Norethisterone Treatment, a Major Risk-Factor for Veno-Occlusive Disease in the Liver After Allogeneic Bone Marrow Transplantation

In this single-center study, we retrospectively analyzed incidenceand risk factors for hepatic veno-occlusive disease (VOD) in 249 consecutive patients who underwent allogeneic hematopoietic stem celltransplantation between January 1990 and June 1995. Twenty-four of the249 transplanted patients developed VOD. The probabilities ofdeveloping VOD were 17% among women and 7% in men (P = .01). In women treated with norethisterone, the incidence was 27%compared with 3% in women without this treatment (P = .007).One-year survival rates were 17% and 73% in patients with (n = 24)or without VOD (n = 225), respectively. The use of heparin prophylaxis (100 IE/kg/24 hours for 1 month) did not alter the incidence or 1-year mortality of VOD. In multivariate analysis, thefollowing risk factors were significant: norethisterone treatment (P < .001), bilirubin >26 µmol/L before bone marrowtransplantation (BMT) (P = .002), one HLA-antigen mismatch(P = .003), previous abdominal irradiation (P = .02), and conditioning with busulphan (P = .02). Ourconclusion is that norethisterone treatment should not be used inpatients undergoing BMT and heparin prophylaxis did not affect theincidence or mortality of VOD.     

A NEW RIBONUCLEOTIDE REDUCTASE SYSTEM AFTER INFECTION WITH PHAGE T4

The ribonucleotide reductase system of Escherichia coli B participates in the biosynthesis of DNA by reducing ribonucleoside diphosphates to the corresponding deoxyribonucleotides. The enzyme is regulated in a complicated way by allosteric modifiers. We now find that infection of E. coli with the bacteriophage T4 results in the appearance of a new ribonucleotide reductase system which shows a somewhat different pattern of regulation.Two new proteins, provisionally called fractions A and B, were purified from the extracts of infected bacteria. The reduction of ribonucleotides by these two fractions required the addition of either dithiothreitol or TPNH and E. coli thioredoxin reductase. Mutants of T4 which lacked fraction A activity were obtained. Fraction B may be a virus-induced thioredoxin.     

No effect of risedronate on femoral periprosthetic bone loss following total hip arthroplasty: A 4-year follow-up of 61 patients in a double-blind,randomized placebo-controlled trial

Background and purpose

We have previously shown that during the first 2 years after total hip arthroplasty (THA), periprosthetic bone resorption can be prevented by 6 months of risedronate therapy. This follow-up study investigated this effect at 4 years.

Patients and methods

A single-center, double-blind, randomized placebo-controlled trial was carried out from 2006 to 2010 in 73 patients with osteoarthritis of the hip who were scheduled to undergo THA. The patients were randomly assigned to receive either 35 mg risedronate or placebo orally, once a week, for 6 months postoperatively. The primary outcome was the percentage change in bone mineral density (BMD) in Gruen zones 1 and 7 in the proximal part of the femur at follow-up. Secondary outcomes included migration of the femoral stem and clinical outcome scores.

Results

61 of the 73 patients participated in this 4-year (3.9- to 4.1-year) follow-up study. BMD was similar in the risedronate group (n = 30) and the placebo group (n = 31). The mean difference was −1.8% in zone 1 and 0.5% in zone 7. Migration of the femoral stem, the clinical outcome, and the frequency of adverse events were similar in the 2 groups.

