimates of pinning site forces (10 pN range) as well as the thermal deactivation energy. Our data provide evidence for a much higher intrinsic domain wall mobility for flexing than previously observed in optically probed µm scale measurements.

Donor-specific immune regulation by CD8 lymphocytes expanded from rejecting human cardiac allografts.

To assess whether regulatory T cells are present in rejecting human cardiac allografts, we performed functional analyses of graft lymphocytes (GLs) expanded from endomyocardial biopsies (EMB; n = 5) with histological signs of acute cellular rejection. The GL cultures were tested for their proliferative capacity and regulatory activity on allogeneic-stimulated peripheral blood mononuclear cells (PBMC) of the patient (ratio PBMC:GLs = 5:1). Three of these GL cultures were hyporesponsive to donor antigens and suppressed the antidonor proliferative T-cell response of PBMC, but not the anti-third-party response. Interestingly, it was the CD8(+) GL subset of these cultures that inhibited the antidonor response (65-91% inhibition of the proportion of proliferating cells); the CD4(+) GLs of the expanded GL cultures were not suppressive. In conclusion, CD8(+) GLs expanded from rejecting human cardiac allografts can exhibit donor-specific immune regulatory activities in vitro. We suggest that during acute cellular rejection, GLs may not only consist of graft-destructing effector T cells, but also of cells of the CD8(+) type with the potential to specifically inhibit antidonor immune reactivity.

Donor-derived mesenchymal stem cells remain present and functional in the transplanted human heart.

Mesenchymal stem cells (MSC) are characterized by their multilineage differentiation capacity and immunosuppressive properties. They are resident in virtually all tissues and we have recently characterized MSC from the human heart. Clinical heart transplantation offers a model to study the fate of transplanted human MSC. In this study, we isolated and expanded MSC from heart tissue taken before, and 1 week up to 6 years after heart transplantation. MSC from posttransplantation tissue were all of donor origin, demonstrating the longevity of endogenous MSC and suggesting an absence of immigration of recipient MSC into the heart. MSC isolated from transplanted tissue showed an immunophenotype that was characteristic for MSC and maintained cardiomyogenic and osteogenic differentiation capacity. They furthermore preserved their ability to inhibit the proliferative response of donor-stimulated recipient peripheral blood mononuclear cells. In conclusion, functional MSC of donor origin remain present in the heart for several years after transplantation.

Guidelines for heart transplantation.

Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic surgery (NVVC and NVT).THE INDICATION FOR HEART TRANSPLANTATION IS DEFINED AS: 'End-stage heart disease not remediable by more conservative measures'.CONTRAINDICATIONS ARE: irreversible pulmonary hypertension/elevated pulmonary vascular resistance; active systemic infection; active malignancy or history of malignancy with probability of recurrence; inability to comply with complex medical regimen; severe peripheral or cerebrovascular disease and irreversible dysfunction of another organ, including diseases that may limit prognosis after heart transplantation.Considering the difficulties in defining end-stage heart failure, estimating prognosis in the individual patient and the continuing evolution of available therapies, the present criteria are broadly defined. The final acceptance is done by the transplant team which has extensive knowledge of the treatment of patients with advanced heart failure on the one hand and thorough experience with heart transplantation and mechanical circulatory support on the other hand. (Neth Heart J 2008;16:79-87.).

Broadband spectroscopy of thermodynamic magnetization fluctuations through a ferromagnetic spin-reorientation transition.

