Anti-thymocyte globulin (ATG), raised in rabbits, is frequently used in allogeneic hematopoietic SCT (HSCT), to prevent graft rejection and acute GVHD. In solid organ transplant patients, antibodies ...to rabbit IgG result in an enhanced clearance of ATG. The occurrence of such antibodies in HSCT recipients and their clinical impact is unknown. Concentrations of ATG and anti-ATG antibodies were measured in 72 pediatric HSCT recipients treated with ATG as part of the conditioning. Anti-ATG antibodies were detected in 20 children (28%), all transplanted with a non-depleted graft. IgG anti-ATG, alone or combined with IgM and/or IgA anti-ATG, appeared in 10 children. Four patients developed IgG anti-ATG antibodies early (before day 22) post-HSCT. They had steep drops in ATG levels and showed rapid T-cell recovery, which was associated with a significantly increased risk of acute GVHD. In six patients IgG anti-ATG responses occurred later (range 28-46 days) after HSCT without an increased risk of GVHD. A total of 10 children only mounted an IgM (and IgA) anti-ATG response, which was without major impact on ATG levels. These results indicate that early development of IgG anti-ATG antibodies has a major impact on acute GVHD. Routine analysis ATG/anti-ATG Ab measurement should be considered.
Ubiquitination plays a major role in many aspects of hematopoiesis. Alterations in ubiquitination have been implicated in hematological cancer. The ubiquitin ligase Triad1 controls the proliferation ...of myeloid cells. Here, we show that two RING (really interesting new gene) domains in Triad1 differentially bind ubiquitin-conjugating enzymes, UbcH7 and Ubc13. UbcH7 and Ubc13 are known to catalyze the formation of different poly-ubiquitin chains. These chains mark proteins for proteasomal degradation or serve crucial non-proteolytic functions, respectively. In line with the dual Ubc interactions, we observed that Triad1 catalyzes the formation of both types of ubiquitin chains. The biological relevance of this finding was studied by testing Triad1 mutants in myeloid clonogenic assays. Full-length Triad1 and three mutants lacking conserved domains inhibited myeloid colony formation by over 50%. Strikingly, deletion of either RING finger completely abrogated the inhibitory effect of Triad1 in clonogenic growth. We conclude that Triad1 exhibits dual ubiquitin ligase activity and that both of its RING domains are crucial to inhibit myeloid cell proliferation. The differential interaction of the RINGs with Ubcs strongly suggests that the ubiquitination mediated through UbcH7 as well as Ubc13 plays a major role in myelopoiesis.
We optimize Δ-full nuclear interactions from chiral effective field theory. The low-energy constants of the contact potentials are constrained by two-body scattering phase shifts, and by properties ...of bound state of A = 2 to 4 nucleon systems and nuclear matter. The pion-nucleon couplings are taken from a Roy-Steiner analysis. The resulting interactions yield accurate binding energies and radii for a range of nuclei from A = 16 to A = 132, and provide accurate equations of state for nuclear matter and realistic symmetry energies. Selected excited states are also in agreement with data.
The Oman‐United Arab Emirates (UAE) ophiolite represents the largest and best‐preserved fragment of obducted oceanic lithosphere in the world. However, debate continues regarding its geodynamic ...history. This debate is in part a consequence of the lateral variability in the later stage magmatic units, with arc signatures considered to be well developed in the north of the ophiolite but less so in the south. In this study, we investigate later stage intrusions in the central and southern part of the ophiolite. These intrusions vary from wehrlite to gabbro and tonalite and crosscut all levels of the main ophiolite sequence from the mantle peridotites up to the sheeted dike complex. They are characterized by the presence of magmatic amphibole, low TiO2 (<1 wt%), document an enrichment in Th, Sr, and Ba, depletion of Y and Dy, and decreasing Dy/Yb and Dy/Dy* with increased fractionation. These data record hydrous fractionation with a significant role for amphibole, which is comparable to many arc‐type magmas. The relative Nb and light rare earth element ((La/Yb)nchon < 1) depletion and coupled Nd and Hf isotope variations indicate the same (but depleted) Indian mid‐ocean ridge basalts‐type mantle source as the main ophiolite sequence. More radiogenic Pb isotope compositions of plagioclase imply the addition of a fluid component likely derived from sediments or altered oceanic crust. These intrusions occur across larger areas than previously reported, implying the entire ophiolite formed in a setting characterized by arc‐type magmas, such as a suprasubduction zone setting.
Key Points
This study documents hydrous subduction related magmatism throughout the Oman‐UAE ophiolite
Amphibole fractionation played an important role during the formation of this type of magmatism
These observations strongly suggest the Oman‐UAE ophiolite formed in a suprasubduction zone setting
•This review discusses 16 studies using 7T MRI to evaluate patients with chronic focal epilepsy.•UHF MRI increases the sensitivity to detect an epileptogenic lesion.•Diagnostic gain of 7T over ...conventional MRI was between 8 and 67%, pooled gain was 31%•FCD, gliosis and HS were the most frequently diagnosed histopathological lesions.•No conclusion can be drawn whether 7T improves surgical treatment and seizure outcome.
Resective epilepsy surgery is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is detection of an epileptogenic lesion by magnetic resonance imaging (MRI). Application of ultra-high field (UHF) MRI, i.e. field strengths ≥ 7 Tesla (T), may increase the sensitivity to detect such a lesion.
