Evidence on methylphenidate in children and adolescents with ADHD is in fact of 'very low quality'.

Banaschewski and colleagues from the European Attention Deficit Hyperactivity Disorder (ADHD) guideline group make a number of critical comments regarding our systematic review on methylphenidate for children and adolescents with ADHD. In this article, we present our views, showing that our trial selection was not flawed and was undertaken with scientific justification. Similarly, our data collection and interpretation was systematic and correct. We have followed a sound methodology for assessing risk of bias and our conclusions are not misleading. We acknowledge that different researchers might make risk of bias judgments at higher or lower thresholds, but we have been consistent and transparent in applying our pre-defined and per reviewed protocol. Although we made minor errors, we demonstrate that the effects are negligible and not affecting our conclusions. We are happy to correct such errors and to engage in debate on methodological and ethical issues. In terms of clinical implications, we are advocating that clinicians, patients and their relatives should weight carefully risks and benefits of methylphenidate. Clinical experience seems to suggest that there are people who benefit from this medication. Our systematic review does, however, raise questions regarding the overall quality of the methylphenidate trials.

Outcome of allogeneic stem cell transplantation for AML and myelodysplastic syndrome in elderly patients (⩾60 years).

Allogeneic stem cell transplantation (SCT) remains the best curative option for patients with refractory AML or with high-risk myelodysplastic syndrome (MDS). For decades, age alone had been widely used as the primary criterion to assess eligibility for allogeneic SCT; however, prospective studies to evaluate allogeneic SCT in elderly patients are still limited. A total of 187 patients (median age of 64 years, range 60-77 years) with AML (87%) or MDS (13%) transplanted between 1999 and 2014 were included in this retrospective analysis. Relapse-free survival (RFS) and overall survival (OS) at 3 years were 32% (95% confidence interval (CI): 25-39%) and 35% (95%CI: 27-42%), respectively. Overall survival was 49% (95%CI: 35-64%) in AML patients who were transplanted in first complete remission (CR1), but even patients with active disease did benefit from transplantation, showing an OS at 3 years of 30% (95%CI: 20-40%). Multivariate analysis revealed disease- and patient-specific risk indices as independent prognostic factors for OS and non-relapse mortality (NRM). In conclusion, our monocenter results indicate that patients should not be generally withheld from allogeneic SCT because of age or disease status only. Specific risk models incorporating disease status and disease-specific risk factors at the time of transplantation as well as existing comorbidities are helpful tools to assess transplantation-associated risk factors of elderly patients.

Treatment strategies in patients with AML or high-risk myelodysplastic syndrome relapsed after Allo-SCT.

Non-relapse mortality after Allo-SCT has significantly decreased over the last years. Nevertheless, relapse remains a major cause for post SCT mortality in patients with AML and high-risk myelodysplastic syndrome (MDS). In this retrospective single-center analysis, we have analyzed the treatment outcomes of 108 patients with AML or MDS, who relapsed after Allo-SCT. Seventy of these patients (65%) were treated with salvage therapies containing chemotherapy alone, allogeneic cell-based treatment or the combination of both. Thirty-eight patients (35%) received palliative treatment. Median OS after diagnosis of relapse was 130 days. Compared with patients who received chemotherapy alone, response to salvage therapy was significantly improved in patients treated with a combination of chemo- and allogeneic cell-based therapy (CR rate 57% vs 13%, P=0.002). Among risk factors concerning pretreatment characteristics, disease status before first Allo-SCT, and details of transplantation, only the time interval from Allo-SCT to relapse was an independent predictor of response to salvage therapy and OS. These data confirmed that time to relapse after transplantation is an important prognostic factor. Up to now, only patients eligible for treatment regimens containing allogeneic cell-based interventions achieved relevant response rates.

CD34(+) lineage specific donor cell chimerism for the diagnosis and treatment of impending relapse of AML or myelodysplastic syndrome after allo-SCT.