We use scanning optical magnetometry to study the broadband frequency spectra of spontaneous magnetization fluctuations, or "magnetization noise", in an archetypal ferromagnetic film that can be smoothly tuned through a spin reorientation transition (SRT). The SRT is achieved by laterally varying the magnetic anisotropy across an ultrathin Pt/Co/Pt trilayer, from the perpendicular to in-plane direction, via graded Ar+ irradiation. In regions exhibiting perpendicular anisotropy, the power spectrum of the magnetization noise, S(ν), exhibits a remarkably robust ν -3/2 power law over frequencies ν from 1 kHz to 1 MHz. As the SRT region is traversed, however, S(ν) spectra develop a steadily-increasing critical frequency, ν 0, below which the noise power is spectrally flat, indicating an evolving low-frequency cutoff for magnetization fluctuations. The magnetization noise depends strongly on applied in- and out-of-plane magnetic fields, revealing local anisotropies and also a field-induced emergence of fluctuations in otherwise stable ferromagnetic films. Finally, we demonstrate that higher-order correlators can be computed from the noise. These results highlight broadband spectroscopy of thermodynamic fluctuations as a powerful tool to characterize the interplay between thermal and magnetic energy scales, and as a means of characterizing phase transitions in ferromagnets.

Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities.

Mesenchymal stem cells (MSCs) have important tissue repair functions and show potent immunosuppressive capacities in vitro. Although usually isolated from the bone marrow, MSCs have been identified in other tissues, including the skin and liver. In the present study, we isolated and characterized MSCs from human heart, spleen, and perirenal adipose tissue. MSCs from these different tissue sites were similar to those derived from bone marrow in that they expressed comparable levels of the cell-surface markers CD90, CD105, CD166, and HLA class I, were negative for CD34, CD45, HLA class II, CD80, and CD86 expression, and were capable of osteogenic and adipogenic differentiation. Like bone marrow-derived MSCs, MSCs from these different tissue sources inhibited the proliferation of alloactivated peripheral blood mononuclear cells (PBMCs), giving 85%, 79%, 79%, and 81% inhibition, respectively. Also in line with bone marrow-derived MSCs they inhibited proliferative responses of PBMCs to phytohemagglutinin, a nonspecific stimulator of lymphocyte proliferation, and reduced-memory T lymphocyte responses to tetanus toxoid. The results of this study demonstrate that MSCs from various tissues have similar immunophenotypes, in vitro immunosuppressive properties, and differentiation potential.

FoxP3+ T cells can be expanded from rejecting cardiac allografts.

A specific subset of T cells, the FoxP3+ regulatory T cells, control effector T-cell responses to self and foreign antigens. In transplant patients, we and others have shown that high intragraft FOXP3 mRNA levels are associated with acute rejection, suggesting that immune regulation is dependent on immune activation. To study whether transplanted grafts harbor FoxP3+ T cells and to functionally analyze them, graft infiltrating lymphocytes (GILs) must be propagated from the transplanted tissue. In the present study, we analyzed whether FoxP3+ T cells can be grown from endomyocardial biopsies (EMBs; n = 5) from patients after heart transplantation during acute cellular rejection. After 18 to 21 days of culture, 0.5 to 1.0 x 10(6) GILs were cultured from the EMBs. Of these GILs, 10.6% (median; range, 1.6%-17.1%) stained positive for FoxP3. Thus Foxp3+ T cells can be grown from EMBs, providing the tools to functionally characterize these cells in depth in forthcoming studies.

[Two pregnant women with shortness of breath due to peripartum cardiomyopathy]. / Twee zwangere vrouwen met kortademigheid op grond van peri-partumcardiomyopathie.

Two primigravidae, 33 and 30 years of age, were admitted for pre-eclampsia after 41 and 32 weeks ofamenorrhoea, respectively. Both complained of dyspnoea that turned out to be due to heart failure. The foetuses both died before birth, but the women recovered following intensive care. Peripartum cardiomyopathy is a relatively rare but serious disease that usually develops during the last month of pregnancy or the first five months after delivery. Adequate diagnosis and treatment of pregnant women with signs of heart failure can prevent much suffering on the part of both mother and child. Because peripartum cardiomyopathy is diagnosed by exclusion, other causes of heart failure should first be ruled out. The subsequent preconceptional advice will depend on the recovery of cardiac function. Women with residual myocardial dysfunction run a severe risk of aggravated heart failure and should be strongly advised against becoming pregnant again.

