Cytoplasmic fatty acid-binding protein facilitates fatty acid utilization by skeletal muscle

The intracellular transport of long-chain fatty acids in muscle cells is facilitated to a great extent by heart-type cytoplasmic fatty acid-binding protein (H-FABP). By virtue of the marked affinity of this 14.5-kDa protein for fatty acids, H-FABP dramatically increases their concentration in the aqueous cytoplasm by non-covalent binding, thereby facilitating both the transition of fatty acids from membranes to the aqueous space and their diffusional transport from membranes (e.g. sarcolemma) to other cellular compartments (e.g. mitochondria). Striking features are the relative abundance of H-FABP in muscle, especially in oxidative muscle fibres, and the modulation of the muscular H-FABP content in concert with the modulation of other proteins and enzymes involved in fatty acid handling and utilization. Newer studies with mice carrying a homozygous or heterozygous deletion of the H-FABP gene show that, in comparison with wild-type mice, hindlimb muscles from heterozygous animals have a markedly lowered (-66%) H-FABP content but unaltered palmitate uptake rate, while in hindlimb muscles from homozygous animals (no H-FABP present) palmitate uptake was reduced by 45%. These findings indicate that H-FABP is present in relative excess and plays a substantial, but merely permissive role in fatty acid uptake by skeletal muscles.     

A Context Analysis with Stakeholders’ Views for Future Implementation of Interventions to Prevent Health Problems Among Employees with a Lower Socioeconomic Position

Journal of Occupational Rehabilitation - Purpose Health problems among employees with a lower socioeconomic position (SEP) often result from an interplay of problems on multiple life domains....     

Trypanosoma cruzi adenylyl cyclase is encoded by a complex multigene family

The parasitic protozoan Trypanosoma cruzi undergoes several differentiation events during its life cycle. Some of these transitions are thought to involve activation of adenylyl cyclase via the binding of peptide ligands to the cell surface. Here we describe the characterisation of the adenylyl cyclase gene family of T. cruzi. Two complete genes and one pseudogene have been sequenced. The protein products appear to have a large extracellular domain, a single transmembrane helix and a cytosolic catalytic domain. The adenylyl cyclase genes are present on at least six chromosomes and are scattered rather than clustered. They form a large polymorphic family in which the extracellular domain is particularly variable. An Escherichia coli adenylyl cyclase mutant could be complemented by expression of the catalytic domain of the T. cruzi enzyme. The recombinant protein had adenylyl cyclase activity in vitro, which was enhanced by increasing concentrations of divalent cations (Mn2+ > Mg2+). This constitutively active recombinant protein will be a useful tool for dissecting the catalytic mechanism of adenylyl cyclase.     

Thiotepa‐based versus total body irradiation‐based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long‐established ones. This retrospective matched‐pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa‐based (n = 121) or a cyclophosphamide/total body irradiation‐based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA‐matched sibling or an unrelated donor. With a median follow‐up of 44 months, the outcome was similar in both groups. Acute graft‐versus‐host disease grade II‐IV was observed in 25% after thiotepa‐containing regimen versus 35% after TBI (P = 0.06). The 2‐yr cumulative incidence of chronic graft‐versus‐host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non‐relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia‐free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting.     

Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission

Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor-risk entity, commonly associated with FLT3-ITD (internal tandem duplication). Allogeneic stem-cell tranplantation (allo-SCT) is recommended, although studies analysing the outcome of allo-SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo-SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo-SCT was the strongest independent prognostic factor, with a two-year leukaemia-free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0·001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo-SCT in CR1.     

Outcome of T cell-depleted transplantation after conditioning with an intensified regimen in patients aged 50 years or more is comparable with that in younger patients

One hundred and thirty-one patients were transplanted for AML-CR1, ALL-CR1 or CML-CP1 after conditioning with 120 mg/kg body weight cyclophosphamide and 2 x 4.5 Gy TBI. Conditioning was intensified with the addition of 42 mg/m2 idarubicin. Grafts were T cell-depleted using counterflow centrifugation. Donors were HLA-identical siblings. We compared outcome of BMT in 109 patients aged less than 50 (median, 35) years with that of 22 patients with an age of 50 years or more (median, 53 years). For the patients aged <50 years, 2-year probabilities of treatment-related mortality, relapse, survival and leukemia-free survival were 26% (95% CI, 17% to 35%), 26% (95% CI, 17% to 35%), 64% (95% CI, 55% to 73%), and 56% (95% CI, 47% to 65%). For the patients aged > or =50 years, these figures were 13% (95% CI, 0% to 30%), 24% (95% CI, 6% to 42%), 66% (95% CI, 46% to 86%), and 67% (95% CI, 47% to 87%), respectively. Outcome did not differ significantly between the two age groups. TRM was within the range of that reported in the literature for recipients of T cell-depleted grafts. We conclude that T cell-depleted transplantation after a conditioning regimen that was intensified with the addition of idarubicin is feasible in patients aged > or =50 years. For this age group of patients, results of nonmyeloablative regimens should be compared with that obtained with T cell-depleted grafts.     

C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons

An elevated level of C-reactive protein is a strong predictor of cardiovascular events in elderly persons. Whether C-reactive protein has direct adverse vascular effects or is a marker of aspecific systemic inflammation remains to be determined. The aim of this study was to investigate the relation between C-reactive protein and the occurrence of fatal strokes in elderly persons. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we studied the levels of C-reactive protein in 80 participants who died from stroke within the first 5 years of follow-up. Levels of C-reactive protein were determined in serum samples at baseline. Levels of C-reactive protein were also determined in 82 control subjects who survived for the first 5 years of follow-up and in 83 participants who died from noncardiovascular causes. Mortality risks were estimated with logistic regression and adjusted for differences in age, sex, smoking, medication, total cholesterol, history of diabetes or hypertension, and previous cardiovascular events. Levels of C-reactive protein at baseline were 2-fold higher in subjects who died from stroke than in control subjects (median 5.7 versus 2.7 mg/L, P<0.005). The levels of C-reactive protein in subjects who died from stroke or from noncardiovascular causes were similar (median 5.7 versus 4.9 mg/L, P=0.7). The risk of death from stroke as well as from noncardiovascular causes increased linearly up to 10-fold in subjects with the highest levels of C-reactive protein at baseline (P<0.001). The levels of C-reactive protein were lower when more time had elapsed between blood sampling and time of death during follow-up (P=0.01). C-reactive protein is a strong but nonspecific risk factor of fatal stroke in old persons. The data do not support the idea that C-reactive protein has direct vascular effects that underlie fatal cerebrovascular disease.