After allo-SCT, analysis of CD34(+) lineage-specific donor cell chimerism (DCC) is a sensitive method for monitoring minimal residual disease in patients with AML or myelodysplastic syndrome (MDS) with CD34 expression. To substantiate evidence of whether immune interventions in patients with impending relapse, defined by incomplete lineage-specific DCC, may prevent hematological relapse, we performed a retrospective nested case control study. Unsorted and lineage-specific DCC were measured in 134 patients. Forty-three patients had an incomplete CD34(+)-DCC with no other evidence of relapse. After immediate tapering of immunosuppressive treatment (30 patients) and/or infusion of donor lymphocytes (10 patients), 21 patients remained in remission (conversion to complete lineage-specific DCC) and 22 relapsed. Relapse-free survival at 3 years of the 91 patients with stable DCC and of the 43 patients with incomplete DCC was 74% (95% confidence interval (CI), 64-83%) and 40% (95% CI, 24-58%), respectively. OS rates were 79% (95% CI, 70-88%) and 52% (95% CI, 35-69%), respectively. These results, with 49% of patients with impending relapse successfully treated with immune intervention, highly suggest that analysis of CD34(+)-DCC is an important tool for monitoring and the management of AML and MDS patients after allo-SCT.

Transmission probability through a Lévy glass and comparison with a Lévy walk.

Recent experiments on the propagation of light over a distance L through a random packing of spheres with a power-law distribution of radii (a so-called Lévy glass) have found that the transmission probability T∝1/L(γ) scales superdiffusively (γ<1). The data has been interpreted in terms of a Lévy walk. We present computer simulations to demonstrate that diffusive scaling (γ≈1) can coexist with a divergent second moment of the step size distribution [p(s)∝1/s(1+α) with α<2]. This finding is in accord with analytical predictions for the effect of step size correlations, but deviates from what one would expect for a Lévy walk of independent steps.

Liver transplantation with grafts from controlled donors after cardiac death: a 20-year follow-up at a single center.

The first liver transplantation (LTx) in Sweden was performed in 1984, but brain death as a legal death criterion was not accepted until 1988. Between November 1984 and May 1988, we performed 40 consecutive LTxs in 32 patients. Twenty-four grafts were from donors after cardiac death (DCD) and 16 grafts from heart-beating donors (HBD). Significantly, more hepatic artery thrombosis and biliary complications occurred in the DCD group (p < 0.01 and p < 0.05, respectively). Graft and patient survival did not differ between the groups. In the total group, there was a significant difference in graft survival between first-time LTx grafts and grafts used for retransplantation. There was better graft survival in nonmalignant than malignant patients, although this did not reach statistical significance. Multivariate analysis revealed cold ischemia time and post-LTx peak ALT to be independent predictive factors for graft survival in the DCD group. In the 11 livers surviving 20 years or more, follow-up biopsies were performed 18-20 years post-LTx (n = 10) and 6 years post-LTx (n = 1). Signs of chronic rejection were seen in three cases, with no difference between DCD and HBD. Our analysis with a 20-year follow-up suggests that controlled DCD liver grafts might be a feasible option to increase the donor pool.

Nosocomial measles cluster in Denmark following an imported case, December 2008-January 2009.

A cluster of six confirmed cases with identical measles virus genotype was reported in Denmark between December 2008 and January 2009. The findings highlight the importance of vaccination before travelling and adherence to the routine vaccination schedule.

Theory of the topological anderson insulator.

We present an effective medium theory that explains the disorder-induced transition into a phase of quantized conductance, discovered in computer simulations of HgTe quantum wells. It is the combination of a random potential and quadratic corrections proportional to p2 sigma(z) to the Dirac Hamiltonian that can drive an ordinary band insulator into a topological insulator (having an inverted band gap). We calculate the location of the phase boundary at weak disorder and show that it corresponds to the crossing of a band edge rather than a mobility edge. Our mechanism for the formation of a topological Anderson insulator is generic, and would apply as well to three-dimensional semiconductors with strong spin-orbit coupling.

Electronic shot noise in fractal conductors.

By solving a master equation in the Sierpinski lattice and in a planar random-resistor network, we determine the scaling with size L of the shot noise power P due to elastic scattering in a fractal conductor. We find a power-law scaling P proportional, variantL;{d_{f}-2-alpha}, with an exponent depending on the fractal dimension d_{f} and the anomalous diffusion exponent alpha. This is the same scaling as the time-averaged current I[over ], which implies that the Fano factor F=P/2eI[over ] is scale-independent. We obtain a value of F=1/3 for anomalous diffusion that is the same as for normal diffusion, even if there is no smallest length scale below which the normal diffusion equation holds. The fact that F remains fixed at 1/3 as one crosses the percolation threshold in a random-resistor network may explain recent measurements of a doping-independent Fano factor in a graphene flake.