Heart transplantation in the Netherlands: quo vadis?

Heart transplantation is limited by the lack of donor organs. Twenty years after the start of the Dutch transplant programmes in Rotterdam and Utrecht the situation has even worsened, despite efforts to increase the donor pool. The Dutch situation seems to be worse than in other surrounding countries, and several factors that may influence donor organ availability and organ utilisation are discussed. The indications and contraindications for heart transplantation are presented, which are rather restrictive in order to select optimal recipients for the scarce donor hearts. Detailed data on donor hearts, rejected for transplantation, are shown to give some insight into the difficult process of dealing with marginal donor organs. It is concluded that with the current low numbers of acceptable quality donor hearts, there is no lack of capacity in the two transplanting centres nor is the waiting list limiting the number of transplants. The influence of our current legal system on organ donation, which requires (prior) permission from donor and relatives, is probably limited. The most important determinants of donor organ availability are: 1. The potential donor pool, consisting of brain dead victims of (traffic) accidents and CVAs and 2. Lack of consent to a request for donation. The potential donor pool is remarkably small in the Netherlands, due to relatively low numbers of (traffic) accidents, with an almost equal number of CVA-related brain dead patients compared with neighbouring countries. Lack of consent can only be pushed back by improved public awareness of the importance of donation and improved skills of professionals in asking permission in case there is no previous consent.

Direct imaging of coexisting ordered and frustrated sublattices in artificial ferromagnetic quasicrystals.

We have used scanning electron microscopy with polarization analysis and photoemission electron microscopy to image the two-dimensional magnetization of permalloy films patterned into Penrose P2 tilings (P2T). The interplay of exchange interactions in asymmetrically coordinated vertices and short-range dipole interactions among connected film segments stabilize magnetically ordered, spatially distinct sublattices that coexist with frustrated sublattices at room temperature. Numerical simulations that include long-range dipole interactions between sublattices agree with images of as-grown P2T samples and predict a magnetically ordered ground state for a two-dimensional quasicrystal lattice of classical Ising spins.

Intracranial hemorrhage in association with thrombolytic therapy: incidence and clinical predictive factors.

In a period of 18 months, 2,469 patients with acute myocardial infarction treated with a thrombolytic agent were prospectively registered in 61 hospitals. Most patients (73%) were treated with streptokinase. Intracranial hemorrhage was observed in 24 patients, corresponding to an incidence rate of 1% (95% confidence interval 0.6% to 1.3%). The median time interval between the start of thrombolytic therapy and the first clinical signs of intracranial bleeding was 16 h (range 3 to 36). In total, 16 (66%) of the 24 patients died as a result of cerebral hematoma. To determine clinical predictive factors, a case-control study was conducted. For every patient with intracranial hemorrhage, two control patients who received thrombolytic therapy because of acute infarction in the same hospital and in the same period were selected. Detailed clinical characteristics of 22 of the 24 patients as well as of 7 other patients with documented intracerebral bleeding from the European Cooperative Study Group and of 2 patients who sustained intracranial hemorrhage outside the registry period were compared with 62 control patients. The results of multivariate logistic regression analysis indicate that patients taking an oral anticoagulant before admission, patients with a body weight less than 70 kg and those greater than 65 years old are at higher risk for intracranial hemorrhage during thrombolytic therapy.

Cytokeratin phenotyping does not help in distinguishing oesophageal adenocarcinoma from cancer of the gastric cardia.