A keyword search strategy was submitted to Pubmed, EMBASE, Cochrane Database and clinicaltrials.gov to select studies on UHF MRI in patients with epilepsy. Follow-up study selection and data extraction were performed following PRISMA guidelines. We focused on I) diagnostic gain of UHF- over conventional MRI, II) concordance of MRI-detected lesion, seizure onset zone and surgical decision-making, and III) postoperative histopathological diagnosis and seizure outcome.
Sixteen observational cohort studies, all using 7T MRI were included. Diagnostic gain of 7T over conventional MRI ranged from 8% to 67%, with a pooled gain of 31%. Novel techniques to visualize pathological processes in epilepsy and lesion detection are discussed. Seizure freedom was achieved in 73% of operated patients; no seizure outcome comparison was made between 7T MRI positive, 7T negative and 3T positive patients. 7T could influence surgical decision-making, with high concordance of lesion and seizure onset zone. Focal cortical dysplasia (54%), hippocampal sclerosis (12%) and gliosis (8.1%) were the most frequently diagnosed histopathological entities.
UHF MRI increases, yet variably, the sensitivity to detect an epileptogenic lesion, showing potential for use in clinical practice. It remains to be established whether this results in improved seizure outcome after surgical treatment. Prospective studies with larger cohorts of epilepsy patients, uniform scan and sequence protocols, and innovative post-processing technology are equally important as further increasing field strengths. Besides technical ameliorations, improved correlation of imaging features with clinical semiology, histopathology and clinical outcome has to be established.
Background
In patients hospitalised with COVID-19, an increased incidence of thromboembolic events, such as pulmonary embolism, deep vein thrombosis and stroke, has been reported
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It is unknown ...whether anticoagulation can prevent these complications and improve outcome.
Methods
A systematic literature search was performed to answer the question: What is the effect of (prophylactic and therapeutic dose) anticoagulation therapy in COVID-19 patients on cardiovascular and thromboembolic complications and clinical outcome? Relevant outcome measures were mortality (crucial), hospital admission, length of stay, thromboembolic complications (pulmonary embolism, stroke, transient ischaemic attack), need for mechanical ventilation, acute kidney injury and use of renal replacement therapy. Medline and Embase databases were searched with relevant search terms until 17 July 2020. After systematic analysis, eight studies were included. Analysis was stratified for the start of anticoagulation before or during hospital admission.
Results
There was insufficient evidence that therapeutic anticoagulation could improve the outcome in patients hospitalised with COVID-19. None of the studies demonstrated improved mortality, except for one very small Italian study. Furthermore, none of the studies showed a positive effect of anticoagulation on other outcome measures in COVID-19, such as ICU admission, length of hospital stay, thromboembolic complications, need for mechanical ventilation, acute kidney failure or need for renal replacement therapy, except for two studies demonstrating an association between anticoagulation and a lower incidence of pulmonary embolism. However, the level of evidence of all studies varied from ‘low’ to ‘very low’, according to the GRADE methodology.
Conclusion
Analysis of the literature showed that there was insufficient evidence to answer our objective on the effect of anticoagulation on outcome in COVID-19 patients, especially due to the low scientific quality of the described studies. Randomised controlled studies are needed to answer this question.
Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The ...hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.
Summary Objective Evaluation whether biomarkers of joint damage are sensitive to change shortly after a joint bleed in hemophilia patients and in a canine model of blood-induced joint damage. Methods ...Blood and urine samples were collected from 10 hemophilia patients after they reported a joint bleed: within 2 days, after 3–5 days, and 12–14 days. Additionally, 90 days after the bleed a blood and urine sample was taken and considered to represent baseline condition. Commercial serum and urine biomarker assays were performed: urinary C-terminal telopeptide of type II collagen (uCTX-II), serum cartilage oligomeric matrix protein (sCOMP), serum cartilage cleavage product C1,2C, and serum chondroitin sulfate 846 (sCS846). The same panel of biomarkers was explored in dogs ( n = 7) after induction of a first joint bleed by intra-articular blood injections. Biosamples were collected at baseline, day 2, 1 and 2 weeks later. Results In hemophilia patients, levels of uCTX-II and sCS846 increased 5 days after joint bleeding when compared with baseline (+52%; P = 0.021 and +14%; P = 0.011, respectively). In dogs, uCTX-II increased statistically significant from day 2 to day 7 (from 75% to 155% of baseline; P = 0.018), and sCOMP from baseline to day 2 (+46%; P = 0.028). Conclusions This study demonstrates that biochemical markers of joint tissue damage increase shortly after a single joint bleed, both in humans with established hemophilic arthropathy (HA) and in an animal model of joint damage upon a first joint bleed. Biomarkers might be useful in monitoring the impact of a joint bleed and in evaluation of treatment of such bleeds.
Using the most comprehensive fish occurrence database, we evaluated the importance of ecological and historical drivers in diversity patterns of subdrainage basins across the Amazon system. Linear ...models reveal the influence of climatic conditions, habitat size and sub-basin isolation on species diversity. Unexpectedly, the species richness model also highlighted a negative upriver-downriver gradient, contrary to predictions of increasing richness at more downriver locations along fluvial gradients. This reverse gradient may be linked to the history of the Amazon drainage network, which, after isolation as western and eastern basins throughout the Miocene, only began flowing eastward 1-9 million years (Ma) ago. Our results suggest that the main center of fish diversity was located westward, with fish dispersal progressing eastward after the basins were united and the Amazon River assumed its modern course toward the Atlantic. This dispersal process seems not yet achieved, suggesting a recent formation of the current Amazon system.
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