Forty years of liver transplantation: personal recollections.

When the first ever successful human liver transplantations were performed by Starzl in Denver in 1967, Groth was a key member of the team. Essential factors that led to success were the use of non-damaged liver grafts and the application of a triple drug immunosuppressive regimen. By now, eight patients have survived for more than 30 years after liver transplantation worldwide; six of these patients are from the Denver series. In 1984, Groth initiated a liver transplant program in Stockholm with eight recipients now surviving beyond 20 years.

Prospects in xenotransplantation: a personal view.

There are 3 major obstacles to performing transplantations from pig to human. They are as follows: a powerful immune barrier, a potential risk for transmitting microorganisms, particularly endogenous retrovirus from animal-to-human, and ethical issues related to patients and society at large. However, steady progress is currently being made in overcoming these obstacles. Once pig organs can be transplanted into humans, there will be unlimited access to undamaged organs and cells for transplantation, and surgeons will be able to offer transplantations to all needy patients without undue delay. Donation from deceased or live human beings will become obsolete. Furthermore, it will be possible to alleviate graft rejection by genetic modification of the source animal.

The global alliance for transplantation.

In 2002, The Transplantation Society proposed the creation of a Global Alliance for Transplantation, with the purpose of reducing the existing disparity regarding transplantation activities across the globe. This alliance should include major international scientific societies, international governmental organizations, and pharmaceutical companies. Consultations with each of these parties have taken place during the past 18 months and three Strategic Programs have been initiated: (1) the collection of information on transplantation; (2) the expansion of education in transplantation; and (3) the development of professional guidelines for organ donation and transplantation.

Bicêtre hospital experience with sirolimus-based therapy in human renal transplantation: the Sirolimus European Renal Transplant Study.

In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P

Immunosuppression with FTY720 and cyclosporine A inhibits rejection of adult porcine islet xenografts in rats.

BACKGROUND: Our aim was to evaluate the effect of FTY720 in discordant islet xenotransplantation. METHODS: Fetal porcine islet-like cell clusters (ICCs) were transplanted into normoglycemic rats that were either left untreated or treated with FTY720 only, with FTY720 plus cyclosporine A (CsA) or with CsA only. Twelve or 24 days after transplantation, graft morphology was evaluated immunohistochemically. Furthermore, adult porcine islets (APIs) were transplanted into diabetic rats immunosuppressed with FTY720 plus CsA. Blood glucose and porcine C-peptide levels were monitored. RESULTS: In untreated rats, the ICC xenografts were completely rejected after 12 days. Treatment with CsA had only a marginal effect on the rejection. In animals given FTY720, only the number of infiltrating cells was somewhat reduced. However, at 12 days, no intact ICCs remained. Immunosuppression with FTY720 plus CsA had a marked inhibitory effect on islet xenograft rejection and plentiful morphologically intact ICCs remained. Twelve days after transplantation, only occasional macrophages and T cells could be detected. At 24 days after transplantation, the findings were similar. Furthermore, diabetic rats transplanted with APIs and immunosuppressed with FTY720 plus CsA remained normoglycemic for 53.0+/-15.8 days. In fact, one animal remained normoglycemic for more than 100 days. Serum levels of porcine C-peptide remained at levels similar to those for human C-peptide in healthy individuals. CONCLUSIONS: Immunosuppression with FTY720 plus CsA inhibited almost all morphological signs of pig-to-rat islet xenograft rejection for up to 24 days after transplantation. Diabetic rats transplanted with APIs and immunosuppressed with FTY720 plus CsA remained normoglycemic for 53.0+/-15.8 days.

Impaired up-regulation of CD70 and CD86 in naive (CD27-) B cells from patients with common variable immunodeficiency (CVID).