BACKGROUND: It is sometimes difficult to distinguish between cardia cancer and oesophageal cancer. AIMS: To evaluate whether cytokeratin (CK) expression of the tumour can be of value in differentiating between the two tumour types. METHODS: Consecutive patients with a malignant tumour in the oesophagus or stomach were recruited. Biopsy specimens were taken for routine haematoxylin and eosin staining. One tissue block with representative tissue was selected for immunohistochemical staining (CK7 and CK20). RESULTS: Endoscopically located adenocarcinoma of the oesophagus was present in 84 patients (64 men, 20 women; mean age, 68 years; range, 44-91). Cancer located primarily in the gastric cardia was present in 63 patients (42 men, 21 women; mean age, 68 years; range, 42-88). The histological diagnosis was metastasis from a primary tumour outside the oesophagus or stomach in 19 patients. The patients were divided into three groups for the immunohistochemical analysis. Patients in group A had definite oesophageal cancer, group B patients had a definite carcinoma located in the gastric cardia, and group C patients had an obstructing tumour distal in the oesophagus at the level of the diaphragm, which could not be passed with the endoscope. Paraffin wax embedded material was available from 122 patients for immunostaining and CK analysis. There was no significant difference in expression or distribution of CK7 or CK20 in the three groups of patients. CONCLUSION: CK phenotyping cannot distinguish between cancer arising from a Barrett's oesophagus and carcinoma originating in the gastric cardia.

Effect of HLA-DR-shared blood transfusion on the clinical outcome of heart transplantation.

Pretransplant blood transfusion can have a favorable effect on renal and cardiac graft survival. In a previous study, we found that HLA-DR-shared blood transfusions led to better graft survival after kidney transplantation. In the present study, we tried to confirm and extend these findings by analyzing the effects of blood transfusion on the clinical course following heart transplantation. According to a predefined protocol, cardiac allograft recipients received random blood transfusion before surgery. A beneficial effect of HLA-DR-shared blood transfusion could be observed on survival and on the number of rejection episodes. Patients who had received an HLA-mismatched transfusion had significantly more infections, and in this group, more patients died due to malignancies. To study a possible role of immunomodulating T cells, patients who had or had not received prophylactic anti-T cell therapy were analyzed separately. In both groups, a beneficial effect of HLA-DR-shared blood transfusion could be demonstrated. These results indicate that the administration of HLA-DR-matched blood transfusion before transplantation is beneficial in cardiac allograft recipients, and that regulatory T cells are either not directly involved or (partly) resistant to modulation by anti-T cell antibody therapy.

Donor-specific cytokine production by graft-infiltrating lymphocytes induces and maintains graft vascular disease in human cardiac allografts.

BACKGROUND: The development of graft vascular disease (GVD) in the allograft is a major impediment for long-term survival of heart transplant recipients. GVD may be mediated by cellular processes, in response to the transplanted heart, and regulated by cytokines. METHODS: We studied donor-specific cytokine production patterns in graft-infiltrating lymphocyte cultures propagated from endomyocardial biopsies. The biopsies were derived from patients with and without signs of GVD, as diagnosed by angiography at 1 year after heart transplantation. RESULTS: In the first year after transplantation, significantly more T-helper (Th) 1 cytokines (interleukin [IL]-2: P=0.04; interferon-gamma: P=0.01), but not Th2 (IL-4 and IL-6) cytokines, were produced by cultures of patients with GVD compared with patients without GVD. Thereafter, the Th1 cytokine levels in patients with GVD normalized to the levels of patients without GVD. Detectable levels of IL-6 were produced significantly more often (P=0.009) by cultures obtained more than 1 year after transplantation from patients with GVD. CONCLUSIONS: The results suggest that high levels of Th1 cytokines produced by graft-infiltrating lymphocytes early after transplantation may be responsible for activation of vascular endothelium, leading to the migration and proliferation of smooth muscle cells that is characteristic of GVD. IL-6, produced later after transplantation, continues this process by promoting smooth muscle cell proliferation.

A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti-interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation.

In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation.

C1.7 monoclonal antibody designates high-avidity CD4+ cytotoxic T lymphocytes involved in clinical heart rejection.