Interpretation

Although risedronate prevents periprosthetic bone loss postoperatively, a decrease in periprosthetic BMD accelerates when therapy is discontinued, and no effect is seen at 4 years. We do not recommend the use of risedronate following THA for osteoarthritis of the hip.Adaptive bone remodeling around the femoral stem following total hip arthroplasty (THA) results in regional loss of bone mass, especially in proximal parts of the femur—most of which takes place within the first postoperative year (Bodén et al. 2006, Sköldenberg et al. 2006). Periprosthetic bone loss may predispose to periprosthetic fracture, aseptic loosening, and difficulties at revision surgery (Lindahl 2007, Streit et al. 2011, Sköldenberg et al. 2014).The bisphosphonate (BP) risedronate has been used successfully to prevent osteoporotic fractures, mainly in the hip and vertebrae, by inhibiting osteoclast activity (McClung et al. 2001). In recent years, the possible use of BPs to prevent or ameliorate periprosthetic adaptive bone resorption, osteolysis, and implant migration has been investigated thoroughly in animal models and humans. The short-term results of several studies showing the effects of postoperative BP treatment in reducing periprosthetic bone loss up to a year after the arthroplasty have already been published (Venesmaa et al. 2001, Wilkinson et al. 2001, Hennigs et al. 2002, Wilkinson et al. 2005, Arabmotlagh et al. 2006).We have previously found that risedronate given once a week for 6 months after THA reduces periprosthetic bone resorption around an uncemented femoral stem in the first and second postoperative year (Sköldenberg et al. 2011). We now report the 4-year outcome in the same cohort.     

Incident diabetes mellitus may explain the association between sleep duration and incident coronary heart disease

Aims/hypothesis

Sleep duration is a risk factor for incident diabetes mellitus and CHD. The primary aim of the present study was to investigate, in sex-specific analyses, the role of incident diabetes as the possible biological mechanism for the reported association between short/long sleep duration and incident CHD. Considering that diabetes is a major risk factor for CHD, we hypothesised that any association with sleep duration would not hold for cases of incident CHD occurring before incident diabetes (‘non-diabetes CHD’) but would hold true for cases of incident CHD following incident diabetes (‘diabetes-CHD’).

Methods

A total of 6966 men and 9378 women aged 45–73 years from the Malmö Diet Cancer Study, a population-based, prospective cohort, who had answered questions on habitual sleep duration and did not have a history of prevalent diabetes or CHD were included in the analyses. Incident cases of diabetes and CHD were identified using national registers. Sex-specific Cox proportional hazards regression models were stratified by BMI and adjusted for known covariates of diabetes and CHD.

Results

Mean follow-up times for incident diabetes (n = 1137/1016 [men/women]), incident CHD (n = 1170/578), non-diabetes CHD (n = 1016/501) and diabetes-CHD (n = 154/77) were 14.2–15.2 years for men, and 15.8–16.5 years for women. In men, short sleep duration (< 6 h) was associated with incident diabetes (HR 1.35, 95% CI 1.01, 1.80), CHD (HR 1.41, 95% CI 1.06, 1.89) and diabetes-CHD (HR 2.34, 95% CI 1.20, 4.55). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.35, 95% CI 0.98, 1.87). Long sleep duration (≥ 9 h) was associated with incident diabetes (HR 1.37, 95% CI 1.03, 1.83), CHD (HR 1.33, 95% CI 1.01, 1.75) and diabetes-CHD (HR 2.10, 95% CI 1.11, 4.00). Long sleep duration was not associated with incident non-diabetes CHD (HR 1.33, 95% CI 0.98, 1.80). In women, short sleep duration was associated with incident diabetes (HR 1.53, 95% CI 1.16, 2.01), CHD (HR 1.46, 95% CI 1.03, 2.07) and diabetes-CHD (HR 2.88, 95% CI 1.37, 6.08). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.29, 95% CI 0.86, 1.93).

Conclusions/interpretation

The associations between sleep duration and incident CHD directly reflect the associations between sleep duration and incident diabetes. Incident diabetes may thus be the explanatory mechanism for the association between short and long sleep duration and incident CHD.

     

Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses

Mesenchymal stem cells (MSCs) suppress alloantigen-induced T-cell functions in vitro and infusion of third-party MSCs seems to be a promising therapy for graft-versus-host disease (GVHD). Little is known about the specificity of immunosuppression by MSCs, in particular the effect on immunity to pathogens. We have studied how MSCs affect T-cell responses specific to Epstein-Barr virus (EBV) and cytomegalovirus (CMV). We found that EBV- and CMV-induced proliferation and interferon- (IFN-) production from peripheral blood mononuclear cells (PBMCs) was less affected by third-party MSCs than the response to alloantigen and that MSCs had no effect on expansion of EBV and CMV pentamer-specific T cells. Established EBV-specific cytotoxic T cells (CTL) or CMV-CTL cultured with MSCs retained the ability to proliferate and produce IFN- in response to their cognate antigen and to kill virally infected targets. Finally, PBMCs from 2 patients who received MSCs for acute GVHD showed persistence of CMV-specific T cells and retained IFN- response to CMV after MSC infusion. In summary, MSCs have little effect on T-cell responses to EBV and CMV, which contrasts to their strong immunosuppressive effects on alloreactive T cells. These data have major implications for immunotherapy of GVHD with MSCs and suggest that the effector functions of virus-specific T cells may be retained after MSC infusion.     

Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: influence of dose and stem cell source shows better outcome with rich marrow

Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 x 10(8)/kg with a median of 2.7 x 10(8)/kg. The PB cell dose ranged from 0.02 to 77 x 10(8)/kg with a median of 9.3 x 10(8)/kg. The median dose for patients receiving BM (2.7 x 10(8)/kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P =.04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P =.013), and better overall survival (RR = 0.64; 95% CI, 0.44-0.92; P =.016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich.     

Vectorcardiogram synthesized from a 12-lead ECG: Superiority of the inverse Dower matrix

Vectorcardiographic (VCG) criteria for the diagnosis of, for example, myocardial infarction and right ventricular hypertrophy, are superior to the corresponding 12-lead ECG criteria. Contour and rotation of the QRS loops are important parts of these VCG criteria that have no direct counterpart in the 12-lead ECG. Therefore, attempts have been made to synthesize VCGs from 12-lead ECGs for diagnostic purposes. Visual comparison of QRS loops from the Frank VCG and three different synthesized VCGs was made by three independent observers to determine which method produces the most Frank-like QRS loops. The inverse transformation matrix of Dower proved to be the best method of synthesis. Normal limits for some clinically important measurements in VCG interpretation were calculated for this synthesis method and the Frank VCG.     

Infection of donor lymphocytes with human T lymphotrophic virus type 1 (HTLV-I) following allogeneic bone marrow transplantation for HTLV-I positive adult T-cell leukaemia

Summary. Human T lymphotrophic virus type 1 (HTLV-I) associated leukaemia has a poor prognosis even with chemotherapy. We describe a patient with adult T-cell leukaemia treated with allogeneic bone marrow transplantation from an HTLV-I negative identical sibling donor. During follow-up after bone marrow transplantation, HTLV-I could be repeatedly isolated inspite of anti-viral prophylaxis. The patient died of an acute encephalitis and HTLV-I could be detected in autopsy material from the brain. By a PCR-based technique using short tandem repeats (STRs) it was shown that the patient's haemopoiesis was of donor origin. This shows the infection of donor cells in vivo by an aetiological agent which has been implicated in the leukaemogenic process for adult T-cell leukaemia.     

Grafted neural stem cells develop into functional pyramidal neurons and integrate into host cortical circuitry

In vitro expanded neural stemprogenitor cells can undergo region-specific differentiation after transplantation to the developing or adult brain, and display morphologies and markers characteristic of mature neurons. Here we have used patch-clamp techniques to explore whether grafted stem cells also can develop physiological properties of mature neurons and become functionally integrated within host neural circuitry. The immortalized neural progenitor cell line, RN33B, prelabeled with GFP by using a lentiviral vector, was transplanted into the cortex or hippocampus of neonatal rats. We found that the grafted GFP-positive cells differentiated into cells with morphological features of cortical or hippocampal pyramidal neurons, and that many of them had established appropriate cortico-thalamic and contralateral hippocampal connections, respectively, as revealed by retrograde tracing. Whole-cell patch-clamp recordings from grafted cells with morphological characteristics of pyramidal neurons showed that they were able to generate action potentials, and received functional excitatory and inhibitory synaptic inputs from neighboring cells. These data provide evidence that grafted neural progenitors can differentiate into morphologically mature pyramidal projection neurons, establish appropriate long-distance axonal projections, exhibit normal electrophysiological properties, and become functionally integrated into host cortical circuitry.