CVID is characterized by reduced serum levels of all switched immunoglobulin isotypes (IgG, IgA, IgE) predisposing patients to recurrent infections of their respiratory and gastrointestinal tract. Correspondingly, most CVID patients exhibit a severely decreased proportion of class switched memory B cells (CD19+CD27+IgD-IgM-IgG+ or IgA+) in their peripheral blood (CVID type I). We previously identified a subgroup of CVID patients showing a significantly reduced expression of CD86 and CD137 following activation in vitro of PBMC or purified B cells (CD19+) with anti-IgM plus IL-2. Here we extend our previous studies by asking whether highly purified, cell-sorted naive B cells show already an expression defect of B cell surface molecules relevant in activation (CD39, CD69), differentiation (CD24, CD27, CD38) or T-B interaction (CD25, CD70, CD86). We stimulated cell-sorted, naive B cells (CD19+CD27-IgM+IgDhighIgG-IgA-) from 10 CVID patients and 10 healthy controls for 4 days with anti-IgM plus IL-2 in the absence or presence of autologous CD4+ T cells and measured the expression of the referred surface molecules. Based on reduced or normal numbers of switched memory B cells the CVID patients had previously been classified into eight type I patients and two type II patients, respectively. Interestingly, only the molecules CD25, CD70 and CD86, all relevant in cognate T-B interaction, showed a significantly lower expression in naive B cells from CVID patients compared to controls. While coculture with autologous CD4+ T cells normalized the CD25 expression, CD70 and CD86 expression remained subnormal, notably in the eight CVID patients of type I. These findings strongly suggest an intrinsic signalling or expression defect for CD70/CD86 at the level of naive B cells in type I CVID patients.

Expression of complement regulatory proteins on islets of Langerhans: a comparison between human islets and islets isolated from normal and hDAF transgenic pigs.

BACKGROUND: The expression of regulators of complement activity (RCAs) on islet cells may be of great importance for protecting them against complement-mediated lysis in the immediate posttransplant period after intraportal islet transplantation. We examined porcine and human islet cells for expression of RCA. We also examined to what extent human decay accelerating factor (hDAF) is expressed on adult and fetal islet cells isolated from hDAF transgenic (TG) pigs having a high transgene expression on endothelial cells. Moreover, the susceptibility of the various types of cells to lysis in human serum and blood was investigated. METHODS: Adult human islets (n=5), normal adult and fetal porcine islets (n=9 and n=8, respectively), and islets from adult and fetal hDAF TG pigs (n=5 and n=6, respectively) were examined. With islet single-cell suspensions and flow cytometry, adult human islet cells were examined for expression of hDAF (CD55), hCD59, and human membrane cofactor protein (hMCP; CD46), while porcine islet cells were examined for expression of pCD59 and pMCP. Islet cells from hDAF TG pigs were also examined for hDAF expression. Porcine peripheral blood lymphocytes, normal and hDAF TG porcine endothelial cell lines, a human endothelial cell line, and the human cell line U937 served as controls. Islet cytotoxicity was assayed after incubation of the islet cells with fresh human serum. Furthermore, adult islets from normal control pigs and hDAF TG pigs were exposed to fresh human blood in vitro for 60 min, and the inflammatory reaction elicited was compared between the different types of islets. RESULTS: All human islet cell preparations expressed hCD59, two of five expressed hMCP, but none expressed hDAF. Porcine islet cells expressed both pCD59 and pMCP. Normal adult porcine islet cells exposed to fresh human serum resulted in 74+/-5.4% cell lysis (mean+/-SEM, n=16). In comparison, only 1.3+/-2.8% (n=20, P<0.001) of human islet cells were lysed in the human serum. One islet cell preparation from an hDAF TG pig expressed small amounts of hDAF. This preparation from hDAF TG pigs bound significantly less C3c than did normal control islets (mean fluorescence ratio 16+/-2.2 and 58+/-4.3, respectively; P=0.046) and were partially protected from cell lysis in fresh human serum (47+/-10% and 78+/-18% cell lysis, respectively; P=0.046). The other four preparations from hDAF TG pigs were negative for hDAF and were equally susceptible to lysis as normal control islets. All fetal pancreatic islet cells from hDAF TG pigs analyzed were negative for hDAF expression. When exposed to fresh human blood in vitro, adult and fetal islets from hDAF TG pigs elicited equally strong inflammatory changes as did the normal control islets. The inflammatory changes were characterized by activation of the complement and coagulation systems, resulting in islet damage with "dumping" of insulin into the blood. CONCLUSIONS: Porcine and human islet cells express species-restricted complement regulatory proteins, with the human islet cells expressing mainly hCD59. A low expression of hDAF was detected on islet cells from one of five hDAF TG pigs. These islet cells displayed reduced islet cell cytotoxicity in fresh human serum. We conclude that protection from complement-mediated lysis will be important in the context of intraportal pig-to-human islet transplantation, and expression of a human RCA on islet cells should be beneficial in this context.