BACKGROUND: It is assumed that not all donor-specific cytotoxic T lymphocytes (CTLs), but only those with a high avidity for donor antigens, can function as terminal effector cells in transplant rejection. METHODS: In the present study, we searched for markers that would exclusively designate these high-avidity CTL. RESULTS: FACS analysis of donor-specific CTL clones obtained from heart transplant patients revealed that high- and low-avidity CTL varied in their expression of p38, a surface molecule involved in signal transduction, which is stained by the antibody C1.7. High- and low-avidity CD8+ CTL and high-avidity CD4+ CTL expressed p38, whereas low-avidity CD4+ CTL did not. Noncytotoxic and naive CD4+ lymphocytes also lacked p38 surface expression. CONCLUSION: Therefore, we conclude that p38 is a marker for CD4+ lymphocytes with the potency to damage the transplanted heart. Accordingly, p38 might be used to analyze the contribution of CD4+ CTL in immune responses, such as transplant rejection.

Differential avidity and cyclosporine sensitivity of committed donor-specific graft-infiltrating cytotoxic T cells and their precursors. Relevance for clinical cardiac graft rejection.

We have used limiting dilution analysis to study the qualitative and quantitative differences between graft-infiltrating cytotoxic T cell populations propagated from endomyocardial biopsies of heart transplant patients who experienced one or more acute rejection episodes and patients who never showed signs of rejection. Limiting dilution cultures were stimulated with autologous or donor cells both in the absence or in presence of cyclosporine and of CD8 in the cytotoxic phase. Almost all antigen-primed, committed cytotoxic T cells (cCTL) present in the graft of patients with rejections were CsA resistant. In contrast, in most patients of the nonrejector group, a substantial part of the cCTL could be inhibited by CsA. The CTL precursors (pCTL) in both groups were predominantly CsA sensitive. Addition of CD8 mAb during the cytotoxicity phase of the limiting dilution analysis was used to differentiate between CTL populations with high avidity for donor antigens and populations with low avidity. The predominant subpopulation in the graft of rejectors was a CsA-resistant cCTL with high avidity, while in the graft of most nonrejectors, cCTL with low avidity dominated. In most rejectors, CD8 mAb had only a minor influence on the pCTL frequency estimates, and thus on T cells with high avidity. CsA-sensitive pCTL with high avidity might represent an intermediate stage between the naive pCTL and mature, functional, CsA-insensitive cCTL with high avidity for donor antigens.

Progressive accumulation of CTL with high avidity for donor antigens during the development of acute cardiac rejection.

To study the importance of cytotoxic T lymphocytes (CTL) with high avidity for donor antigens (Ag) in the development of acute cardiac allograft rejection, their appearance within the graft in relation to rejection was analyzed. For this study, donor directed CTL propagated from sequentially taken endomyocardial biopsies (EMB) were enumerated by limiting dilution analysis (LDA). Subsequentially, the fraction of these CTL having high avidity for donor Ag was determined by addition of a CD8 monoclonal antibody (mAb) to the cytotoxic phase of the LDA. Analysis of 37 EMB cultures obtained from 11 heart transplant (HTx) patients before, during, or after they experienced rejection, revealed the kinetics of donor specific CTL in relation to rejection for HTx patients in general. For 5 individual recipients, a more detailed analysis was performed. The kinetics found for individual patients confirmed the pattern found for the total group of HTx recipients tested. Frequencies of donor specific precursor CTL (pCTL) as well as of in vivo primed donor reactive CTL (committed CTL or cCTL) increased towards rejection and decreased after successful rejection therapy. More than 2 weeks before rejection was diagnosed, only a small fraction of the graft infiltrating donor specific pCTL and cCTL had high avidity for donor Ag (median = 35% and 11%, respectively). Within 2 weeks preceding rejection, this fraction increased gradually (median = 52% and 55%, respectively) and became dominant during rejection (median = 87% and 78%, respectively). After successful rejection therapy, a decrease to basal levels (median = 18% and 24%, respectively) was observed. Conclusively, intragraft accumulation of high avidity, donor specific pCTL and cCTL may cause transplant rejection.